FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Funderburg, NT Mehta, NN AF Funderburg, Nicholas T. Mehta, Nehal N. TI Lipid Abnormalities and Inflammation in HIV Inflection SO CURRENT HIV/AIDS REPORTS LA English DT Article DE Antiretroviral therapy; Inflammation; Lipid composition; Oxidized LDL; Statins; HDL cholesterol efflux ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHOLESTEROL EFFLUX CAPACITY; HIGH-DENSITY-LIPOPROTEIN; CORONARY-ARTERY-DISEASE; ACUTE MYOCARDIAL-INFARCTION; INTIMA-MEDIA THICKNESS; ACTIVE ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; OXIDIZED LDL; STATIN THERAPY AB Infection with the human immunodeficiency virus (HIV), and subsequent treatment with antiretroviral therapy (ART), is often associated with perturbations in lipid profiles. Furthermore, persistent inflammation, in spite of suppression of viral replication by ART, likely contributes to modifications in lipid composition and function, exacerbating risk for development of cardiovascular disease (CVD). Increased levels of several pro-inflammatory lipid species, including oxidized low-density lipoprotein (LDL) and high-density lipoprotein (HDL), have been measured in HIV-infected persons and are associated with markers of immune activation. The mechanisms linked to this bidirectional relationship in which inflammation increases lipid levels and promotes their modification, and these modified lipid species perpetuate inflammatory processes, require further investigation. Treatment with statins and other lifestyle modifications, including improvement in dietary intake and exercise, are critical to reducing CVD risk. Well-designed clinical trials that take into account the complex relationships among lipids and inflammation within persons infected with HIV need to be considered. C1 [Funderburg, Nicholas T.] Ohio State Univ, Sch Hlth & Rehabil Sci, Div Med Lab Sci, 453 W 10th Ave,535A Atwell Hall, Columbus, OH 43210 USA. [Mehta, Nehal N.] NHLBI, Sect Inflammat & Cardiometab Dis, Bethesda, MD 20892 USA. RP Mehta, NN (reprint author), NHLBI, Sect Inflammat & Cardiometab Dis, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov FU NHLBI FX Nicholas T. Funderburg reports grants from NHLBI and has served as consultant for Gilead Inc. NR 106 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1548-3568 EI 1548-3576 J9 CURR HIV-AIDS REP JI Curr. Hiv/Aids Rep. PD AUG PY 2016 VL 13 IS 4 BP 218 EP 225 DI 10.1007/s11904-016-0321-0 PG 8 WC Infectious Diseases SC Infectious Diseases GA DU1XF UT WOS:000382003000005 PM 27245605 ER PT J AU Varma, VR Tang, XY Carlson, MC AF Varma, Vijay R. Tang, Xiaoying Carlson, Michelle C. TI Hippocampal Sub-Regional Shape and Physical Activity in Older Adults SO HIPPOCAMPUS LA English DT Article DE aging; surface area; subiculum; accelerometer; exercise ID MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; DENTATE GYRUS; ENVIRONMENTAL ENRICHMENT; RANDOMIZED-TRIAL; VENTRICULAR STRUCTURES; VOLUNTARY EXERCISE; AEROBIC EXERCISE; BRAIN HEALTH; IN-VIVO AB Hippocampal atrophy is a hallmark of Alzheimer's disease pathology, and a target biomarker region for testing intervention efficacy. Over the last few decades, a growing body of evidence from animal and human models suggests that physical activity (PA) is associated with structural benefits to the hippocampus in older adults. Very few human studies, however have explored hippocampal sub-regional specificity of PA; this is significant considering that sub-regions of the hippocampus are associated with distinct cognitive tasks and are differentially affected by disease pathology. This study used objective and self-reported measures of daily walking activity and exercise, and surface-based regional shape analysis using high-field hippocampal sub-regional partitions to explore sub-region specific hippocampal associations in a sample of nondemented, community-dwelling older adults at elevated sociodemographic risk for cognitive decline. Vertex-wise surface areas, which may be more sensitive than global volume measures, were calculated using shape diffeomorphometry, and PA was assessed using step activity monitors and PA questionnaires. We found that daily walking activity in a participant's environment was associated in cross-section mainly with larger surface areas of the subiculum in women. Associations remained significant when controlling for self-reported exercise. Prior studies have found that PA related to exercise and aerobic fitness may be most closely associated with the anterior hippocampus, particu-larly the dentate gyrus of the hippocampus. These novel findings are the first, to our knowledge, in human models to suggest that PA related to navigation that may not reach the level of moderate-intensity exercise may be associated with specific sub-regions of the hippocampus. These findings underscore the importance of better understanding the independent and related biological mechanisms and pathways by which increasing exercise as well as non-exercise, lifestyle PA may influence structural brain health. (C) 2016 Wiley Periodicals, Inc. C1 [Varma, Vijay R.; Carlson, Michelle C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Hampton House 8th Floor,624 N Broadway St, Baltimore, MD USA. [Varma, Vijay R.; Carlson, Michelle C.] Johns Hopkins Univ, Ctr Aging & Hlth, Baltimore, MD USA. [Tang, Xiaoying] SYSU CMU, Joint Inst Engn, Pittsburgh, PA USA. [Tang, Xiaoying] SYSU CMU, Shunde Int Joint Res Inst, Pittsburgh, PA USA. [Varma, Vijay R.] NIA, Clin & Translat Neurosci Unit, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. RP Varma, VR (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Hampton House 8th Floor,624 N Broadway St, Baltimore, MD USA. EM vvarma1@jhu.edu; mcarlso2@jhu.edu FU National Institute on Aging [P01-AG027735, 3P01AG027735-03S2, 3P01AG027735-02S3, P30-AG021334]; Memory and Aging Training Grant [5T32AG027668]; Epidemiology and Biostatistics of Aging Training Grant [5T32AG000247]; National Natural Science Foundation of China [NSFC 81501546]; SYSU-CMU Shunde International Joint Research Institute Start-up Grant [20150306]; Johns Hopkins OAIC Pepper Center; John D. and Catherine T. MacArthur Foundation; Johns Hopkins Neurobehavioral Research Unit FX Grant sponsor: National Institute on Aging; Grant numbers: P01-AG027735, 3P01AG027735-03S2, 3P01AG027735-02S3, P30-AG021334; Grant sponsor: Memory and Aging Training Grant; Grant number: 5T32AG027668; Grant sponsor: Epidemiology and Biostatistics of Aging Training Grant; Grant number: 5T32AG000247; Grant sponsor: National Natural Science Foundation of China; Grant number: NSFC 81501546; Grant sponsor: the SYSU-CMU Shunde International Joint Research Institute Start-up Grant; Grant number: 20150306; Grant sponsors: Johns Hopkins OAIC Pepper Center; John D. and Catherine T. MacArthur Foundation; Johns Hopkins Neurobehavioral Research Unit. NR 92 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1050-9631 EI 1098-1063 J9 HIPPOCAMPUS JI Hippocampus PD AUG PY 2016 VL 26 IS 8 BP 1051 EP 1060 DI 10.1002/hipo.22586 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DV9PN UT WOS:000383273400007 PM 27009597 ER PT J AU Batsis, M Dagalakis, U Stratakis, CA Prodanov, T Papadakis, GZ Adams, K Lodish, M Pacak, K AF Batsis, M. Dagalakis, U. Stratakis, C. A. Prodanov, T. Papadakis, G. Z. Adams, K. Lodish, M. Pacak, K. TI Attention Deficit Hyperactivity Disorder in Pediatric Patients with Pheochromocytoma and Paraganglioma SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE catecholamines; neuroendocrine tumor; epinephrine ID DEFICIT/HYPERACTIVITY DISORDER; STIMULANT-DRUGS; SYMPTOMS; CHILDREN; ADOLESCENTS; MANAGEMENT; DIAGNOSIS; UPDATE; ADHD AB The aim of the study is to evaluate if there is an association between attention deficit hyperactivity disorder (ADHD) and the diagnosis of pheochromocytoma/paraganglioma (PHEO/PGL) in pediatric patients. A case series study of 43 patients under the age of 18 with PHEO/PGL tumors who were evaluated at the National Institute of Health between January 2006 and May 2014 is reported. Prior diagnosis of ADHD and treatment course with stimulant medications was recorded. Patient symptoms, catecholamine and metanephrine levels, tumor characteristics, and genetic analyses for syndromes associated with PHEO/PGL were evaluated. A chi-squared test was used to assess the prevalence of ADHD in the PHEO/PGL patients compared to the general population. Nine out of 43 (21%) of patients diagnosed with PHEO/PGL had been diagnosed with ADHD prior to tumor identification. Four of the 9 patients had been treated with amphetamine, dextroamphetamine, and/or methylphenidate, potentially exacerbating an adrenergic crisis. In addition, 4 patients exhibited hypertension at the initial diagnosis of their PHEO/PGL. Three patients had resolution of their ADHD symptoms after successful surgical removal of PHEO/PGL. Our study found a prevalence of ADHD in 21% of our PHEO/PGL patients, significantly higher than 7.2% seen in the general pediatric population. Symptoms of anxiety and difficulty in concentration in these patients may have been related to their underlying PHEO/PGL and were not recognized as part of the constellation of symptoms in a child with PHEO/PGL. In pediatric patients with hypertension and ADHD symptomatology, an evaluation to rule out PHEO/PGL is warranted prior to treatment with stimulant medications. C1 [Batsis, M.; Dagalakis, U.; Stratakis, C. A.; Lodish, M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet Pediat Endocrinol, Interinst Training Program,NIH, Bethesda, MD 20892 USA. [Dagalakis, U.] Albany Med Coll, Albany, NY 12208 USA. [Prodanov, T.; Adams, K.; Pacak, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Papadakis, G. Z.] NIH, Dept Radiol & Imaging Sci, CC, Bldg 10, Bethesda, MD 20892 USA. RP Lodish, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet Pediat Endocrinol, Interinst Training Program,NIH,DEB NICHD, 10 Ctr Dr, Bethesda, MD 20892 USA. EM lodishma@mail.nih.gov FU Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 23 TC 0 Z9 0 U1 1 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 EI 1439-4286 J9 HORM METAB RES JI Horm. Metab. Res. PD AUG PY 2016 VL 48 IS 8 BP 509 EP 513 DI 10.1055/s-0042-106725 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DV8HI UT WOS:000383177700004 PM 27171833 ER PT J AU Mayama, T Marr, AK Kino, T AF Mayama, T. Marr, A. K. Kino, T. TI Differential Expression of Glucocorticoid Receptor Noncoding RNA Repressor Gas5 in Autoimmune and Inflammatory Diseases SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE autoimmune diseases; fasting; glucocorticoids; mammalian target of rapamycin (mTOR); tissue glucocorticoid sensitivity ID CELL-PROLIFERATION; POOR-PROGNOSIS; DECREASED EXPRESSION; BLOOD TRANSCRIPTOME; PROSTATE-CANCER; GENE-EXPRESSION; DOWN-REGULATION; GROWTH ARREST; SARCOIDOSIS; INFLUENZA AB Glucocorticoids have strong regulatory actions on the immune system and act as potent therapeutic compounds for autoimmune and inflammatory diseases. We previously reported that the long noncoding RNA growth arrest-specific 5 (Gas5), which accumulates inside the cells in response to cellular starvation/growth arrest, functions as a potent repressor of the glucocorticoid receptor (GR) through its RNA glucocorticoid response element (GRE). To evaluate potential roles of Gas5 in immune-related disorders, we examined Gas5 RNA levels in various autoimmune, inflammatory, and infectious diseases using the microarray data available in the Gene Expression Omnibus. We found that Gas5 levels were altered in whole blood or leukocytes of the patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and sarcoidosis. Gas5 levels were also altered in infectious diseases, such as by the human immunodeficiency virus type-1 and influenza virus, and bacterial sepsis. In our experimental analysis using mice, Gas5 levels were kept at high basal levels and did not respond to fasting in immune organs, such as spleen and thymus, while its levels in metabolic organs, including liver, fat, and skeletal muscles, were low at baseline and were highly elevated upon this treatment, possibly through suppression of the mTOR pathway. These results suggest that Gas5 plays a role in the regulation of immune functions and pathogenesis/pathophysiology of autoimmune, inflammatory, and infectious diseases in part through modulation of the GR transcriptional activity via its decoy RNA GRE. Changes in the Gas5 levels may also influence disease response to immunosuppressive glucocorticoid therapy. C1 [Mayama, T.; Kino, T.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Nihon Univ, Bethesda, MD USA. [Mayama, T.] Chiba Univ, Dept Integrate Biosci, Grad Sch Med & Pharmaceut Sci, Chiba, Japan. [Marr, A. K.; Kino, T.] Sidra Med & Res Ctr, Div Genet, Doha, Qatar. RP Kino, T (reprint author), Sidra Med & Res Ctr, Div Genet, Out Patient Clin, 5th Floor Rm C5-340 POB 26999,Al Luqta St, Doha, Qatar. EM tkino@sidra.org FU Intramural Research Program of the Sidra Medical and Research Center; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [Z01 HD008732-05 HNT] FX This study was funded by the Intramural Research Program of the Sidra Medical and Research Center, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Z01 HD008732-05 HNT). We thank Drs. D. Chaussabel, D. Rinchai, N. Marr, and W. Chen for the use of GXB and helpful discussion. NR 55 TC 3 Z9 4 U1 4 U2 4 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 EI 1439-4286 J9 HORM METAB RES JI Horm. Metab. Res. PD AUG PY 2016 VL 48 IS 8 BP 550 EP 557 DI 10.1055/s-0042-106898 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DV8HI UT WOS:000383177700011 PM 27214311 ER PT J AU Shizukuda, Y Tripodi, DJ Rosing, DR AF Shizukuda, Yukitaka Tripodi, Dorothy J. Rosing, Douglas R. TI Iron Overload or Oxidative Stress? Insight into a Mechanism of Early Cardiac Manifestations of Asymptomatic Hereditary Hemochromatosis Subjects with C282Y Homozygosity SO JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH LA English DT Letter DE Hemochromatosis; Arrhythmia; Oxidative stress; Iron overload; Biomarkers; Electrocardiogram AB Hereditary hemochromatosis (HH) is a genetic disorder which affects the heart due to systemic iron overload and concomitant elevated oxidative stress. Increasing numbers of patients are diagnosed at an asymptomatic stage due to genetic testing. Subclinical abnormal left ventricular diastolic function (LVDF) and increased arrhythmias are noted in this population; however, the mechanism leading to these observances has not been well understood. In this study, we assessed the relationship between arrhythmia activity and biomarkers of oxidative stress and iron overload in order to elucidate the role of oxidative stress in this population since we observed a significant association with LVDF previously. A significant correlation between plasma malondialdehyde, a biomarker of oxidative stress, and supraventricular arrhythmia activity without a significant association with iron overload was identified (n = 22). Our findings further highlight a possible role of oxidative stress in early cardiac manifestations of HH. Further investigation is warranted to assess this role. C1 [Shizukuda, Yukitaka; Tripodi, Dorothy J.; Rosing, Douglas R.] NHLBI, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Shizukuda, Yukitaka] Univ Cincinnati, Div Cardiovasc Hlth & Dis, Dept Internal Med, Cincinnati, OH 45220 USA. [Shizukuda, Yukitaka] Cincinnati VA Med Ctr, Cincinnati, OH 45220 USA. RP Shizukuda, Y (reprint author), NHLBI, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA.; Shizukuda, Y (reprint author), Univ Cincinnati, Div Cardiovasc Hlth & Dis, Dept Internal Med, Cincinnati, OH 45220 USA.; Shizukuda, Y (reprint author), Cincinnati VA Med Ctr, Cincinnati, OH 45220 USA. EM shizukya@uc.edu FU Intramural NIH HHS [Z99 HL999999] NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1937-5387 EI 1937-5395 J9 J CARDIOVASC TRANSL JI J. Cardiovasc. Transl. Res. PD AUG PY 2016 VL 9 IS 4 BP 400 EP 401 DI 10.1007/s12265-016-9704-2 PG 2 WC Cardiac & Cardiovascular Systems; Medicine, Research & Experimental SC Cardiovascular System & Cardiology; Research & Experimental Medicine GA DU1UN UT WOS:000381995400013 PM 27271161 ER PT J AU Brown, WV Garg, A Gorden, P Shamburek, R AF Brown, William Virgil Garg, Abhimanyu Gorden, Phillip Shamburek, Robert TI JCL roundtable: Diagnosis and clinical management of lipodystrophy SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Editorial Material DE Lipodystrophy; HDL cholesterol; Triglycerides; Obesity; Adipose tissue AB Lipodystrophy comes in several forms, some involving the complete failure to develop adipose tissue and others with a partial absence in various bodily distributions. All appear to have a major genetic basis, and all involve a high frequency of lipoprotein disorders. High triglycerides and low high-density lipoprotein cholesterol are the usual findings that raise interesting questions as to how such abnormalities characteristic of obesity can be caused by genetic variants that produce a paucity of adiposity. We are learning to link some specific genetic variants that seem causal and to manage these disorders in more effective ways. We are joined by 3 experts who have been leaders in the study of the clinical presentation, genetics, abnormal physiology, and the management of lipodystrophy in recent years. They are Drs Abhimanyu Garg from the University of Texas Southwestern, Phillip Gorden of the National Institute of Diabetes, Digestive and Kidney Diseases, and Robert Shamburek of the National Heart, Lung and Blood Institute. (C) 2016 National Lipid Association. All rights reserved. C1 [Brown, William Virgil] Emory Univ, Sch Med, 3208 Habersham Rd, Atlanta, GA 30305 USA. [Garg, Abhimanyu] UT Southwestern Med Ctr, Dallas, TX USA. [Gorden, Phillip; Shamburek, Robert] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Brown, WV (reprint author), Emory Univ, Sch Med, 3208 Habersham Rd, Atlanta, GA 30305 USA. EM wbrow925@bellsouth.net NR 7 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 EI 1876-4789 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD AUG PY 2016 VL 10 IS 4 BP 728 EP 736 DI 10.1016/j.jacl.2016.06.005 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DV7KN UT WOS:000383114900002 PM 27578101 ER PT J AU Etzion, O Novack, V Perl, Y Abel, O Schwartz, D Munteanu, D Abufreha, N Ben-Yaakov, G Maoz, ED Moshaklo, A Dizingf, V Fich, A AF Etzion, Ohad Novack, Victor Perl, Yael Abel, Olga Schwartz, Doron Munteanu, Daniella Abufreha, Naim Ben-Yaakov, Gil Maoz, Eyal D. Moshaklo, Alex Dizingf, Vitaly Fich, Alex TI Sci-B-Vac(TM) Vs ENGERIX-B Vaccines for Hepatitis B Virus in Patients with Inflammatory Bowel Diseases: A Randomised Controlled Trial SO JOURNAL OF CROHNS & COLITIS LA English DT Article DE Hepatitis B virus vaccine; inflammatory bowel disease; immunosuppression ID OPPORTUNISTIC INFECTIONS; CROHNS-DISEASE; COMPARATIVE IMMUNOGENICITY; PRE-S; VACCINATION; INFLIXIMAB; THERAPY; REACTIVATION; RESPONDERS; MANAGEMENT AB Response rate to second-generation hepatitis B virus vaccines is relatively low in patients with inflammatory bowel diseases compared with the general healthy population. We compared the efficacy and safety of a third- vs a second-generation hepatitis B virus vaccine in a group of patients with inflammatory bowel diseases treated with immunosuppressive medications. Prospective, randomised, single-blind, controlled study. Eligible patients were randomly assigned to receive one of two vaccines, ENGERIX-B or Sci-B-Vac. The vaccines were administered in three doses at 0, 1, and 6 months. The primary endpoint was defined as the titre of anti-hepatitis B S [HBs] antibodies following the standard three-dose hepatitis B virus vaccination schedule. A total of 72 patients complied with study protocol [37 and 35 patients in the ENGERIX-B and Sci-B-Vac groups, respectively]. Overall, 75% of the cohort seroconverted. The primary endpoint was met in 81.1% in the ENGERIX-B group and 68.6% in the Sci-B-Vac group [p = 0.22]. Patients in the Sci-B-Vac group showed a statistically significant decreased seroconversion rate compared with the ENGERIX-B group, with use of tumour necrosis factor [TNF] alpha inhibitors [p = 0.03], and higher degree of disease activity [p = 0.03]. Overall seroconversion rate in our cohort was higher than in previous reports in the literature, possibly due to a low disease activity state in the majority of participants. Third-generation hepatitis B virus vaccines showed no apparent advantage over standard of care vaccine in this patient group. C1 [Etzion, Ohad] NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 4-4730, Bethesda, MD 20892 USA. [Etzion, Ohad; Schwartz, Doron; Munteanu, Daniella; Abufreha, Naim; Ben-Yaakov, Gil; Moshaklo, Alex; Dizingf, Vitaly; Fich, Alex] Ben Gurion Univ Negev, Soroka Univ Med Ctr, Dept Gastroenterol & Hepatol, Beer Sheva, Israel. [Novack, Victor; Perl, Yael; Abel, Olga; Maoz, Eyal D.] Ben Gurion Univ Negev, Soroka Univ Med Ctr, Clin Res Ctr, Beer Sheva, Israel. RP Etzion, O (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 4-4730, Bethesda, MD 20892 USA. EM ohad.etzion@nih.gov FU Scigen Ltd. FX This work was supported by Scigen Ltd. The funding source had no role in the study design, collection, analysis, and interpretation of results, writing of the report, or the decision to submit the paper for publication. NR 27 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1873-9946 EI 1876-4479 J9 J CROHNS COLITIS JI J. Crohns Colitis PD AUG PY 2016 VL 10 IS 8 BP 905 EP 912 DI 10.1093/ecco-jcc/jjw046 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DV8RR UT WOS:000383204800006 PM 26928962 ER PT J AU Patel, EU Cox, AL Mehta, SH Boon, D Mullis, CE Astemborski, J Osburn, WO Quinn, J Redd, AD Kirk, GD Thomas, DL Quinn, TC Laeyendecker, O AF Patel, Eshan U. Cox, Andrea L. Mehta, Shruti H. Boon, Denali Mullis, Caroline E. Astemborski, Jacquie Osburn, William O. Quinn, Jeffrey Redd, Andrew D. Kirk, Gregory D. Thomas, David L. Quinn, Thomas C. Laeyendecker, Oliver TI Use of Hepatitis C Virus (HCV) Immunoglobulin G Antibody Avidity as a Biomarker to Estimate the Population-Level Incidence of HCV Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HCV; HIV; surveillance; recent infection; antibody response; incidence testing; people who inject drugs ID GENOTYPE 1 INFECTION; INJECT DRUGS; UNITED-STATES; HIV; PEOPLE; EPIDEMIOLOGY; SURVEILLANCE; PREVENTION; ACCESS; HEALTH AB Background. Sensitive methods are needed to estimate the population-level incidence of hepatitis C virus (HCV) infection. Methods. We developed an HCV immunoglobulin G (IgG) antibody avidity assay by modifying the Ortho 3.0 HCV enzyme-linked immunoassay and tested 997 serum or plasma samples from 568 people who inject drugs enrolled in prospective cohort studies. Avidity-based testing algorithms were evaluated by their (1) mean duration of recent infection (MDRI), defined as the average time an individual is identified as having been recently infected, according to a given algorithm; (2) false-recent rate, defined as the proportion of samples collected >2 years after HCV seroconversion that were misclassified as recent; (3) sample sizes needed to estimate incidence; and (4) power to detect a reduction in incidence between serial cross-sectional surveys. Results. A multiassay algorithm (defined as an avidity index of <30%, followed by HCV viremia detection) had an MDRI of 147 days (95% confidence interval [CI], 125-195 days), and the false-recent rates were 0.7% (95% CI,.2%-1.8%) and 7.6% (95% CI, 4.2%-12.3%) among human immunodeficiency virus (HIV)-negative and HIV-positive persons, respectively. In various simulated high-risk populations, this algorithm required <1000 individuals to estimate incidence (relative standard error, 30%) and had >80% power to detect a 50% reduction in incidence. Conclusions. Avidity-based algorithms have the capacity to accurately estimate HCV infection incidence and rapidly assess the impact of public health efforts among high-risk populations. Efforts to optimize this method should be prioritized. C1 [Patel, Eshan U.; Redd, Andrew D.; Quinn, Thomas C.; Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Lab Immunoregulat, Div Intramural Res,NIAID,NIH, 855 N Wolfe St,Rangos Bldg,Rm 538A, Baltimore, MD 21205 USA. [Cox, Andrea L.; Osburn, William O.; Quinn, Jeffrey; Redd, Andrew D.; Kirk, Gregory D.; Thomas, David L.; Quinn, Thomas C.; Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Dept Med, 855 N Wolfe St,Rangos Bldg,Rm 538A, Baltimore, MD 21205 USA. [Patel, Eshan U.; Mehta, Shruti H.; Boon, Denali; Astemborski, Jacquie; Kirk, Gregory D.; Thomas, David L.; Quinn, Thomas C.; Laeyendecker, Oliver] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Mullis, Caroline E.] New York Med Coll, Dept Med, New York, NY USA. RP Laeyendecker, O (reprint author), Johns Hopkins Univ, 855 N Wolfe St,Rangos Bldg,Rm 538A, Baltimore, MD 21205 USA. EM olaeyen1@jhmi.edu OI Patel, Eshan/0000-0003-2174-5004 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); NIH [T32DA007292, U19 AI088791, R01AI108403, R01AI077757, R01DA12568, R37DA013806, U01DA036297, UM1-AI068613] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); and by extramural NIH grants (T32DA007292, U19 AI088791, R01AI108403, R01AI077757, R01DA12568, R37DA013806, U01DA036297, and UM1-AI068613). NR 47 TC 1 Z9 1 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 1 PY 2016 VL 214 IS 3 BP 344 EP 352 DI 10.1093/infdis/jiw005 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV9NI UT WOS:000383267100003 PM 26768250 ER PT J AU Buckner, CM Kardava, L Zhang, XZ Gittens, K Justement, JS Kovacs, C McDermott, AB Li, YX Sajadi, MM Chun, TW Fauci, AS Moir, S AF Buckner, Clarisa M. Kardava, Lela Zhang, Xiaozhen Gittens, Kathleen Justement, J. Shawn Kovacs, Colin McDermott, Adrian B. Li, Yuxing Sajadi, Mohammad M. Chun, Tae-Wook Fauci, Anthony S. Moir, Susan TI Maintenance of HIV-Specific Memory B-Cell Responses in Elite Controllers Despite Low Viral Burdens SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; B cells; elite controllers; humoral immunity; viremia ID HUMAN-IMMUNODEFICIENCY-VIRUS; LOW-LEVEL VIREMIA; CD8(+) T-CELLS; ANTIRETROVIRAL THERAPY; INFECTED INDIVIDUALS; UNDETECTABLE VIREMIA; IMMUNE ACTIVATION; REPLICATION; SUPPRESSORS; ANTIBODIES AB Human immunodeficiency virus (HIV)-specific B-cell responses in infected individuals are maintained by active HIV replication. Suppression of viremia by antiretroviral therapy (ART) leads to quantitative and qualitative changes that remain unclear. Accordingly, B-cell responses were investigated in elite controllers (ECs), who maintain undetectable HIV levels without ART, and in individuals whose viremia was suppressed by ART. Despite a higher HIV burden in the ART group, compared with the EC group, frequencies of HIV-specific B cells were higher in the EC group, compared with those in the ART group. However, the initiation of ART in several ECs was associated with reduced frequencies of HIV-specific B cells, suggesting that responses are at least in part sustained by HIV replication. Furthermore, B-cell responses to tetanus toxin but not influenza hemagglutinin in the ART group were lower than those in the EC group. Thus, the superior HIV-specific humoral response in ECs versus ART-treated individuals is likely due to a more intact humoral immune response in ECs and/or distinct responses to residual HIV replication. C1 [Buckner, Clarisa M.; Kardava, Lela; Zhang, Xiaozhen; Justement, J. Shawn; Chun, Tae-Wook; Fauci, Anthony S.; Moir, Susan] NIAID, Immunoregulat Lab, 9000 Rockville Pk,Bldg 10,Rm 6A02, Bethesda, MD 20892 USA. [McDermott, Adrian B.] NIAID, Vaccine Res Ctr, 9000 Rockville Pk,Bldg 10,Rm 6A02, Bethesda, MD 20892 USA. [Gittens, Kathleen] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Li, Yuxing] Inst Biosci & Biotechnol Res, Rockville, MD USA. [Sajadi, Mohammad M.] Univ Maryland, Inst Human Virol, College Pk, MD USA. [Sajadi, Mohammad M.] Baltimore VA Med Ctr, Dept Med, Baltimore, MD USA. [Kovacs, Colin] Univ Toronto, Dept Med, Toronto, ON, Canada. [Kovacs, Colin] Maple Leaf Med Clin, Toronto, ON, Canada. RP Moir, S (reprint author), NIAID, Immunoregulat Lab, NIH, 9000 Rockville Pk,Bldg 10,Rm 6A02, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov FU NIAID, National Institutes of Health FX This work was supported by the Intramural Research Program of the NIAID, National Institutes of Health. NR 50 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 1 PY 2016 VL 214 IS 3 BP 390 EP 398 DI 10.1093/infdis/jiw163 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV9NI UT WOS:000383267100008 PM 27122593 ER PT J AU Boeve, B Rosen, H Boxer, A Coppola, G Dheel, C Dickerson, B Faber, K Fields, J Foroud, T Gavrilova, R Ghoshal, N Goldman, J Graff-Radford, N Grossman, M Heuer, H Hsiao, J Hsiung, R Huey, E Irwin, D Kantarci, K Karydas, A Knopman, D Kornak, J Kramer, J Kukull, W Mackenzie, I Miller, B Phelps, C Rademakers, R Rankin, K Shaw, L Sutherland, M Toga, A Trojanowski, J Vetor, A Weintraub, S Wszolek, Z AF Boeve, B. Rosen, H. Boxer, A. Coppola, G. Dheel, C. Dickerson, B. Faber, K. Fields, J. Foroud, T. Gavrilova, R. Ghoshal, N. Goldman, J. Graff-Radford, N. Grossman, M. Heuer, H. Hsiao, J. Hsiung, R. Huey, E. Irwin, D. Kantarci, K. Karydas, A. Knopman, D. Kornak, J. Kramer, J. Kukull, W. Mackenzie, I. Miller, B. Phelps, C. Rademakers, R. Rankin, K. Shaw, L. Sutherland, M. Toga, A. Trojanowski, J. Vetor, A. Weintraub, S. Wszolek, Z. TI Similar findings on clinical and neuropsychological measures in asymptomatic mutation versus non-mutation carriers: preliminary data from LEFFTDS SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Boeve, B.; Dheel, C.; Fields, J.; Gavrilova, R.; Kantarci, K.; Knopman, D.] Mayo Clin, Rochester, MN USA. [Rosen, H.; Boxer, A.; Heuer, H.; Karydas, A.; Kornak, J.; Kramer, J.; Miller, B.; Rankin, K.] UCSF, San Francisco, CA USA. [Coppola, G.] UCLA, Los Angeles, CA USA. [Dickerson, B.] Massachusetts Gen Hosp, Boston, MA USA. [Faber, K.; Foroud, T.; Vetor, A.] Indiana Univ, Indianapolis, IN USA. [Ghoshal, N.; Graff-Radford, N.] Washington Univ, St Louis, MO USA. [Goldman, J.; Huey, E.] Columbia Univ, New York, NY USA. [Graff-Radford, N.; Rademakers, R.; Wszolek, Z.] Mayo Clin, Jacksonville, FL USA. [Grossman, M.; Irwin, D.; Shaw, L.; Trojanowski, J.] Univ Penn, Philadelphia, PA USA. [Hsiao, J.; Phelps, C.] NIA, Bethesda, MD USA. [Hsiung, R.; Mackenzie, I.] Univers British Columbia, Vancouver, BC, Canada. [Kukull, W.] Univ Washington, Seattle, WA USA. [Sutherland, M.] NINDS, Bethesda, MD USA. [Toga, A.] USC, LONI, Los Angeles, CA USA. [Weintraub, S.] Northwestern Univ, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P118 BP 287 EP 287 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400173 ER PT J AU Rosen, H Boeve, B Boxer, A Coppola, G Dheel, C Dickerson, B Faber, K Fields, J Faroud, T Gavrilova, R Ghoshal, N Goldman, J Graff-Radford, N Grossman, M Heuer, H Hsiao, J Hsiung, GYR Huey, ED Irwin, D Kantarci, K Karydas, A Knopman, D Kornak, J Kramer, J Kukull, W Mackenzie, I Miller, B Phelps, C Rademakers, R Rankin, K Shaw, L Sutherland, M Toga, A Trojanowski, J Vetor, A Weintraub, S Wszolek, Z AF Rosen, H. Boeve, B. Boxer, A. Coppola, G. Dheel, C. Dickerson, B. Faber, K. Fields, J. Faroud, T. Gavrilova, R. Ghoshal, N. Goldman, J. Graff-Radford, N. Grossman, M. Heuer, H. Hsiao, J. Hsiung, G. -Y. R. Huey, E. D. Irwin, D. Kantarci, K. Karydas, A. Knopman, D. Kornak, J. Kramer, J. Kukull, W. Mackenzie, I. Miller, B. Phelps, C. Rademakers, R. Rankin, K. Shaw, L. Sutherland, M. Toga, A. Trojanowski, J. Vetor, A. Weintraub, S. Wszolek, Z. TI Differences on neuropsychiatric measures in asymptomatic (CDR=0) versus mildly symptomatic (CDR=0.5) mutation carriers: preliminary data from LEFFTDS SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Rosen, H.; Heuer, H.; Karydas, A.; Kornak, J.; Kramer, J.; Miller, B.; Rankin, K.] Univ Calif San Francisco, Neurol, San Francisco, CA 94143 USA. [Boeve, B.; Dheel, C.; Fields, J.; Gavrilova, R.; Kantarci, K.; Knopman, D.] Mayo Clin, Rochester, MN USA. [Coppola, G.; Toga, A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Dickerson, B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Faber, K.; Faroud, T.] Indiana Univ, Indianapolis, IN 46204 USA. [Ghoshal, N.; Vetor, A.] Washington Univ, St Louis, MO USA. [Goldman, J.] Columbia Univ, New York, NY USA. [Graff-Radford, N.; Rademakers, R.; Wszolek, Z.] Mayo Clin, Jacksonville, FL 32224 USA. [Grossman, M.; Irwin, D.; Shaw, L.; Trojanowski, J.] Univ Penn, Philadelphia, PA 19104 USA. [Hsiao, J.; Phelps, C.] NIA, Bethesda, MD 20892 USA. [Hsiung, G. -Y. R.; Mackenzie, I.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Kukull, W.] Univ Washington, Seattle, WA 98195 USA. [Sutherland, M.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Weintraub, S.] Norhtwestern Univ, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P119 BP 287 EP 287 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400174 ER PT J AU Kramer, J Weintraub, S Boeve, B Rosen, H Boxer, A Coppola, G Dheel, C Dickerson, B Faber, K Fields, J Faroud, T Gavrilova, R Ghoshal, N Goldman, J Graff-Radford, N Grossman, M Heuer, H Hsiao, J Hsiung, R Huey, E Irwin, D Kantarci, K Karydas, A Knopman, D Kornak, J Kukull, W Mackenzie, I Miller, B Phelps, C Rademakers, R Rankin, K Shaw, L Sutherland, M Toga, A Trojanowski, J Vetor, A Wszolek, Z AF Kramer, J. Weintraub, S. Boeve, B. Rosen, H. Boxer, A. Coppola, G. Dheel, C. Dickerson, B. Faber, K. Fields, J. Faroud, T. Gavrilova, R. Ghoshal, N. Goldman, J. Graff-Radford, N. Grossman, M. Heuer, H. Hsiao, J. Hsiung, R. Huey, E. Irwin, D. Kantarci, K. Karydas, A. Knopman, D. Kornak, J. Kukull, W. Mackenzie, I. Miller, B. Phelps, C. Rademakers, R. Rankin, K. Shaw, L. Sutherland, M. Toga, A. Trojanowski, J. Vetor, A. Wszolek, Z. TI Differences on neuropsychological measures in asymptomatic (CDR=0) versus mildly symptomatic (CDR=0.5) mutation carriers: preliminary data from LEFFTDS SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Kramer, J.; Rosen, H.; Boxer, A.; Heuer, H.; Kantarci, K.; Kornak, J.; Miller, B.; Rankin, K.] UCSF, San Francisco, CA USA. [Weintraub, S.] Northwestern, Chicago, IL USA. [Boeve, B.; Dheel, C.; Fields, J.; Gavrilova, R.; Kantarci, K.; Knopman, D.] Mayo Clin, Rochester, MN USA. [Coppola, G.] Univ Calif Los Angeles, Los Angeles, CA USA. [Dickerson, B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Faber, K.; Faroud, T.; Vetor, A.] Indiana Univ, Indianapolis, IN 46204 USA. [Ghoshal, N.] Washington Univ, St Louis, MO USA. [Goldman, J.; Huey, E.] Columbia Univ, New York, NY USA. [Graff-Radford, N.; Rademakers, R.; Wszolek, Z.] Mayo Clin, Jacksonville, FL 32224 USA. [Grossman, M.; Irwin, D.; Shaw, L.; Trojanowski, J.] Univ Penn, Philadelphia, PA 19104 USA. [Hsiao, J.; Phelps, C.] NIA, Bethesda, MD 20892 USA. [Hsiung, R.; Mackenzie, I.] Univ British Columbia, Vancouver, BC, Canada. [Kukull, W.] Univ Washington, Seattle, WA 98195 USA. [Sutherland, M.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Toga, A.] USC, LONI, Los Angeles, CA 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 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P127 BP 290 EP 291 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400182 ER PT J AU Rankin, K Kramer, J Rosen, H Boeve, B Boxer, A Coppola, G Dickerson, B Dheel, C Fields, J Gavrilova, R Ghoshal, N Goldman, J Graff-Radford, N Grossman, M Heuer, H Hsiao, J Hsiung, R Huey, E Irwin, D Kantarci, K Karydas, A Kornak, J Knopman, D Kukull, W Mackenzie, I Miller, B Phelps, C Rademakers, R Shaw, L Sutherland, M Toga, A Trojanowski, J Vetor, A Weintraub, S Wszolek, Z AF Rankin, K. Kramer, J. Rosen, H. Boeve, B. Boxer, A. Coppola, G. Dickerson, B. Dheel, C. Fields, J. Gavrilova, R. Ghoshal, N. Goldman, J. Graff-Radford, N. Grossman, M. Heuer, H. Hsiao, J. Hsiung, R. Huey, E. Irwin, D. Kantarci, K. Karydas, A. Kornak, J. Knopman, D. Kukull, W. Mackenzie, I. Miller, B. Phelps, C. Rademakers, R. Shaw, L. Sutherland, M. Toga, A. Trojanowski, J. Vetor, A. Weintraub, S. Wszolek, Z. TI Differences on novel measures of social comportment in asymptomatic (CDR=0) versus mildly symptomatic (CDR=0.5) mutation carriers: preliminary data from LEFFTDS SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Rankin, K.; Kramer, J.; Rosen, H.; Boxer, A.; Heuer, H.; Karydas, A.; Kornak, J.; Miller, B.] Univ Calif San Francisco, Neurol, San Francisco, CA 94143 USA. [Boeve, B.; Dheel, C.; Fields, J.; Gavrilova, R.; Kantarci, K.; Knopman, D.] Mayo Clin, Rochester, MN USA. [Coppola, G.] Univ Calif Los Angeles, Los Angeles, CA USA. [Dickerson, B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ghoshal, N.] Washington Univ, St Louis, MO USA. [Goldman, J.; Huey, E.] Columbia Univ, New York, NY USA. [Graff-Radford, N.; Rademakers, R.; Wszolek, Z.] Mayo Clin, Jacksonville, FL 32224 USA. [Grossman, M.; Shaw, L.; Trojanowski, J.] Univ Penn, Philadelphia, PA 19104 USA. [Hsiao, J.; Phelps, C.] NIA, Bethesda, MD 20892 USA. [Hsiung, R.; Mackenzie, I.] Univ British Columbia, Vancouver, BC, Canada. [Kukull, W.] Univ Washington, Seattle, WA 98195 USA. [Sutherland, M.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Toga, A.] USC LONI, Los Angeles, CA USA. [Vetor, A.] Indiana Univ, Indianapolis, IN 46204 USA. [Weintraub, S.] Northwestern Univ, Chicago, IL 60611 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 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P150 BP 299 EP 299 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400204 ER PT J AU Boeve, B Rosen, H Boxer, A Coppola, G Dheel, C Dickerson, B Faber, K Fields, J Foroud, T Gavrilova, R Ghoshal, N Goldman, J Graff-Radford, N Grossman, M Heuer, H Hsiao, J Hsiung, R Huey, E Irwin, D Kantarci, K Karydas, A Knopman, D Kornak, J Kramer, J Kukull, W Mackenzie, I Miller, B Phelps, C Rademakers, R Rankin, K Shaw, L Sutherland, M Toga, A Trojanowski, J Vetor, A Weintraub, S Wszolek, Z AF Boeve, B. Rosen, H. Boxer, A. Coppola, G. Dheel, C. Dickerson, B. Faber, K. Fields, J. Foroud, T. Gavrilova, R. Ghoshal, N. Goldman, J. Graff-Radford, N. Grossman, M. Heuer, H. Hsiao, J. Hsiung, R. Huey, E. Irwin, D. Kantarci, K. Karydas, A. Knopman, D. Kornak, J. Kramer, J. Kukull, W. Mackenzie, I. Miller, B. Phelps, C. Rademakers, R. Rankin, K. Shaw, L. Sutherland, M. Toga, A. Trojanowski, J. Vetor, A. Weintraub, S. Wszolek, Z. TI Characteristics and Progress on the Initial 147 Subjects in the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Protocol SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Boeve, B.; Dheel, C.; Fields, J.; Gavrilova, R.; Kantarci, K.; Knopman, D.] Mayo Clin, Rochester, MN USA. [Rosen, H.; Boxer, A.; Heuer, H.; Karydas, A.; Kornak, J.; Kramer, J.; Miller, B.; Rankin, K.] UCSF, San Francisco, CA USA. [Coppola, G.] Univ Calif Los Angeles, Los Angeles, CA USA. [Dickerson, B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Faber, K.; Foroud, T.; Vetor, A.] Indiana Univ, Indianapolis, IN 46204 USA. [Ghoshal, N.] Washington Univ, St Louis, MO 63130 USA. [Goldman, J.; Huey, E.] Columbia Univ, New York, NY USA. [Graff-Radford, N.; Rademakers, R.; Wszolek, Z.] Mayo Clin, Jacksonville, FL USA. [Grossman, M.; Irwin, D.; Shaw, L.; Trojanowski, J.] Univ Penn, Philadelphia, PA 19104 USA. [Hsiao, J.; Phelps, C.] NIA, Bethesda, MD 20892 USA. [Hsiung, R.; Mackenzie, I.] Univ British Columbia, Vancouver, BC, Canada. [Kukull, W.] Univ Washington, Seattle, WA 98195 USA. [Sutherland, M.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Toga, A.] LONI, USC, Los Angeles, CA USA. [Weintraub, S.] Northwestern Univ, Chicago, IL 60611 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 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P172 BP 309 EP 309 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400226 ER PT J AU Ferrari, R Grassi, M Graziano, F Palluzzi, F Archetti, S Bonomi, E Bruni, A Maletta, R Bernardi, L Cupidi, C Colao, R Rainero, I Rubino, E Pinessi, L Galimberti, D Scarpini, E Serpente, M Nacmias, B Piaceri, I Bagnoli, S Rossi, G Rossi, G Giaccone, G Tagliavini, F Benussi, L Binetti, G Ghidoni, R Singleton, A Hardy, J Momeni, P Padovani, A Borroni, B AF Ferrari, R. Grassi, M. Graziano, F. Palluzzi, F. Archetti, S. Bonomi, E. Bruni, A. Maletta, R. Bernardi, L. Cupidi, C. Colao, R. Rainero, I. Rubino, E. Pinessi, L. Galimberti, D. Scarpini, E. Serpente, M. Nacmias, B. Piaceri, I. Bagnoli, S. Rossi, G. Rossi, G. Giaccone, G. Tagliavini, F. Benussi, L. Binetti, G. Ghidoni, R. Singleton, A. Hardy, J. Momeni, P. Padovani, A. Borroni, B. TI Effects of multiple genetic loci on age at onset in frontotemporal dementia SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Ferrari, R.; Hardy, J.] UCL, Mol Neurosci, London, England. [Grassi, M.; Graziano, F.; Palluzzi, F.] Univ Pavia, Dept Brain & Behav Sci, Med & Genom Stat Unit, Pavia, Italy. [Archetti, S.] Brescia Hosp, Dept Labs, Lab Anal 3, Brescia, Italy. [Bonomi, E.; Padovani, A.; Borroni, B.] Univ Brescia, Dept Clin & Expt Sci, Neurol Unit, Brescia, Italy. [Bruni, A.; Maletta, R.; Bernardi, L.; Cupidi, C.; Colao, R.] Neurogenet Reg Ctr ASPCZ Lamezia Terme, Lamezia Terme, Italy. [Rainero, I.; Rubino, E.; Pinessi, L.] Univ Turin, Turin, Italy. [Rainero, I.; Rubino, E.; Pinessi, L.] Citta Salute & Sci Torino, Neurol 1, Dept Neurosci, Turin, Italy. [Galimberti, D.; Scarpini, E.; Serpente, M.] Univ Milan, Fdn Ca Granda, IRCCS Osped Policlin, Neurol Unit,Dept Pathophysiol & Transplantat, Milan, Italy. [Nacmias, B.; Piaceri, I.; Bagnoli, S.; Rossi, G.] Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy. [Rossi, G.; Rossi, G.; Giaccone, G.; Tagliavini, F.] Fdn IRCCS Ist Neurol Carlo Besta, Div Neurol & Neuropathol 5, Milan, Italy. [Benussi, L.; Binetti, G.; Ghidoni, R.] IRCCS Ist Ctr San Giovanni Dio Fatebenefratell, Mol Markers Lab, Brescia, Italy. [Singleton, A.] NIA, NIH, Neurogenet Lab, Bethesda, MD 20892 USA. [Momeni, P.] Omixy, London, England. RI Hardy, John/C-2451-2009 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 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P183 BP 313 EP 314 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400237 ER PT J AU Rosen, H Ljubenkov, P Boeve, B Kramer, J Boxer, A Coppola, G Dheel, C Fields, J Gavrilova, R Ghoshal, N Goldman, J Graff-Radford, N Grossman, M Heuer, H Hsiao, J Hsiung, GYR Huey, ED Irwin, D Kantarci, K Karydas, A Knopman, D Kornak, J Kukull, W Mackensie, I Miller, B Phelps, C Rademakers, R Shaw, L Sutherland, M Toga, A Weintraub, S Wszolek, Z Faroud, T Faber, K Vetor, A Trojanowski, J Rankin, K AF Rosen, H. Ljubenkov, P. Boeve, B. Kramer, J. Boxer, A. Coppola, G. Dheel, C. Fields, J. Gavrilova, R. Ghoshal, N. Goldman, J. Graff-Radford, N. Grossman, M. Heuer, H. Hsiao, J. Hsiung, G. -Y. R. Huey, E. D. Irwin, D. Kantarci, K. Karydas, A. Knopman, D. Kornak, J. Kukull, W. Mackensie, I. Miller, B. Phelps, C. Rademakers, R. Shaw, L. Sutherland, M. Toga, A. Weintraub, S. Wszolek, Z. Faroud, T. Faber, K. Vetor, A. Trojanowski, J. Rankin, K. TI NIH EXAMINER as tool for tracking executive dysfunction in carriers of FTLD-causing mutations within the LEFFTDS Consortium SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Rosen, H.; Ljubenkov, P.; Kramer, J.; Boxer, A.; Heuer, H.; Karydas, A.; Kornak, J.; Miller, B.; Rankin, K.] Univ Calif San Francisco, Neurol, San Francisco, CA 94143 USA. [Boeve, B.; Dheel, C.; Fields, J.; Gavrilova, R.; Kantarci, K.; Knopman, D.] Mayo Clin, Rochester, MN USA. [Coppola, G.] Univ Calif Los Angeles, Los Angeles, CA USA. [Ghoshal, N.] Washington Univ, St Louis, MO 63130 USA. [Goldman, J.; Huey, E. D.] Columbia Univ, New York, NY USA. [Graff-Radford, N.; Rademakers, R.; Wszolek, Z.] Mayo Clin, Jacksonville, FL 32224 USA. [Grossman, M.; Irwin, D.; Shaw, L.; Trojanowski, J.] Univ Penn, Philadelphia, PA 19104 USA. [Hsiao, J.; Phelps, C.] NIA, Bethesda, MD 20892 USA. [Hsiung, G. -Y. R.; Mackensie, I.] Univ British Columbia, Vancouver, BC, Canada. [Kukull, W.] Univ Washington, Seattle, WA 98195 USA. [Sutherland, M.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Toga, A.] Univ Southern Calif, Los Angeles, CA USA. [Weintraub, S.] Northwestern Univ, Chicago, IL 60611 USA. [Faroud, T.; Faber, K.; Vetor, A.] Indiana Univ, Indianapolis, IN 46204 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 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P185 BP 314 EP 314 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400239 ER PT J AU Knopman, D Boeve, B Rosen, H Boxer, A Coppola, G Dheel, C Dickerson, B Faber, K Fields, J Foroud, T Gavrilova, R Ghoshal, N Goldman, J Graff-Radford, N Grossman, M Heuer, H Hsiao, J Huey, E Hsiung, R Irwin, D Kantarci, K Karydas, A Kornak, J Kramer, J Kukull, W Mackenzie, I Miller, B Phelps, C Rademakers, R Rankin, K Shaw, L Sutherland, M Toga, A Trojanowski, J Weintraub, S Wszolek, Z Vetor, A AF Knopman, D. Boeve, B. Rosen, H. Boxer, A. Coppola, G. Dheel, C. Dickerson, B. Faber, K. Fields, J. Foroud, T. Gavrilova, R. Ghoshal, N. Goldman, J. Graff-Radford, N. Grossman, M. Heuer, H. Hsiao, J. Huey, E. Hsiung, R. Irwin, D. Kantarci, K. Karydas, A. Kornak, J. Kramer, J. Kukull, W. Mackenzie, I. Miller, B. Phelps, C. Rademakers, R. Rankin, K. Shaw, L. Sutherland, M. Toga, A. Trojanowski, J. Weintraub, S. Wszolek, Z. Vetor, A. TI Absence of differences on key measures in mildly (CDR=0.5) versus overtly (CDR >= 1) symptomatic mutation carriers: preliminary data from LEFFTDS SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Knopman, D.; Boeve, B.; Dheel, C.] Mayo Clin, Neurol, Rochester, MN USA. [Rosen, H.; Boxer, A.; Heuer, H.; Karydas, A.; Kornak, J.; Kramer, J.; Miller, B.; Rankin, K.] Univ Calif San Francisco, Neurol, San Francisco, CA 94143 USA. [Coppola, G.] Univ Calif Los Angeles, Los Angeles, CA USA. [Dickerson, B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Faber, K.; Foroud, T.; Vetor, A.] Indiana Univ, Indianapolis, IN 46204 USA. [Fields, J.; Gavrilova, R.; Kantarci, K.] Mayo Clin, Rochester, MN USA. [Ghoshal, N.] Washington Univ, St Louis, MO 63130 USA. [Goldman, J.; Huey, E.] Columbia Univ, New York, NY USA. [Graff-Radford, N.; Rademakers, R.; Wszolek, Z.] Mayo Clin, Jacksonville, FL USA. [Grossman, M.; Irwin, D.; Shaw, L.; Trojanowski, J.] Univ Penn, Philadelphia, PA 19104 USA. [Hsiao, J.; Phelps, C.; Sutherland, M.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Hsiung, R.; Mackenzie, I.] Univ British Columbia, Vancouver, BC, Canada. [Kukull, W.] Univ Washington, Seattle, WA 98195 USA. [Toga, A.] LONI, USC, Los Angeles, CA USA. [Weintraub, S.] Northwestern Univ, Chicago, IL 60611 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 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P189 BP 316 EP 316 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400243 ER PT J AU Knopman, D Boeve, B Rosen, H Boxer, A Coppola, G Dheel, C Dickerson, B Faber, K Fields, J Foroud, T Gavrilova, R Ghoshal, N Goldman, J Graff-Radford, N Grossman, M Heuer, H Hsiao, J Hsiung, R Huey, E Irwin, D Kantarci, K Karydas, A Kramer, J Kukull, W Mackenzie, I Miller, B Phelps, C Rademakers, R Rankin, K Shaw, L Sutherland, M Toga, A Trojanowski, J Vetor, A Weintraub, S Wszolek, Z AF Knopman, D. Boeve, B. Rosen, H. Boxer, A. Coppola, G. Dheel, C. Dickerson, B. Faber, K. Fields, J. Foroud, T. Gavrilova, R. Ghoshal, N. Goldman, J. Graff-Radford, N. Grossman, M. Heuer, H. Hsiao, J. Hsiung, R. Huey, E. Irwin, D. Kantarci, K. Karydas, A. Kramer, J. Kukull, W. Mackenzie, I. Miller, B. Phelps, C. Rademakers, R. Rankin, K. Shaw, L. Sutherland, M. Toga, A. Trojanowski, J. Vetor, A. Weintraub, S. Wszolek, Z. TI Differences on clinical measures in asymptomatic (CDR=0) versus mildly symptomatic (CDR=0.5) mutation carriers: preliminary data from LEFFTDS SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Knopman, D.; Boeve, B.; Dheel, C.; Gavrilova, R.] Mayo Clin, Neurol, Rochester, MN USA. [Rosen, H.; Boxer, A.; Heuer, H.; Karydas, A.; Kramer, J.; Miller, B.; Rankin, K.] Univ Calif San Francisco, Neurol, San Francisco, CA 94143 USA. [Coppola, G.] Univ Calif Los Angeles, Los Angeles, CA USA. [Dickerson, B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Faber, K.; Foroud, T.; Vetor, A.] Indiana Univ, Indianapolis, IN 46204 USA. [Fields, J.] Mayo Clin, Psychiat, Rochester, MN USA. [Ghoshal, N.] Washington Univ, St Louis, MO 63130 USA. [Goldman, J.; Huey, E.] Columbia Univ, New York, NY USA. [Graff-Radford, N.; Rademakers, R.; Wszolek, Z.] Mayo Clin, Jacksonville, FL USA. [Grossman, M.; Irwin, D.; Shaw, L.; Trojanowski, J.] Univ Penn, Philadelphia, PA 19104 USA. [Hsiao, J.; Phelps, C.; Sutherland, M.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Hsiung, R.; Mackenzie, I.] Univ British Columbia, Vancouver, BC, Canada. [Kantarci, K.] Mayo Clin, Radiol, Rochester, MN USA. [Kukull, W.] Univ Washington, Seattle, WA 98195 USA. [Toga, A.] LONI, USC, Los Angeles, CA USA. [Weintraub, S.] Northwestern Univ, Chicago, IL 60611 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 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P191 BP 317 EP 317 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400245 ER PT J AU Capozzo, R Sassi, C Benahmed-Hammer, M Arcuti, S Zecca, C Barulli, MR Tortelli, R Carnicella, F Dell'Aquila, C Valluzzi, F Panza, F Singleton, A Logroscino, G AF Capozzo, R. Sassi, C. Benahmed-Hammer, M. Arcuti, S. Zecca, C. Barulli, M. R. Tortelli, R. Carnicella, F. Dell'Aquila, C. Valluzzi, F. Panza, F. Singleton, A. Logroscino, G. TI Clinical and genetic analyses of familial and sporadic Frontotemporal Dementia patients in Southern Italy (The Apulia_FTD_Registry) SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Capozzo, R.; Arcuti, S.; Zecca, C.; Barulli, M. R.; Tortelli, R.; Panza, F.; Logroscino, G.] Univ Bari, Dept Clin Neurol & Res, Pia Fdn Cardinale G Panico, Tricase Le, Italy. [Sassi, C.; Benahmed-Hammer, M.; Singleton, A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Sassi, C.] UCL, Dept Mol Neurosci, UCL Inst Neurol, London, England. [Carnicella, F.; Dell'Aquila, C.] Bonomo Hosp, Dept Neurol, Andria, Italy. [Valluzzi, F.] S Giacomo Hosp, Neurol Unit, Monopoli, Italy. [Panza, F.] Univ Study Aldo Moro, Dept Interdisciplinary Med, Geriatr Med Memory Unit, Rare Dis Ctr, Bari, Italy. [Logroscino, G.] Univ Bari, Neurodegenerat Dis Unit, Dept Basic Med Sci Neurosci & Sense Organs, Bari, Italy. 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 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P209 BP 324 EP 324 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400263 ER PT J AU Boyd, C Tierney, M Wassermann, E Spina, S Oblak, A Ghetti, B Grafman, J Huey, E AF Boyd, C. Tierney, M. Wassermann, E. Spina, S. Oblak, A. Ghetti, B. Grafman, J. Huey, E. TI Visuoperception test predicts pathologic diagnosis of Alzheimer disease in corticobasal syndrome SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Boyd, C.] Columbia Univ, Neurol, New York, NY USA. [Tierney, M.; Wassermann, E.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Spina, S.; Oblak, A.; Ghetti, B.] Indiana Univ, Pathol, Indianapolis, IN 46204 USA. [Grafman, J.] Rehabil Inst Chicago, Brain Injury Res Program, Chicago, IL 60611 USA. [Huey, E.] Columbia Univ, Psychiat & Neurol, New York, NY 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 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P308 BP 361 EP 361 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400360 ER PT J AU Floeter, MK Katipally, R Kim, M Schanz, O Stephen, M Danielian, L Wu, T Huey, E Meoded, A AF Floeter, M. K. Katipally, R. Kim, M. Schanz, O. Stephen, M. Danielian, L. Wu, T. Huey, E. Meoded, A. TI Impaired corticopontocerebellar tracts underlie pseudobulbar affect in motor neuron disorders SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Floeter, M. K.; Katipally, R.; Kim, M.; Schanz, O.; Stephen, M.; Danielian, L.; Wu, T.; Meoded, A.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Huey, E.] Columbia Univ, Psychiat & Neurol, New York, NY 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 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P307 BP 361 EP 361 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400359 ER PT J AU Boxer, A Rosen, H Boeve, B Heuer, H Laxineta, S Grossman, M Coppola, G Dickerson, B Bordelon, Y Conwit, R Dheel, C Faber, K Feldman, H Ferguson, J Fields, J Fong, J Foroud, T Galpern, W Ghoshal, N Graff-Radford, N Hsiung, R Huey, E Irwin, D Kantarci, K Kaufer, D Karydas, A Klein, A Knopman, D Kornak, J Kramer, J Kukull, W Litvan, I Mackenzie, I Mendez, M Miller, B Miller, M Onyike, C Pantelyat, A Rademakers, R Roberson, E Sutherland, M Tartaglia, MC Tatton, N Toga, A Vetor, A Weintraub, S Wszolek, Z AF Boxer, A. Rosen, H. Boeve, B. Heuer, H. Laxineta, S. Grossman, M. Coppola, G. Dickerson, B. Bordelon, Y. Conwit, R. Dheel, C. Faber, K. Feldman, H. Ferguson, J. Fields, J. Fong, J. Foroud, T. Galpern, W. Ghoshal, N. Graff-Radford, N. Hsiung, R. Huey, E. Irwin, D. Kantarci, K. Kaufer, D. Karydas, A. Klein, A. Knopman, D. Kornak, J. Kramer, J. Kukull, W. Litvan, I. Mackenzie, I. Mendez, M. Miller, B. Miller, M. Onyike, C. Pantelyat, A. Rademakers, R. Roberson, E. Sutherland, M. Tartaglia, M. C. Tatton, N. Toga, A. Vetor, A. Weintraub, S. Wszolek, Z. TI Characteristics and progress on the Initial 256 participants in the advancing research and treatment in frontotemporal lobar degeneration (ARTFL) North American Rare disease clinical research consortium SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 10th International Conference on Frontotemporal Dementias CY AUG 31-SEP 02, 2016 CL Munich, GERMANY C1 [Boxer, A.; Rosen, H.; Heuer, H.; Laxineta, S.; Fong, J.; Karydas, A.; Kornak, J.; Kramer, J.; Miller, B.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Boeve, B.; Dheel, C.; Fields, J.; Kantarci, K.; Knopman, D.; Miller, M.] Mayo Clin, Rochester, MN USA. [Grossman, M.; Irwin, D.] Univ Penn, Philadelphia, PA 19104 USA. [Coppola, G.; Bordelon, Y.; Mendez, M.] Univ Calif Los Angeles, Los Angeles, CA USA. [Dickerson, B.] Massachusetts Gen Hosp, Cambridge, MA USA. [Conwit, R.; Ferguson, J.; Sutherland, M.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Faber, K.; Foroud, T.; Vetor, A.] NCRAD, Indianapolis, IN USA. [Feldman, H.; Hsiung, R.; Mackenzie, I.] Univ British Columbia, Vancouver, BC, Canada. [Galpern, W.] Janssen Pharmaceut, Washington, DC USA. [Ghoshal, N.] Washington Univ, St Louis, MO USA. [Graff-Radford, N.; Rademakers, R.; Roberson, E.; Wszolek, Z.] Mayo Clin, Jacksonville, FL 32224 USA. [Huey, E.] Columbia Univ, New York, NY USA. [Kaufer, D.] Univ N Carolina, Chapel Hill, NC USA. [Klein, A.] CurePSP, New York, NY USA. [Kukull, W.] Univ Washington, Seattle, WA 98195 USA. [Litvan, I.] Univ Calif San Diego, San Diego, CA 92103 USA. [Mendez, M.; Onyike, C.; Pantelyat, A.] Johns Hopkins Univ, Baltimore, MD USA. [Roberson, E.] Univ Alabama Birmingham, Birmingham, AL USA. [Tartaglia, M. C.] Univ Toronto, Toronto, ON, Canada. [Tatton, N.] AFTD, Radnor, PA USA. [Toga, A.] Univ Southern Calif, Los Angeles, CA USA. [Weintraub, S.] Northwestern Univ, Chicago, IL 60611 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 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 SU 1 SI SI MA P352 BP 379 EP 379 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU9WI UT WOS:000382568400403 ER PT J AU Moore, AZ Hernandez, DG Tanaka, T Pilling, LC Nalls, MA Bandinelli, S Singleton, AB Ferrucci, L AF Moore, Ann Zenobia Hernandez, Dena G. Tanaka, Toshiko Pilling, Luke C. Nalls, Mike A. Bandinelli, Stefania Singleton, Andrew B. Ferrucci, Luigi TI Change in Epigenome-Wide DNA Methylation Over 9 Years and Subsequent Mortality: Results From the InCHIANTI Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Epigenome-wide DNA methylation; Chronological age; Survival ID NF-KAPPA-B; HUMAN-DISEASE; EPIGENETICS; AGE AB Patterns of DNA methylation (DNAm) that track with aging have been identified. However, the relevance of these patterns for aging outcomes remains unclear. Longitudinal epigenome-wide DNAm information was obtained from the InCHIANTI study, a large representative European population. DNAm was evaluated using the Illumina HumanMethylation450 array on blood samples collected at baseline and 9-year follow-up: observations from 499 participants with paired longitudinal blood sample and information on differential blood count were included in analyses. A total of 56,579 markers were significantly associated with age in cross-sectional analysis of DNAm at year 9, 31,252 markers were changed significantly over the 9-year follow-up, and 16,987 markers were both cross-sectionally associated with age and significantly changed over time. Rates of change at 76 markers and year 9 level of DNAm at 88 markers were identified as strongly associated with mortality in Cox proportional hazard models adjusted for age and relevant covariates (mean follow-up time 4.4 years). Less than 0.05% of markers associated with age or that changed over time were also associated with mortality after adjusting for chronological age. Although the influence of DNAm on health and longevity remains unclear, these findings confirm that aging is associated cross-sectionally and longitudinally with robust and consistent patterns of methylation change. C1 [Moore, Ann Zenobia; Tanaka, Toshiko; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Hernandez, Dena G.; Nalls, Mike A.; Singleton, Andrew B.] NIA, Lab Neurogenet, Bethesda, MD 20892 USA. [Pilling, Luke C.] Univ Exeter, Sch Med, Epidemiol & Publ Hlth, Exeter EX4 4QJ, Devon, England. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. RP Moore, AZ (reprint author), Biomed Res Ctr, 251 Bayview Blvd,Rm 10B121, Baltimore, MD 21224 USA. EM mooreaz@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging; 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]; Intramural Research Program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. 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-ups 2 and 3 studies (2004-2010) were financed by the U.S. National Institute on Aging (Contract: N01-AG-5-0002); supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland. NR 25 TC 4 Z9 4 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 2016 VL 71 IS 8 BP 1029 EP 1035 DI 10.1093/gerona/glv118 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DV9BX UT WOS:000383235400006 PM 26355017 ER PT J AU Schrack, JA Cooper, R Koster, A Shiroma, EJ Murabito, JM Rejeski, WJ Ferrucci, L Harris, TB AF Schrack, Jennifer A. Cooper, Rachel Koster, Annemarie Shiroma, Eric J. Murabito, Joanne M. Rejeski, W. Jack Ferrucci, Luigi Harris, Tamara B. TI Assessing Daily Physical Activity in Older Adults: Unraveling the Complexity of Monitors, Measures, and Methods SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Review DE Physical activity; Exercise; Physical performance; Functional performance; Physical function ID RANDOMIZED CONTROLLED-TRIAL; ACTIVITY ENERGY-EXPENDITURE; SEDENTARY BEHAVIOR; ACCELEROMETER MEASUREMENTS; CARDIOVASCULAR HEALTH; PRIMARY PREVENTION; ACTIVITY PATTERNS; NATIONAL-SURVEY; WOMENS HEALTH; UNITED-STATES AB At the 67th Gerontological Society of America Annual Meeting, a preconference workshop was convened to discuss the challenges of accurately assessing physical activity in older populations. The advent of wearable technology (eg, accelerometers) to monitor physical activity has created unprecedented opportunities to observe, quantify, and define physical activity in the real-world setting. These devices enable researchers to better understand the associations of physical activity with aging, and subsequent health outcomes. However, a consensus on proper methodological use of these devices in older populations has not been established. To date, much of the validation research regarding device type, placement, and data interpretation has been performed in younger, healthier populations, and translation of these methods to older populations remains problematic. A better understanding of these devices, their measurement properties, and the data generated is imperative to furthering our understanding of daily physical activity, its effects on the aging process, and vice versa. The purpose of this article is to provide an overview of the highlights of the preconference workshop, including properties of the different types of accelerometers, the methodological challenges of employing accelerometers in older study populations, a brief summary of ongoing aging-related research projects that utilize different types of accelerometers, and recommendations for future research directions. C1 [Schrack, Jennifer A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 North Wolfe St,E7144, Baltimore, MD 21205 USA. [Cooper, Rachel] UCL, MRC Unit Lifelong Hlth & Ageing, London, England. [Koster, Annemarie] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Social Med, NL-6200 MD Maastricht, Netherlands. [Shiroma, Eric J.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Shiroma, Eric J.] Harvard Med Sch, Brigham & Womens Hosp, Div Prevent Med, Boston, MA USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Sect Gen Internal Med, Dept Med, Boston, MA 02215 USA. [Murabito, Joanne M.] NHLBI, Framingham Heart Study, Boston, MA USA. [Rejeski, W. Jack] Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Schrack, JA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 North Wolfe St,E7144, Baltimore, MD 21205 USA. EM jschrac1@jhu.edu RI Koster, Annemarie/E-7438-2010 FU UK Medical Research Council [MC_UU_12019/4, MC_UU_12019/1]; National Heart, Lung and Blood Institute [N01-HC-25195, HHSN268201500001l]; Intramural Research Program of the National Institute on Aging; National Institutes of Health [CA154647]; Intramural Research Program of the National Institutes of Health, National Institute on Aging; NIA [N01-AG-1-2100]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Science Foundation Graduate Research Fellowship [DGE-0940903]; National Institutes of Health Intramural Research Program [Z01 DK071013, Z01 DK071014]; [R01AG047645]; [K01AG048765]; [HHSN311210300177P] FX The MRC National Survey of Health and Development is funded by the UK Medical Research Council. The authors wish to acknowledge the NSHD participants and scientific and data collection teams (led by Professor Diana Kuh and including members of the MRC Unit for Lifelong Health and Ageing at UCL and the MRC Epidemiology Unit, University of Cambridge). Dr. Cooper is funded by the UK Medical Research Council (program codes: MC_UU_12019/4 and MC_UU_12019/1).; The Framingham Heart Study is supported by contract N01-HC-25195 and HHSN268201500001l of the National Heart, Lung and Blood Institute. The accelerometry study was supported by R01AG047645. The authors wish to acknowledge FHS participants and staff for participation in the Actical study.; The Baltimore Longitudinal Study of Aging is supported by the Intramural Research Program of the National Institute on Aging. The authors wish to acknowledge BLSA participants and staff for participation in the study. Dr. Schrack is supported by K01AG048765 and HHSN311210300177P.; The WHS accelerometry ancillary study was supported by research grants CA154647 from the National Institutes of Health. Dr. Shiroma was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging.; The Age, Gene/Environment Susceptibility-Reykjavik Study has been funded by NIA contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). This work was also supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-0940903 and by the National Institutes of Health Intramural Research Program, study numbers: Z01 DK071013 and Z01 DK071014 to R.J.B. and K.Y.C. The researchers are indebted to the participants for their willingness to participate in the study. NR 71 TC 2 Z9 2 U1 13 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 2016 VL 71 IS 8 BP 1039 EP 1048 DI 10.1093/gerona/glw026 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DV9BX UT WOS:000383235400007 PM 26957472 ER PT J AU Koob, GF Volkow, ND AF Koob, George F. Volkow, Nora D. TI Neurobiology of addiction: a neurocircuitry analysis SO LANCET PSYCHIATRY LA English DT Review ID CORTICOTROPIN-RELEASING-FACTOR; VENTROMEDIAL PREFRONTAL CORTEX; POSTTRAUMATIC-STRESS-DISORDER; INDUCED DOPAMINE RELEASE; KAPPA-OPIOID RECEPTORS; VENTRAL TEGMENTAL AREA; HEAVY ALCOHOL-USE; NUCLEUS-ACCUMBENS; COCAINE-SEEKING; DRUG-ADDICTION AB Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction. C1 [Koob, George F.] NIAAA, 5635 Fishers Lane,Room 2001,Suite 2000, Rockville, MD 20852 USA. [Volkow, Nora D.] NIDA, NIH, Rockville, MD USA. RP Koob, GF (reprint author), NIAAA, 5635 Fishers Lane,Room 2001,Suite 2000, Rockville, MD 20852 USA. EM gkoob@scripps.edu RI koob, george/P-8791-2016 NR 186 TC 13 Z9 13 U1 59 U2 67 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD AUG PY 2016 VL 3 IS 8 BP 760 EP 773 PG 14 WC Psychiatry SC Psychiatry GA DU5TU UT WOS:000382276500025 PM 27475769 ER PT J AU Deeks, SG Lewin, SR Ross, AL Ananworanich, J Benkirane, M Cannon, P Chomont, N Douek, D Lifson, JD Lo, YR Kuritzkes, D Margolis, D Mellors, J Persaud, D Tucker, JD Barre-Sinoussi, F Alter, G Auerbach, J Autran, B Barouch, DH Behrens, G Cavazzana, M Chen, ZW Cohen, EA Corbelli, GM Eholie, S Eyal, N Fidler, S Garcia, L Grossman, C Henderson, G Henrich, TJ Jefferys, R Kiem, HP McCune, J Moodley, K Newman, PA Nijhuis, M Nsubuga, MS Ott, M Palmer, S Richman, D Saez-Cirion, A Sharp, M Siliciano, J Silvestri, G Singh, J Spire, B Taylor, J Tolstrup, M Valente, S van Lunzen, J Walensky, R Wilson, I Zack, J AF Deeks, Steven G. Lewin, Sharon R. Ross, Anna Laura Ananworanich, Jintanat Benkirane, Monsef Cannon, Paula Chomont, Nicolas Douek, Daniel Lifson, Jeffrey D. Lo, Ying-Ru Kuritzkes, Daniel Margolis, David Mellors, John Persaud, Deborah Tucker, Joseph D. Barre-Sinoussi, Francoise Alter, Galit Auerbach, Judith Autran, Brigitte Barouch, Dan H. Behrens, Georg Cavazzana, Marina Chen, Zhiwei Cohen, Eric A. Corbelli, Giulio Maria Eholie, Serge Eyal, Nir Fidler, Sarah Garcia, Laurindo Grossman, Cynthia Henderson, Gail Henrich, Timothy J. Jefferys, Richard Kiem, Hans-Peter McCune, Joseph Moodley, Keymanthri Newman, Peter A. Nijhuis, Monique Nsubuga, Moses Supercharger Ott, Melanie Palmer, Sarah Richman, Douglas Saez-Cirion, Asier Sharp, Matthew Siliciano, Janet Silvestri, Guido Singh, Jerome Spire, Bruno Taylor, Jeffrey Tolstrup, Martin Valente, Susana van Lunzen, Jan Walensky, Rochelle Wilson, Ira Zack, Jerome CA Int AIDS Soc Cure Working Grp TI International AIDS Society global scientific strategy: towards an HIV cure 2016 SO NATURE MEDICINE LA English DT Article ID CD4(+) T-CELLS; SUPPRESSIVE ANTIRETROVIRAL THERAPY; BROADLY NEUTRALIZING ANTIBODIES; HISTONE DEACETYLASE INHIBITOR; HIGHLY PATHOGENIC SIV; LATENT HIV-1; VIRAL RESERVOIR; IN-VIVO; TREATMENT INTERRUPTION; RALTEGRAVIR INTENSIFICATION AB Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy. C1 [Deeks, Steven G.; Auerbach, Judith; Henrich, Timothy J.; McCune, Joseph] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Lewin, Sharon R.] Univ Melbourne, Peter Doherty Inst Infect & Immun, Melbourne, Vic, Australia. [Lewin, Sharon R.] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Lewin, Sharon R.] Alfred Hosp, Dept Infect Dis, Melbourne, Vic, Australia. [Lewin, Sharon R.] Monash Univ, Melbourne, Vic, Australia. [Ross, Anna Laura] ANRS, Int & Sci Relat Off, Paris, France. [Ananworanich, Jintanat] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. [Ananworanich, Jintanat] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD 20817 USA. [Benkirane, Monsef] Univ Montpellier, CNRS UPR 1142, Inst Human Genet, Mol Virol Lab, Montpellier, France. [Cannon, Paula] Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Chomont, Nicolas] Univ Montreal, Fac Med, CRCHUM, Montreal, PQ, Canada. [Chomont, Nicolas] Univ Montreal, Fac Med, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada. [Douek, Daniel] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lifson, Jeffrey D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab, Frederick, MD 21702 USA. [Lo, Ying-Ru] World Hlth Org Reg Off Western Pacific, Manila, Philippines. [Kuritzkes, Daniel; Henrich, Timothy J.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Margolis, David; Henderson, Gail] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. [Mellors, John] Univ Pittsburgh, Dept Med, Div Infect Dis, 930 Scaife Hall, Pittsburgh, PA 15260 USA. [Persaud, Deborah] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. [Persaud, Deborah] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Tucker, Joseph D.] Univ North Carolina Project China, Guangzhou, Guangdong, Peoples R China. [Barre-Sinoussi, Francoise] Inst Pasteur, Paris, France. [Alter, Galit; Barouch, Dan H.] MIT & Harvard, Ragon Inst MGH, Boston, MA USA. [Autran, Brigitte] Univ Paris 06, Sorbonne Univ, CIMI, Paris, France. [Autran, Brigitte] CIMI Paris, INSERM, U1135, Paris, France. [Autran, Brigitte] Hop La Pitie Salpetriere, AP HP, Dept Immunol, Paris, France. [Barouch, Dan H.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Behrens, Georg] Hannover Med Sch, Clin Immunol & Rhematol, Hannover, Germany. [Cavazzana, Marina] Hop Necker Enfants Malad, Ctr Invest Clin Biotherapie, Paris, France. [Chen, Zhiwei] Univ Hong Kong, AIDS Inst, Pok Fu Lam, Hong Kong, Peoples R China. [Cohen, Eric A.] Univ Montreal, Inst Rech Clin Montreal, Montreal, PQ, Canada. [Corbelli, Giulio Maria] European AIDS Treatment Grp, Rome, Italy. [Eholie, Serge] Ctr Hosp Univ Treichville, Programme PAC CI, Abidjan, Cote Ivoire. [Eyal, Nir] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. [Fidler, Sarah] Imperial Coll London, Dept Med, London, England. [Garcia, Laurindo] B Change Grp, Manila, Philippines. [Grossman, Cynthia] NIMH, NIH, Bethesda, MD 20892 USA. [Jefferys, Richard] Treatment Act Grp, New York, NY 10016 USA. [Kiem, Hans-Peter] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Moodley, Keymanthri] Univ Stellenbosch, Dept Med, Ctr Med Eth & Law, Western Cape, South Africa. [Newman, Peter A.] Univ Toronto, Factor Inwentash Fac Social Work, Toronto, ON, Canada. [Nijhuis, Monique] Univ Med Ctr Utrecht, Dept Med Microbiol, Virol, Utrecht, Netherlands. [Nsubuga, Moses Supercharger] Joint Clin Res Ctr, Kampala, Uganda. [Ott, Melanie] Univ Calif San Francisco, Gladstone Inst, San Francisco, CA 94143 USA. [Palmer, Sarah] Univ Sydney, Westmead Millennium Inst Med Res, Sydney, NSW, Australia. [Richman, Douglas] Virginia San Diego Healthcare Syst, San Diego, CA 92161 USA. [Richman, Douglas] Univ Calif San Diego, San Diego, CA 92103 USA. [Saez-Cirion, Asier] Inst Pasteur, Paris, France. [Sharp, Matthew] Independent HIV Educ & Advocacy Consultant, San Francisco, CA USA. [Siliciano, Janet] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Silvestri, Guido] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Singh, Jerome] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Durban, South Africa. [Spire, Bruno] INSERM, UMR S912, Marseille, France. [Taylor, Jeffrey] CARE Collaboratory Community Advisory Board, Palm Springs, CA USA. [Tolstrup, Martin] Aarhus Univ, Inst Clin Med, Aarhus, Denmark. [Valente, Susana] Scripps Res Inst, Dept Immunol & Microbial Sci, Jupiter, FL 33458 USA. [van Lunzen, Jan] ViiV Healthcare, London, England. [Walensky, Rochelle] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Wilson, Ira] Brown Univ, Sch Publ Hlth, Dept Hlth Serv Policy & Practice, Providence, RI 02912 USA. [Zack, Jerome] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Deeks, SG (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM steven.deeks@ucsf.edu RI Behrens, Georg/Q-4486-2016; Spire, Bruno/F-5546-2013; OI Spire, Bruno/0000-0002-3546-8020; Deeks, Steven/0000-0001-6371-747X; Saez-Cirion, Asier/0000-0003-2406-7536; Lewin, Sharon Ruth/0000-0002-0330-8241 FU federal funds from the NCI/NIH [HHSN261200800001E] FX J.L. is supported in part by federal funds from the NCI/NIH under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the DHHS, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. government. The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army, the Department of Defense or the US National Institutes of Health. Y.-R.L. is a World Health Organization (WHO) staff member. The opinions herein are those of the authors and should not be construed as official or representing the views of the WHO. The authors acknowledge T. Rasmussen, T. Mota and M. Crane for assistance with preparation of figures. NR 125 TC 12 Z9 12 U1 16 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD AUG PY 2016 VL 22 IS 8 BP 839 EP 850 DI 10.1038/nm.4108 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DS7YV UT WOS:000381000200009 PM 27400264 ER PT J AU Kabanova, A Marcandalli, J Zhou, TQ Bianchi, S Baxa, U Tsybovsky, Y Lilleri, D Silacci-Fregni, C Foglierini, M Fernandez-Rodriguez, BM Druz, A Zhang, BS Geiger, R Pagani, M Sallusto, F Kwong, PD Corti, D Lanzavecchia, A Perez, L AF Kabanova, Anna Marcandalli, Jessica Zhou, Tongqing Bianchi, Siro Baxa, Ulrich Tsybovsky, Yaroslav Lilleri, Daniele Silacci-Fregni, Chiara Foglierini, Mathilde Fernandez-Rodriguez, Blanca Maria Druz, Aliaksandr Zhang, Baoshan Geiger, Roger Pagani, Massimiliano Sallusto, Federica Kwong, Peter D. Corti, Davide Lanzavecchia, Antonio Perez, Laurent TI Platelet-derived growth factor-alpha receptor is the cellular receptor for human cytomegalovirus gHgLgO trimer SO NATURE MICROBIOLOGY LA English DT Article ID DISINTEGRIN-LIKE DOMAIN; ENDOTHELIAL-CELLS; ELECTRON-MICROSCOPY; EPITHELIAL-CELLS; ENTRY; TROPISM; COMPLEX; FUSION; GENES; VISUALIZATION AB Human cytomegalovirus encodes at least 25 membrane glycoproteins that are found in the viral envelope(1). While gB represents the fusion protein, two glycoprotein complexes control the tropism of the virus: the gHgLgO trimer is involved in the infection of fibroblasts, and the gHgLpUL128L pentamer is required for infection of endothelial, epithelial and myeloid cells(2-5). Two reports suggested that gB binds to ErbB1 and PDGFRa (refs 6,7); however, these results do not explain the tropism of the virus and were recently challenged(8,9). Here, we provide a 19 angstrom reconstruction for the gHgLgO trimer and show that it binds with high affinity through the gO subunit to PDGFRa, which is expressed on fibroblasts but not on epithelial cells. We also provide evidence that the trimer is essential for viral entry in both fibroblasts and epithelial cells. Furthermore, we identify the pentamer, which is essential for infection of epithelial cells, as a trigger for the ErbB pathway. These findings help explain the broad tropism of human cytomegalovirus and indicate that PDGFRa and the viral gO subunit could be targeted by novel anti-viral therapies. C1 [Kabanova, Anna; Marcandalli, Jessica; Silacci-Fregni, Chiara; Foglierini, Mathilde; Fernandez-Rodriguez, Blanca Maria; Geiger, Roger; Sallusto, Federica; Lanzavecchia, Antonio; Perez, Laurent] Univ Italian Switzerland, Inst Res Biomed, Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland. [Zhou, Tongqing; Druz, Aliaksandr; Zhang, Baoshan; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Bianchi, Siro; Corti, Davide] Humabs BioMed SA, Via Mirasole 1, CH-6500 Bellinzona, Switzerland. [Baxa, Ulrich; Tsybovsky, Yaroslav] Frederick Natl Lab Canc Res, Electron Microscopy Lab, Canc Res Technol Program, Leidos Biomed Res, Frederick, MD 21702 USA. [Lilleri, Daniele] Fdn IRCCS Policlin San Matteo, Lab Sperimentali Ricerca Area Trapiantol, I-27100 Pavia, Italy. [Geiger, Roger; Lanzavecchia, Antonio] Swiss Fed Inst Technol, Inst Microbiol, Wolfgang Pauli Str 10, CH-8093 Zurich, Switzerland. [Pagani, Massimiliano] Ist Nazl Genet Mol Romeo & Enrica Invernizzi, I-20122 Milan, Italy. [Kabanova, Anna] Univ Siena, Dept Life Sci, Via Aldo Moro 2, I-53100 Siena, Italy. RP Lanzavecchia, A; Perez, L (reprint author), Univ Italian Switzerland, Inst Res Biomed, Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland.; Lanzavecchia, A (reprint author), Swiss Fed Inst Technol, Inst Microbiol, Wolfgang Pauli Str 10, CH-8093 Zurich, Switzerland. EM lanzavecchia@irb.usi.ch; laurent.perez@irb.usi.ch FU Helmut Horten Foundation; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Leidos Biomedical Research FX The authors thank A. von Heyl for graphical representation, the Virologia e Microbiologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, for the HCMV clinical isolate and deficient virus, Horizon Genomics GmbH for the HAP-1 parental line and CRISPR/Cas9 KO cells and Oxford University, Central Proteomics Facility, Oxford, UK, for mass spectrometry analysis. The Institute for Research in Biomedicine is supported by the Helmut Horten Foundation. This project has been funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract no. HHSN261200800001E, and by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Leidos Biomedical Research provided support in the form of a salary for author Y.T. NR 39 TC 4 Z9 4 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND EI 2058-5276 J9 NAT MICROBIOL JI NAT. MICROBIOL PD AUG PY 2016 VL 1 IS 8 AR 16082 DI 10.1038/NMICROBIOL.2016.82 PG 8 WC Microbiology SC Microbiology GA DW4IH UT WOS:000383605900018 PM 27573107 ER PT J AU Pisklakova, A McKenzie, B Zemp, F Lun, XQ Kenchappa, RS Etame, AB Rahman, MM Reilly, K Pilon-Thomas, S McFadden, G Kurz, E Forsyth, PA AF Pisklakova, Alexandra McKenzie, Brienne Zemp, Franz Lun, Xueqing Kenchappa, Rajappa S. Etame, Arnold B. Rahman, Masmudur M. Reilly, Karlyne Pilon-Thomas, Shari McFadden, Grant Kurz, Ebba Forsyth, Peter A. TI M011L-deficient oncolytic myxoma virus induces apoptosis in brain tumor-initiating cells and enhances survival in a novel immunocompetent mouse model of glioblastoma SO NEURO-ONCOLOGY LA English DT Article DE apoptosis; brain tumor-initiating cells; glioma; oncolytic virus ID STEM-CELLS; PREVENTS APOPTOSIS; MICE; M11L; CANCER; BCL-2; PROLIFERATION; MITOCHONDRIA; INHIBITOR; ANTITUMOR AB Myxoma virus (MYXV) is a promising oncolytic agent and is highly effective against immortalized glioma cells but less effective against brain tumor initiating cells (BTICs), which are believed to mediate glioma development/recurrence. MYXV encodes various proteins to attenuate host cell apoptosis, including an antiapoptotic Bcl-2 homologue known as M011L. Such proteins may limit the ability of MYXV to kill BTICs, which have heightened resistance to apoptosis. We hypothesized that infecting BTICs with an M011L-deficient MYXV construct would overcome BTIC resistance to MYXV. We used patient-derived BTICs to evaluate the efficacy of M011L knockout virus (vMyx-M011L-KO) versus wild-type MYXV (vMyx-WT) and characterized the mechanism of virus-induced cell death in vitro. To extend our findings in a novel immunocompetent animal model, we derived, cultured, and characterized a C57Bl/6J murine BTIC (mBTIC0309) from a spontaneous murine glioma and evaluated vMyx-M011L-KO efficacy with and without temozolomide (TMZ) in mBTIC0309-bearing mice. We demonstrated that vMyx-M011L-KO induces apoptosis in BTICs, dramatically increasing sensitivity to the virus. vMyx-WT failed to induce apoptosis as M011L protein prevented Bax activation and cytochrome c release. In vivo, intracranial implantation of mBTIC0309 generated tumors that closely recapitulated the pathological and molecular profile of human gliomas. Treatment of tumor-bearing mice with vMyx-M011L-KO significantly prolonged survival in immunocompetent-but not immunodeficient-mouse models, an effect that is significantly enhanced in combination with TMZ. Our data suggest that vMyx-M011L-KO is an effective, well-tolerated, proapoptotic oncolytic virus and a strong candidate for clinical translation. C1 [Pisklakova, Alexandra; Kenchappa, Rajappa S.; Etame, Arnold B.; Forsyth, Peter A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Neurooncol & Tumor Biol, Tampa, FL USA. [McKenzie, Brienne; Zemp, Franz; Lun, Xueqing; Kurz, Ebba; Forsyth, Peter A.] Univ Calgary, Southern Alberta Canc Res Inst, Calgary, AB, Canada. [Rahman, Masmudur M.; McFadden, Grant] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA. [Reilly, Karlyne] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Pilon-Thomas, Shari] H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL USA. [McKenzie, Brienne] Univ Alberta, Dept Med Microbiol & Immunol, Heritage Med Res Ctr 6 11, Edmonton, AB T6G 2R3, Canada. RP Forsyth, PA (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Dept Neurooncol, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM peter.forsyth@moffitt.org FU V Foundation; Moffitt Cancer Center Foundation; Terry Fox Foundation; Florida Center for Brain Tumor Research and Accelerate Brain Cancer Cure; Canadian Institutes for Health Research (CIHR); Alberta Innovates-Health Solutions; CIHR; Izaak Walton Killam scholarship; NIH [R01 AI080607, R01 CA138541]; National Cancer Institute, USA FX This work was supported by the V Foundation (P.A.F.), Moffitt Cancer Center Foundation (P.A.F.), and Terry Fox Foundation (P.A.F.). Funding (P.A.F.) was also provided by a research grant from the Florida Center for Brain Tumor Research and Accelerate Brain Cancer Cure (ABC). B.A.M. was funded the Canadian Institutes for Health Research (CIHR). F.J.Z. was funded by Alberta Innovates-Health Solutions, a Vanier scholarship (CIHR), and the Izaak Walton Killam scholarship. G.M.'s lab was funded by NIH grants R01 AI080607 and R01 CA138541. K.M.R. is supported by the Intramural Research Program of the National Cancer Institute, USA. NR 39 TC 0 Z9 0 U1 5 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD AUG PY 2016 VL 18 IS 8 BP 1088 EP 1098 DI 10.1093/neuonc/now006 PG 11 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DV9TT UT WOS:000383285800007 ER PT J AU Weaver, KR Fourie, NH Abey, SK Sherwin, LB Henderson, WA AF Weaver, K. R. Fourie, N. H. Abey, S. K. Sherwin, L. B. Henderson, W. A. TI Microbial translocation in IBS; relevance of sex, stress, and IBS subtype SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 [Weaver, K. R.; Fourie, N. H.; Abey, S. K.; Sherwin, L. B.; Henderson, W. A.] NINR, NIH, Bethesda, MD 20892 USA. [Weaver, K. R.] NYU, Coll Nursing, New York, NY USA. [Sherwin, L. B.] Univ Missouri, Sch Nursing, Columbia, MO 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 1350-1925 EI 1365-2982 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD AUG PY 2016 VL 28 SU 1 SI SI MA 92 BP 33 EP 33 PG 1 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA DV9VS UT WOS:000383290900092 ER PT J AU Sherwin, LB Henderson, WA Leary, E AF Sherwin, L. B. Henderson, W. A. Leary, E. TI The influence of catastrophizing on psychosocial and functional outcomes in irritable bowel syndrome SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 [Sherwin, L. B.; Leary, E.] Univ Missouri, Columbia, MO USA. [Sherwin, L. B.; Henderson, W. A.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1350-1925 EI 1365-2982 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD AUG PY 2016 VL 28 SU 1 SI SI MA 202 BP 62 EP 62 PG 1 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA DV9VS UT WOS:000383290900198 ER PT J AU Fourie, NH Wang, D Abey, SK Creekmore, AL Hong, S Wiley, JW Henderson, WA AF Fourie, N. H. Wang, D. Abey, S. K. Creekmore, A. L. Hong, S. Wiley, J. W. Henderson, W. A. TI Structural and functional alterations in the colonic microbiome in a chronic stress rat model of irritable bowel syndrome SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 [Fourie, N. H.; Wang, D.; Abey, S. K.; Henderson, W. A.] DHHS, Div Intramural Res, Digest Disorders Unit, NIH, Bethesda, MD USA. [Creekmore, A. L.; Hong, S.; Wiley, J. W.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 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 1350-1925 EI 1365-2982 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD AUG PY 2016 VL 28 SU 1 SI SI MA 323 BP 95 EP 95 PG 1 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA DV9VS UT WOS:000383290900317 ER PT J AU Mellem, MS Jasmin, KM Peng, C Martin, A AF Mellem, Monika S. Jasmin, Kyle M. Peng, Cynthia Martin, Alex TI Sentence processing in anterior superior temporal cortex shows a social-emotional bias SO NEUROPSYCHOLOGIA LA English DT Article DE Affective; Emotion; fMRI; Language; Social brain ID FUNCTIONAL CONNECTIVITY; PHYSIOLOGICAL NOISE; SEMANTIC MEMORY; 1.5 T; LOBES; BRAIN; COGNITION; REPRESENTATION; MODULATION; KNOWLEDGE AB The anterior region of the left superior temporal gyms/superior temporal sulcus (aSTG/STS) has been implicated in two very different cognitive functions: sentence processing and social-emotional processing. However, the vast majority of the sentence stimuli in previous reports have been of a social or social-emotional nature suggesting that sentence processing may be confounded with semantic content. To evaluate this possibility we had subjects read word lists that differed in phrase/constituent size (single words, 3-word phrases, 6-word sentences) and semantic content (social-emotional, social, and inanimate objects) while scanned in a 7 T environment. This allowed us to investigate if the aSTG/STS responded to increasing constituent structure (with increased activity as a function of constituent size) with or without regard to a specific domain of concepts, i.e., social and/or social-emotional content. Activity in the left aSTG/STS was found to increase with constituent size. This region was also modulated by content, however, such that social-emotional concepts were preferred over social and object stimuli. Reading also induced content type effects in domain-specific semantic regions. Those preferring social-emotional content included aSTG/STS, inferior frontal gyrus, posterior STS, lateral fusiform, ventromedial prefrontal cortex, and amygdala, regions included in the "social brain", while those preferring object content included parahippocampal gyrus, retrosplenial cortex, and caudate, regions involved in object processing. These results suggest that semantic content affects higher-level linguistic processing and should be taken into account in future studies. (C) 2016 Published by Elsevier Ltd. C1 [Mellem, Monika S.; Jasmin, Kyle M.; Peng, Cynthia; Martin, Alex] NIMH, Sect Cognit Neuropsychol, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Jasmin, Kyle M.] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. RP Mellem, MS (reprint author), Bldg 10,Room 4C-104 MSC 1366, Bethesda, MD 20892 USA. EM monika.mellem@nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health FX We thank Sophie Wohltjen for help with data analysis and Steve Gotts for helpful discussions. This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, and it was conducted under NIH Clinical Study Protocol 93-M-0170 (ZIAMH002588); NCT00001360. NR 53 TC 0 Z9 0 U1 6 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 EI 1873-3514 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD AUG PY 2016 VL 89 BP 217 EP 224 DI 10.1016/j.neuropsychologia.2016.06.019 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA DV5XD UT WOS:000383003100020 PM 27329686 ER PT J AU Kang, L Liu, AY Tian, LL AF Kang, Le Liu, Aiyi Tian, Lili TI Linear combination methods to improve diagnostic/prognostic accuracy on future observations SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE Multiple biomarkers; receiver operating characteristic curve; area under the receiver operating characteristic curve; linear combination; diagnostic; prognostic accuracy ID OPERATING CHARACTERISTIC CURVE; LOGISTIC-REGRESSION; DISCRIMINANT-ANALYSIS; BIOMARKERS; CLASSIFICATION; PROBABILITY; EFFICIENCY; INFERENCE; SUBJECT; MARKERS AB Multiple diagnostic tests or biomarkers can be combined to improve diagnostic accuracy. The problem of finding the optimal linear combinations of biomarkers to maximise the area under the receiver operating characteristic curve has been extensively addressed in the literature. The purpose of this article is threefold: (1) to provide an extensive review of the existing methods for biomarker combination; (2) to propose a new combination method, namely, the nonparametric stepwise approach; (3) to use leave-one-pair-out cross-validation method, instead of re-substitution method, which is overoptimistic and hence might lead to wrong conclusion, to empirically evaluate and compare the performance of different linear combination methods in yielding the largest area under receiver operating characteristic curve. A data set of Duchenne muscular dystrophy was analysed to illustrate the applications of the discussed combination methods. C1 [Kang, Le] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Bethesda, MD USA. [Tian, Lili] SUNY Buffalo, Dept Biostat, 706 Kimball Tower,3435 Main St, Buffalo, NY 14214 USA. RP Tian, LL (reprint author), SUNY Buffalo, Dept Biostat, 706 Kimball Tower,3435 Main St, Buffalo, NY 14214 USA. EM ltian@buffalo.edu OI Liu, Aiyi/0000-0002-6618-5082 FU US Department of Energy; US Food and Drug Administration; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX Le Kang was supported in part by an appointment to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. Aiyi Liu was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. The opinions expressed are solely those of the authors and not necessarily those of the Editors. The authors thank the referees for helpful discussion and comments. A supplementary R code to implement the methods described in this article is in the Appendix. NR 32 TC 4 Z9 4 U1 8 U2 8 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD AUG PY 2016 VL 25 IS 4 SI SI BP 1359 EP 1380 DI 10.1177/0962280213481053 PG 22 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA DV4CA UT WOS:000382871200018 PM 23592714 ER PT J AU Cervenakoya, L Saa, P Yakoyleva, O Vasilyeva, I de Castro, J Brown, P Dodd, R AF Cervenakoya, Larisa Saa, Paula Yakoyleva, Oksana Vasilyeva, Irina de Castro, Jorge Brown, Paul Dodd, Roger TI Are prions transported by plasma exosomes? SO TRANSFUSION AND APHERESIS SCIENCE LA English DT Review DE Prion protein; Blood; Plasma; Extracellular vesicles; Prion infectivity ID CREUTZFELDT-JAKOB-DISEASE; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY; MISFOLDING CYCLIC AMPLIFICATION; CHRONIC WASTING DISEASE; INFECTIOUS PRIONS; EXTRACELLULAR VESICLES; BLOOD INFECTIVITY; PROTEIN; VARIANT; SCRAPIE AB Blood has been shown to contain disease-associated misfolded prion protein (PrPTsE) in animals naturally and experimentally infected with various transmissible spongiform encephalopathy (TSE) agents, and in humans infected with variant Creutzfeldt-Jakob disease (vCJD). Recently, we have demonstrated PrPTsE in extracellular vesicle preparations (EVs) containing exosomes from plasma of mice infected with mouse-adapted vCJD by Protein Misfolding Cyclic Amplification (PMCA). Here we report the detection of PrPTsE by PMCA in EVs from plasma of mice infected with Fukuoka-1 (FU), an isolate from a Gerstmann-Straussler-Scheinker disease patient. We used Tga20 transgenic mice that over-express mouse cellular prion protein, to assay by intracranial injections the level of infectivity in a FU infected brain homogenate from wild-type mice (FU-BH), and in blood cellular components (BCC), consisting of red blood cells, white blood cells and platelets, plasma EVs, and plasma EVs subjected to multiple rounds of PMCA. Only FU-BH and plasma EVs from FU-infected mice subjected to PMCA that contained PrPTsE transmitted disease to Tga20 mice. Plasma EVs not subjected to PMCA and BCC from FU-infected mice failed to transmit disease. These findings confirm the high sensitivity of PMCA for PrPTsE detection in plasma EVs and the efficiency of this in vitro method to produce highly infectious prions. The results of our study encourage further research to define the role of EVs and, more specifically exosomes, as blood-borne carriers of PrPTsE. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Cervenakoya, Larisa; Saa, Paula; Yakoyleva, Oksana; Vasilyeva, Irina; de Castro, Jorge; Dodd, Roger] Amer Natl Red Cross, Sci Affairs, Rockville, MD USA. [Yakoyleva, Oksana] US FDA, Lab Bacterial & Transmissible Spongiforrn Encepha, DETTD, OBRR,CBER, Silver Spring, MD USA. [de Castro, Jorge] Meso Scale Diagnost LLC, Rockville, MD USA. [Brown, Paul] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Cervenakoya, L (reprint author), Amer Natl Red Cross, Sci Affairs, JH Holland Lab, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. EM larisa.cervenakova@redcross.org FU Fondation pour la Recherche Medicale/Foundation Alliance BioSecure, France; American National Red Cross FX We are grateful to Professor Charles Weissmann for permission to use Tga20 mice and Prnp0/0 mice, Dr. Ragy Ragheb (Malvern Instruments) for NTA analysis of mouse plasma EV samples, Mr. Carroll McKenzie and Mr. Anton Cervenak for excellent technical assistance, and Mr. Craig Mayer and Mr. Ward B. Cunningham for daily animal care. This study was funded by the Fondation pour la Recherche Medicale/Foundation Alliance BioSecure, France and by the American National Red Cross. NR 87 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1473-0502 J9 TRANSFUS APHER SCI JI Transfus. Apher. Sci. PD AUG PY 2016 VL 55 IS 1 BP 70 EP 83 DI 10.1016/j.transci.2016.07.013 PG 14 WC Hematology SC Hematology GA DV5YW UT WOS:000383007600010 PM 27499183 ER PT J AU Christophersen, IE Yin, XY Larson, MG Lubitz, SA Magnani, JW McManus, DD Ellinor, PT Benjamin, EJ AF Christophersen, Ingrid E. Yin, Xiaoyan Larson, Martin G. Lubitz, Steven A. Magnani, Jared W. McManus, David D. Ellinor, Patrick T. Benjamin, Emelia J. TI A comparison of the CHARGE-AF and the CHA(2)DS(2)-VASc risk scores for prediction of atrial fibrillation in the Framingham Heart Study SO AMERICAN HEART JOURNAL LA English DT Article ID PROPORTIONAL HAZARDS MODEL; AFRICAN-AMERICANS; SURVIVAL ANALYSIS; COMPETING RISKS; ISCHEMIC-STROKE; CHADS(2); COHORT; VALIDATION; OUTCOMES; SUBDISTRIBUTION AB Background Atrial fibrillation (AF) affects more than 33 million individuals worldwide and increases risks of stroke, heart failure, and death. The CHARGE-AF risk score was developed to predict incident AF in three American cohorts and it was validated in two European cohorts. The CHA(2)DS(2)-VASc risk score was derived to predict risk of stroke, peripheral embolism, and pulmonary embolism in individuals with AF, but it has been increasingly used for AF risk prediction. We compared CHARGE-AF risk score versus CHA(2)DS(2)-VASc risk score for incident AF risk in a community-based cohort. Methods and Results We studied Framingham Heart Study participants aged 46 to 94 years without prevalent AF and with complete covariates. We predicted AF risk using Fine-Gray proportional sub-distribution hazards regression. We used the Wald chi(2) statistic for model fit, C-statistic for discrimination, and Hosmer-Lemeshow (HL) chi(2) statistic for calibration. We included 9722 observations (mean age 63.9 +/- 10.6 years, 56% women) from 4548 unique individuals: 752 (16.5%) developed incident AF and 793 (17.4%) died. The mean CHARGE-AF score was 12.0 +/- 1.2 and the sub-distribution hazard ratio (sHR) for AF per unit increment was 2.15 (95% CI, 99-131%; P <.0001). The mean CHA(2)DS(2)-VASc score was 2.0 +/- 1.5 and the sHR for AF per unit increment was 1.43 (95% CI, 37%-51%; P<.0001). The CHARGE-AF model had better fit than CHA(2)DS(2)-VASc (Wald chi(2) = 403 vs 209, both with 1 df), improved discrimination (C-statistic = 0.75, 95% CI, 0.73-0.76 vs C-statistic = 0.71, 95% CI, 0.69-0.73), and better calibration (HL chi(2) = 5.6, P =.69 vs HL chi(2) = 28.5, P <.0001). Conclusion The CHARGE-AF risk score performed better than the CHA(2)DS(2)-VASc risk score at predicting AF in a community-based cohort. C1 [Christophersen, Ingrid E.; Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Christophersen, Ingrid E.; Lubitz, Steven A.; Ellinor, Patrick T.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Christophersen, Ingrid E.] Vestre Viken Hosp Trust, Brum Hosp, Dept Med Res, Drammen, Norway. [Yin, Xiaoyan; Larson, Martin G.; Magnani, Jared W.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Yin, Xiaoyan; Larson, Martin G.; Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Boston, MA 02215 USA. [Yin, Xiaoyan; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Cardiovasc Med Div, Worcester, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Benjamin, EJ (reprint author), Boston Univ, Sch Med, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA.; Benjamin, EJ (reprint author), Boston Univ, Sch Publ Hlth, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM emelia@bu.edu FU Bayer HealthCare FX Dr Ellinor is a principal investigator on a grant from Bayer HealthCare to the Broad Institute. NR 52 TC 1 Z9 1 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD AUG PY 2016 VL 178 BP 45 EP 54 DI 10.1016/j.ahj.2016.05.004 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DT6JK UT WOS:000381590300006 PM 27502851 ER PT J AU Inaguma, S Wang, ZF Lasota, J Sarlomo-Rikala, M McCue, PA Ikeda, H Miettinen, M AF Inaguma, Shingo Wang, Zengfeng Lasota, Jerzy Sarlomo-Rikala, Maarit McCue, Peter A. Ikeda, Hiroshi Miettinen, Markku TI Comprehensive Immunohistochemical Study of Programmed Cell Death Ligand 1 (PD-L1) Analysis in 5536 Cases Revealed Consistent Expression in Trophoblastic Tumors SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE programmed cell death ligand 1 (PD-L1); immunohistochemistry; choriocarcinoma; classical Hodgkin lymphoma; anaplastic large cell lymphoma (ALCL); schwannoma; mismatch-repair deficiency; Epstein-Barr virus ID EPSTEIN-BARR-VIRUS; B7-H1 EXPRESSION; LUNG-CANCER; HEPATOCELLULAR-CARCINOMA; CLINICAL-SIGNIFICANCE; HODGKIN LYMPHOMA; B7 FAMILY; NIVOLUMAB; MEMBER; IMMUNOSUPPRESSION AB Programmed cell death 1/programmed cell death ligand (PD-1/PD-Ls) axis is crucial for the modulation of immune responses and self-tolerance. Also, aberrant PD-L1 expression on the tumor cells or tumor-associated inflammatory cells accelerates immune evasion of tumor cells. In the past decade, PD-1/PD-L immune checkpoint inhibitors were introduced to cancer treatment trials and, in some cases, showed significant anticancer effects. PD-L1 immunohistochemical staining is considered a potential predictor of clinical response to PD-1/PD-L immune checkpoint inhibitor treatment. However, immunohistochemical data on PD-L1 expression in different types of cancer especially rare entities remain incomplete. In this study, PD-L1 expression was immunohistochemically analyzed in 5536 tumors including germ cell, epithelial, mesenchymal, melanocytic/neuroectodermal, and lymphohematopoietic tumors, as well as in a set of human normal tissues including a fetus. Immunohistochemical analysis was performed with E1L3N rabbit monoclonal antibody and Leica Bond Max automation using multitumor blocks containing up to 70 tumor samples. PD-L1 was constitutively and strongly expressed in placental trophoblasts as well as choriocarcinomas and trophoblastic components of germ cell tumors. Also, the neoplastic cells of classical Hodgkin lymphoma, anaplastic large cell lymphoma, schwannoma, thymoma, and squamous cell carcinoma of various sites frequently expressed PD-L1. In gastrointestinal adenocarcinomas, PD-L1-expression was associated with EBER positivity and mismatch-repair deficiency. In addition, PD-L1 was variably expressed in non-neoplastic macrophages and dendritic cells. PD-L1 immunohistochemistry may have some role in the immunophenotypic differential diagnosis of tumors and pinpointing potential candidates for anti-PD-1/PD-L immune checkpoint therapy. C1 [Inaguma, Shingo; Wang, Zengfeng; Lasota, Jerzy; Miettinen, Markku] NCI, Pathol Lab, Bldg 10,Room B1B47,Ctr Dr 10, Bethesda, MD 20892 USA. [McCue, Peter A.] Thomas Jefferson Univ, Jefferson Med Coll, Dept Pathol Cell Biol & Anat, Philadelphia, PA 19107 USA. [McCue, Peter A.] Univ Hosp, Philadelphia, PA USA. [Inaguma, Shingo; Ikeda, Hiroshi] Aichi Med Univ, Sch Med, Dept Pathol, Nagakute, Aichi, Japan. [Sarlomo-Rikala, Maarit] Helsinki Univ Hosp, Dept Pathol, Haartman Inst, Helsinki, Finland. [Sarlomo-Rikala, Maarit] Helsinki Univ Hosp, HusLab, Helsinki, Finland. RP Inaguma, S (reprint author), NCI, Pathol Lab, Bldg 10,Room B1B47,Ctr Dr 10, Bethesda, MD 20892 USA. EM inaguma@aichi-med-u.ac.jp FU National Cancer Institute's intramural research program FX Supported as a part of National Cancer Institute's intramural research program. The authors have disclosed that they have no relationships with, or financial interest in, any commercial companies pertaining to this article. NR 39 TC 6 Z9 6 U1 9 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD AUG PY 2016 VL 40 IS 8 BP 1133 EP 1142 DI 10.1097/PAS.0000000000000653 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA DT4CT UT WOS:000381428400016 PM 27158757 ER PT J AU Rice, TA Brenner, TA Percopo, CM Ma, M Keicher, JD Domachowske, JB Rosenberg, HF AF Rice, Tyler A. Brenner, Todd A. Percopo, Caroline M. Ma, Michelle Keicher, Jesse D. Domachowske, Joseph B. Rosenberg, Helene F. TI Signaling via pattern recognition receptors NOD2 and TLR2 contributes to immunomodulatory control of lethal pneumovirus infection SO ANTIVIRAL RESEARCH LA English DT Article DE Inflammation; Cytokines; Pattern recognition receptors; Pneumovirus; Probiotic ID RESPIRATORY SYNCYTIAL VIRUS; TOLL-LIKE RECEPTORS; MOUSE LUNG-TISSUE; MICE PVM MODEL; TRAINED IMMUNITY; VIRAL BRONCHIOLITIS; TRACT INFECTIONS; PNEUMONIA VIRUS; INNATE IMMUNITY; RESPONSES AB Pattern recognition receptors (PRRs) engage microbial components in the lung, although their role in providing primary host defense against respiratory virus infection is not fully understood. We have previously shown that Gram-positive Lactobacillus plantarum (Lp) administered to the respiratory tract promotes full and sustained protection in response to an otherwise lethal mouse pneumovirus (PVM) infection, a robust example of heterologous immunity. While Lp engages PRRs TLR2 and NOD2 in ex vivo signaling assays, we found that Lp-mediated protection was unimpaired in single gene-deleted TLR2(-/-) and NOD2(-/-) mice. Here we demonstrate substantial loss of Lp-mediated protection in a double gene deleted NOD2(-/-)TLR2(-/-) strain. Furthermore, we demonstrate protection against PVM infection by administration of the bi-functional NOD2 TLR2 agonist, CL-429. The bi-functional NOD2-TLR2 ligand CL 429 not only suppresses virus-induced inflammation, it is significantly more effective at preventing lethal infection than equivalent amounts of mono-molecular TLR2 and NOD2 agonists. Interestingly, and in contrast to biochemical NOD2 and/or TLR2 agonists, Lp remained capable of eliciting primary proinflammatory responses from NOD2(-/-)TLR2(-/-) mice in vivo and from alveolar macrophages challenged ex vivo. Taken together, we conclude that coordinate engagement of NOD2 and TLR2 constitutes a key step in the genesis of Lp-mediated protection from a lethal respiratory virus infection, and represents a critical target for modulation of virus-induced inflammatory pathology. Published by Elsevier B.V. C1 [Rice, Tyler A.; Brenner, Todd A.; Percopo, Caroline M.; Ma, Michelle; Rosenberg, Helene F.] NIAID, Inflammat Immunobiol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Keicher, Jesse D.] GlaxoSmithKline, Drug Discovery Infect Dis, Res Triangle Pk, NC 27709 USA. [Domachowske, Joseph B.] SUNY Upstate Med Ctr, Div Infect Dis, Dept Pediat, Syracuse, NY 13210 USA. [Rice, Tyler A.] Yale Univ, Grad Dept Immunobiol, New Haven, CT USA. [Keicher, Jesse D.] Symmune Therapeut, Durham, NC 27701 USA. RP Rosenberg, HF (reprint author), NIAID, NIH, Bldg 10,Room 11C215 MSC 1883,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU NIAID Division of Intramural Research [AI000943] FX This manuscript is dedicated to Dr. Kimberly D. Dyer and include our wishes for her speedy recovery. The work herein was supported by funds from NIAID Division of Intramural Research (AI000943) to HFR. NR 64 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD AUG PY 2016 VL 132 BP 131 EP 140 DI 10.1016/j.antiviral.2016.06.002 PG 10 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA DU6SO UT WOS:000382345100018 PM 27312104 ER PT J AU Robinson, LM Waran, NK Leach, MC Morton, FB Paukner, A Lonsdorf, E Handel, I Wilson, VAD Brosnan, SF Weiss, A AF Robinson, Lauren M. Waran, Natalie K. Leach, Matthew C. Morton, F. Blake Paukner, Annika Lonsdorf, Elizabeth Handel, Ian Wilson, Vanessa A. D. Brosnan, Sarah F. Weiss, Alexander TI Happiness is positive welfare in brown capuchins (Sapajus apella) SO APPLIED ANIMAL BEHAVIOUR SCIENCE LA English DT Article DE Capuchin; Personality; Primate; Stereotypy; Subjective well-being; Welfare ID MACAQUES MACACA-MULATTA; QUALITY-OF-LIFE; ANIMAL-WELFARE; RHESUS MACAQUES; CEBUS-APELLA; PERSONALITY; BEHAVIOR; RATINGS; MONKEYS; HEALTH AB Questionnaires that allow people who are familiar with individual animals to rate the welfare of these animals are an underutilised tool. We designed a 12-item welfare questionnaire and tested its reliability and associations with subjective well-being (SWB), locomotor stereotypy, and personality traits. The welfare questionnaire included questions relating to physical health, stress and coping, satisfaction with social relationships, psychological stimulation, and the display of positive and negative welfare indicators. We collected ratings of 66 brown capuchins (Sapajus apella) living in three facilities. Each capuchin was rated on the welfare questionnaire by an average of 2.8 raters. The interrater reliability of the welfare questionnaire items ranged from ICC(3,k) 0.51 to 0.86. A principal components analysis indicated that the 12 welfare items loaded onto one component. We repeated this process with the welfare and four items used to measure subjective well-being and found all the items were defined by a single component (welfareSWB). We then conducted three sets of analyses, one predicting the welfare component, one predicting the SWB component, and predicting the welfareSWB component. The independent variables were frequency of locomotor stereotypy, personality, age, and sex; facility was included as a random effect. In models including stereotypy, age, and sex we found frequency of stereotypy to be significantly associated with all three predicted components (ps < 0.01). After controlling for stereotypy (b = -0.25, p = 0.17), age (b = -0.54, p = 0.01), and sex (b = -0.32, p = 0.07), the personality traits of Sociability (b = 1.02, p < 0.001), Assertiveness, (b = 0.63, p < 0.001), and Attentiveness (b = 0.54, p = 0.01) were associated with higher scores on the joint welfareSWB component; Neuroticism was negatively associated with welfare SWB (b = -0.60, p = 0.01). Our results suggest that welfare questionnaires is a useful, reliable, and valid tool for primate welfare assessment. (C) 2016 Elsevier B.V. All rights reserved. C1 [Robinson, Lauren M.; Wilson, Vanessa A. D.; Weiss, Alexander] Univ Edinburgh, Sch Philosophy Psychol & Language Sci, Dept Psychol, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. [Robinson, Lauren M.; Waran, Natalie K.] Univ Edinburgh, Royal Dick Sch Vet Studies, Jeanne Marchig Int Ctr Anim Welf Educ, Easter Bush Vet Ctr, Roslin EH25 9RG, Midlothian, Scotland. [Robinson, Lauren M.; Morton, F. Blake; Wilson, Vanessa A. D.; Weiss, Alexander] Scottish Primate Res Grp, Edinburgh, Midlothian, Scotland. [Leach, Matthew C.] Newcastle Univ, Food & Rural Dev, Sch Agr, Agr Bldg, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Morton, F. Blake; Lonsdorf, Elizabeth] Franklin & Marshall Coll, Dept Psychol, Lancaster, PA 17603 USA. [Paukner, Annika] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, Dickerson, MD 20842 USA. [Handel, Ian] Univ Edinburgh, Roslin Inst, Roslin EH25 9RG, Midlothian, Scotland. [Handel, Ian] Univ Edinburgh, Royal Dick Sch Vet Studies, Roslin EH25 9RG, Midlothian, Scotland. [Brosnan, Sarah F.] Georgia State Univ, Dept Psychol, Atlanta, GA 30303 USA. RP Robinson, LM (reprint author), Univ Edinburgh, Sch Philosophy Psychol & Language Sci, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. EM l.robinson@ed.ac.uk NR 61 TC 0 Z9 0 U1 7 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1591 EI 1872-9045 J9 APPL ANIM BEHAV SCI JI Appl. Anim. Behav. Sci. PD AUG PY 2016 VL 181 BP 145 EP 151 DI 10.1016/j.applanim.2016.05.029 PG 7 WC Agriculture, Dairy & Animal Science; Behavioral Sciences; Veterinary Sciences SC Agriculture; Behavioral Sciences; Veterinary Sciences GA DT0KB UT WOS:000381171300019 ER PT J AU Dorans, KS Wilker, EH Li, WY Rice, MB Ljungman, PL Schwartz, J Coull, BA Kloog, I Koutrakis, P D'Agostino, RB Massaro, JM Hoffmann, U O'Donnell, CJ Mittleman, MA AF Dorans, Kirsten S. Wilker, Elissa H. Li, Wenyuan Rice, Mary B. Ljungman, Petter L. Schwartz, Joel Coull, Brent A. Kloog, Itai Koutrakis, Petros D'Agostino, Ralph B., Sr. Massaro, Joseph M. Hoffmann, Udo O'Donnell, Christopher J. Mittleman, Murray A. TI Residential Proximity to Major Roads, Exposure to Fine Particulate Matter, and Coronary Artery Calcium: The Framingham Heart Study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE air pollution; atherosclerosis; coronary artery calcium; epidemiology; multidetector computed tomography ID LONG-TERM EXPOSURE; INTIMA-MEDIA THICKNESS; ACUTE MYOCARDIAL-INFARCTION; AIR-POLLUTION; CARDIOVASCULAR-DISEASE; SCIENTIFIC STATEMENT; ATHEROSCLEROSIS; ASSOCIATION; METAANALYSIS; MORTALITY AB Objective Long-term exposure to traffic and particulate matter air pollution is associated with a higher risk of cardiovascular disease, potentially via atherosclerosis promotion. Prior research on associations of traffic and particulate matter with coronary artery calcium Agatston score (CAC), an atherosclerosis correlate, has yielded inconsistent findings. Given this background, we assessed whether residential proximity to major roadway or fine particulate matter were associated with CAC in a Northeastern US study. Approach and Results We measured CAC 2 times from 2002 to 2005 and 2008 to 2011 among Framingham Offspring or Third-Generation Cohort participants. We assessed associations of residential distance to major roadway and residential fine particulate matter (2003 average; spatiotemporal model) with detectable CAC, using generalized estimating equation regression. We used linear mixed effects models to assess associations with log(e)(CAC). We also assessed associations with CAC progression. Models were adjusted for demographic variables, socioeconomic position markers, and time. Among 3399 participants, 51% had CAC measured twice. CAC was detectable in 47% of observations. At first scan, mean age was 52.2 years (standard deviation 11.7); 51% male. There were no consistent associations with detectable CAC, continuous CAC, or CAC progression. We observed heterogeneous associations of distance to major roadway with odds of detectable CAC by hypertensive status; interpretation of these findings is questionable. Conclusions Our findings add to prior work and support evidence against strong associations of traffic or fine particulate matter with the presence, extent, or progression of CAC in a region with relatively low levels of and little variation in fine particulate matter. C1 [Dorans, Kirsten S.; Wilker, Elissa H.; Li, Wenyuan; Schwartz, Joel; Mittleman, Murray A.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Wilker, Elissa H.; Schwartz, Joel; Koutrakis, Petros] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Coull, Brent A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dorans, Kirsten S.; Wilker, Elissa H.; Li, Wenyuan; Rice, Mary B.; Ljungman, Petter L.; Mittleman, Murray A.] Harvard Med Sch, Cardiovasc Epidemiol Res Unit, Dept Cardiol, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Rice, Mary B.] Harvard Med Sch, Div Pulm Crit Care & Sleep Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Hoffmann, Udo] Harvard Med Sch, Cardiac MR PET CT Program, Dept Radiol, Massachusetts Gen Hosp, Boston, MA USA. [O'Donnell, Christopher J.] Harvard Med Sch, Cardiovasc Med, Brigham & Womens Hosp, Boston, MA USA. [Ljungman, Petter L.] Karolinska Inst, Inst Environm Med, Environm Epidemiol Unit, Stockholm, Sweden. [Kloog, Itai] Ben Gurion Univ Negev, Dept Geog & Environm Dev, Beer Sheva, Israel. [D'Agostino, Ralph B., Sr.; Massaro, Joseph M.; O'Donnell, Christopher J.] NHLBI, Framingham, MA USA. [D'Agostino, Ralph B., Sr.; Massaro, Joseph M.; O'Donnell, Christopher J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [O'Donnell, Christopher J.] Boston Vet Adm Hlth Syst, Cardiol Sect, Dept Med, Boston, MA USA. RP Mittleman, MA (reprint author), Harvard TH Chan Sch Publ Hlth, 677 Huntington Ave,Suite 505, Boston, MA 02215 USA. EM mmittlem@hsph.harvard.edu OI Dorans, Kirsten/0000-0002-3182-5633 FU National Institutes of Health (NIH) [NHLBI T32 HL007575, NIEHS R00 ES022243, K23ES026204]; US Environmental Protection Agency [RD-83479801, RD-83587201]; NHLBI's Framingham Heart Study [HHSN268201500001I] FX This work was supported by the National Institutes of Health (NIH; NHLBI T32 HL007575; NIEHS R00 ES022243, K23ES026204). This publication was made possible by US Environmental Protection Agency grants RD-83479801 and RD-83587201. Its contents are solely the responsibility of the grantee and do not necessarily represent the official views of the US Environmental Protection Agency. Further, US Environmental Protection Agency does not endorse the purchase of any commercial products or services mentioned in the publication. From the Framingham Heart Study of the NHLBI of the NIH and Boston University School of Medicine; this work was supported by the NHLBI's Framingham Heart Study (Contract No. HHSN268201500001I). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the NHLBI, the NIH, or the US Department of Health and Human Services. NR 34 TC 3 Z9 3 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD AUG PY 2016 VL 36 IS 8 BP 1679 EP 1685 DI 10.1161/ATVBAHA.116.307141 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DT4TM UT WOS:000381474000025 PM 27312220 ER PT J AU Yamada, Y Schneider, JP AF Yamada, Yuji Schneider, Joel P. TI Fragmentation of Injectable Bioadhesive Hydrogels Affords Chemotherapeutic Macromolecules SO BIOMACROMOLECULES LA English DT Article ID DOXORUBICIN CONJUGATE; DELIVERY; NANOPARTICLES; DEXTRAN; PHARMACOKINETICS; THERAPEUTICS; CARRIER AB Implantation of drug delivery depots into or proximal to targeted tissue is an effective method to deliver anticancer drugs in a sustained localized manner. Herein, syringe-injectable polydextran aldehyde (PDA)-based bioadhesive gels are prepared that can locally deliver cytotoxins upon their hydrolytic fragmentation. Adhesive gels are formed by mixing doxorubicin (DOX)-functionalized PDA (DOXPDA) and bovine serum albumin (BSA) using a dual-barrel syringe. Upon mixing and delivery, the DOX-PDA reacts with the cross-linker BSA as well as the extracellular matrix via imine bond formation to define the cohesive and adhesive properties of the gel, respectively. Resulting gels are mechanically rigid (similar to 10 kPa) and adherent (adhesive stress similar to 4 kPa). Once formed, the DOX-PDA-BSA gels undergo slow hydrolytic degradation (>2 months) locally releasing free DOX and DOX-PDA as expected. Surprisingly, we found that macromolecules composed of DOX, PDA, and BSA are also released from the bulk material. These DOX-PDA-BSA macromolecules, along with free DOX and DOX-PDA conjugate, are internalized by A549 lung carcinoma cells, resulting in potent cell death. C1 [Yamada, Yuji; Schneider, Joel P.] NCI, Biol Chem Lab, NIH, Frederick, MD 21701 USA. RP Schneider, JP (reprint author), NCI, Biol Chem Lab, NIH, Frederick, MD 21701 USA. EM joel.schneider@nih.gov FU JSPS Fellowship for Japanese Biomedical and Behavioral Researcher at NIH (KAITOKU-NIH); Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This research was supported by a JSPS Fellowship for Japanese Biomedical and Behavioral Researcher at NIH (KAITOKU-NIH) and the Intramural Research Program of the National Cancer Institute, National Institutes of Health. We thank Dr. Michael Giano for collecting the fibrin glue maximal adhesive stress data. NR 20 TC 0 Z9 0 U1 18 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1525-7797 EI 1526-4602 J9 BIOMACROMOLECULES JI Biomacromolecules PD AUG PY 2016 VL 17 IS 8 BP 2634 EP 2641 DI 10.1021/acs.biomac.6b00701 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Organic; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA DT1HF UT WOS:000381231600014 PM 27388026 ER PT J AU Fink, BC Steele, VR Maurer, MJ Fede, SJ Calhoun, VD Kiehl, KA AF Fink, Brandi C. Steele, Vaughn R. Maurer, Michael J. Fede, Samantha J. Calhoun, Vince D. Kiehl, Kent A. TI Brain potentials predict substance abuse treatment completion in a prison sample SO BRAIN AND BEHAVIOR LA English DT Article DE Event-related potentials; pattern classifier; principal component analysis; prison inmate; substance abuse treatment; support vector machine ID FOLLOW-UP OUTCOMES; WORKING-MEMORY; DRUG-ABUSE; DEPENDENT INDIVIDUALS; PATTERN-RECOGNITION; P300 DECREMENTS; TASK; COMPONENT; COCAINE; RESPONSES AB IntroductionNational estimates suggest that up to 80% of prison inmates meet diagnostic criteria for a substance use disorder. Because more substance abuse treatment while incarcerated is associated with better post-release outcomes, including a reduced risk of accidental overdose death, the stakes are high in developing novel predictors of substance abuse treatment completion in inmate populations. MethodsUsing electroencephalography (EEG), this study investigated stimulus-locked ERP components elicited by distractor stimuli in three tasks (VO-Distinct, VO-Repeated, Go/NoGo) as a predictor of treatment discontinuation in a sample of male and female prison inmates. We predicted that those who discontinued treatment early would exhibit a less positive P3a amplitude elicited by distractor stimuli. ResultsOur predictions regarding ERP components were partially supported. Those who discontinued treatment early exhibited a less positive P3a amplitude and a less positive PC4 in the VO-D task. In the VO-R task, however, those who discontinued treatment early exhibited a more negative N200 amplitude rather than the hypothesized less positive P3a amplitude. The discontinuation group also displayed less positive PC4 amplitude. Surprisingly, there were no time-domain or principle component differences among the groups in the Go/NoGo task. Support Vector Machine (SVM) models of the three tasks accurately classified individuals who discontinued treatment with the best model accurately classifying 75% of inmates. PCA techniques were more sensitive in differentiating groups than the classic time-domain windowed approach. ConclusionsOur pattern of findings are consistent with the context-updating theory of P300 and may help identify subtypes of ultrahigh-risk substance abusers who need specialized treatment programs. C1 [Fink, Brandi C.] Univ New Mexico, Clin & Translat Sci Ctr, Dept Psychiat & Behav Sci, Albuquerque, NM 87131 USA. [Steele, Vaughn R.] NIDA, Intramural Res Program, Neuroimaging Res Branch, NIH, Baltimore, MD USA. [Steele, Vaughn R.; Maurer, Michael J.; Fede, Samantha J.; Calhoun, Vince D.; Kiehl, Kent A.] Mind Res Network & Lovelace Biomed & Environm Res, Albuquerque, NM USA. [Steele, Vaughn R.; Maurer, Michael J.; Fede, Samantha J.; Kiehl, Kent A.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. RP Fink, BC (reprint author), Univ New Mexico, Dept Psychiat & Behav Sci, MSC 09 5030, Albuquerque, NM 87131 USA. EM bcfink@unm.edu FU National Institute on Alcohol Abuse and Alcoholism [R21 AA022367]; National Center for Advancing Translational Sciences [KL2 TR001448, UL1 TR001449]; Intramural Research Program of the National Institute on Drug Abuse, National Institute on Drug Abuse [R01 DA020870-01] FX National Institute on Alcohol Abuse and Alcoholism (Grant/Award Number: R21 AA022367), National Center for Advancing Translational Sciences (Grant/Award Number: KL2 TR001448, UL1 TR001449), Intramural Research Program of the National Institute on Drug Abuse, National Institute on Drug Abuse (Grant/Award Number: R01 DA020870-01). NR 52 TC 0 Z9 0 U1 3 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2162-3279 J9 BRAIN BEHAV JI Brain Behav. PD AUG PY 2016 VL 6 IS 8 AR e00501 DI 10.1002/brb3.501 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DV1JK UT WOS:000382676900013 PM 27547503 ER PT J AU Sheng, Y Filichia, E Shick, E Preston, KL Phillips, KA Cooperman, L Lin, ZC Tesar, P Hoffer, B Luo, Y AF Sheng, Yang Filichia, Emily Shick, Elizabeth Preston, Kenzie L. Phillips, Karran A. Cooperman, Leslie Lin, Zhicheng Tesar, Paul Hoffer, Barry Luo, Yu TI Using iPSC-derived human DA neurons from opioid-dependent subjects to study dopamine dynamics SO BRAIN AND BEHAVIOR LA English DT Article DE 3 VNTR; hDAT gene; iPSCs; opioid dependent ID PLURIPOTENT STEM-CELLS; VENTRAL TEGMENTAL AREA; TRANSPORTER GENE DAT1; VALPROIC ACID; PARKINSONS-DISEASE; MAINTENANCE TREATMENT; RECEPTOR EXPRESSION; HUNTINGTONS-DISEASE; SUBSTANTIA-NIGRA; CLINICAL-TRIAL AB IntroductionThe dopaminergic (DA) system plays important roles in addiction. However, human DA neurons from drug-dependent subjects were not available for study until recent development in inducible pluripotent stem cells (iPSCs) technology. MethodsIn this study, we produced DA neurons differentiated using iPSCs derived from opioid-dependent and control subjects carrying different 3 VNTR (variable number tandem repeat) polymorphism in the human dopamine transporter (DAT or SLC6A3). In addition, the effects of valproic acid (VPA) exposures on iPSC-derived human DA neurons are also examined. ResultsWe present the first evidence suggesting that the 3 VNTR polymorphism in the hDAT gene affects DAT expression level in iPSC-derived human DA neurons. In human DA neurons, which provide an appropriate cellular milieu, VPA treatment alters the expression of several genes important for dopaminergic neuron function including DAT, Nurr1, and TH; this might partly explain its action in regulating addictive behaviors. VPA treatment also significantly increased DA D2 receptor (Drd2) expression, especially in the opioid-dependent iPSC cell lines. ConclusionsOur data suggest that human iPSC-derived DA neurons may be useful in invitro experimental model to examine the effects of genetic variation in gene regulation, to examine the underlying mechanisms in neurological disorders including drug addiction, and to serve as a platform for therapeutic development. C1 [Sheng, Yang; Filichia, Emily; Hoffer, Barry; Luo, Yu] Case Western Reserve Univ, Dept Neurol Surg, Cleveland, OH 44106 USA. [Shick, Elizabeth; Cooperman, Leslie; Tesar, Paul] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. [Preston, Kenzie L.; Phillips, Karran A.] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Lin, Zhicheng] Harvard Univ, McLean Hosp, Dept Psychiat, Belmont, MA 02478 USA. RP Luo, Y (reprint author), Case Western Reserve Univ, Dept Neurol Surg, Cleveland, OH 44106 USA. EM yxl710@case.edu FU NIH, NIDA [R21DA032962, R01DA021409]; National Institute on Drug Abuse, National Institutes of Health FX This study was supported by NIH, NIDA (R21DA032962, R01DA021409) and by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 61 TC 0 Z9 0 U1 3 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2162-3279 J9 BRAIN BEHAV JI Brain Behav. PD AUG PY 2016 VL 6 IS 8 AR e00491 DI 10.1002/brb3.491 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DV1JK UT WOS:000382676900006 PM 27547496 ER PT J AU Parekh, PR Choudhuri, R Weyemi, U Martin, OA Bonner, WM Redon, CE AF Parekh, Palak R. Choudhuri, Rohini Weyemi, Urbain Martin, Olga A. Bonner, William M. Redon, Christophe E. TI Evaluation of surrogate tissues as indicators of drug activity in a melanoma skin model SO CANCER MEDICINE LA English DT Article DE Apoptosis; drug response; melanoma tissue model; surrogate tissue; H2 AX ID PHASE-II TRIAL; ONCOLOGY CLINICAL-TRIALS; HUMAN PROSTATE TISSUE; DOUBLE-STRAND BREAKS; DNA-DAMAGE; INHIBITOR SELUMETINIB; H2AX PHOSPHORYLATION; COMBINATION THERAPY; GAMMA-H2AX ASSAY; RANDOMIZED-TRIAL AB The development of novel cancer treatments is a challenging task, partly because results from model systems often fail to predict drug efficacy in humans, and also tumors are often inaccessible for biochemical analysis, preventing effective monitoring of drug activity in vivo. Utilizing a model system, we evaluated the use of drug-induced DNA damage in surrogate tissues as indicators of drug efficacy. Samples of a commercially available melanoma skin model (Mattek MLNM-FT-A375) containing keratinocyte and fibroblast layers with melanoma nodules were subjected to various chemotherapeutic regimens for one, four, or eight days. At these times they were analyzed for DNA double-stranded breaks (H2AX foci) and apoptosis (TUNEL). A wide range of drug responses in both tumor and normal tissues were observed and cataloged. For the melanoma, the most common drug response was apoptosis. The basal keratinocyte layer, which was the most reliable indicator of drug response in the melanoma skin model, responded with H2AX foci formation that was abrupt and transient. The relationships between tumor and surrogate tissue drug responses are complex, indicating that while surrogate tissue drug responses may be useful clinical tools, careful control of variables such as the timing of sampling may be important in interpreting the results. C1 [Parekh, Palak R.] Univ Maryland, Sch Med, Dept Radiat Oncol, Greenbaum Canc Ctr, 655 W Baltimore St,Bressler Res Bldg,Rm 10-010, Baltimore, MD 21201 USA. [Parekh, Palak R.; Choudhuri, Rohini; Weyemi, Urbain; Martin, Olga A.; Bonner, William M.; Redon, Christophe E.] NCI, Genom Integr Grp, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Choudhuri, Rohini] Univ Maryland, College Pk, MD 20742 USA. [Martin, Olga A.] Univ Melbourne, Div Radiat Oncol, Melbourne, Vic, Australia. [Martin, Olga A.] Univ Melbourne, Peter MacCallum Canc Ctr, Canc Imaging & Mol Radiat Biol Lab, Melbourne, Vic, Australia. [Martin, Olga A.] Univ Melbourne, Dept Oncol, Melbourne, Vic, Australia. RP Parekh, PR (reprint author), Univ Maryland, Sch Med, Dept Radiat Oncol, Greenbaum Canc Ctr, 655 W Baltimore St,Bressler Res Bldg,Rm 10-010, Baltimore, MD 21201 USA. EM pparekh@som.umaryland.edu FU Intramural Research Program of the National Cancer Institute; Center for Cancer Research; National Institutes of Health FX This work was funded by the Intramural Research Program of the National Cancer Institute, the Center for Cancer Research, the National Institutes of Health. NR 42 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD AUG PY 2016 VL 5 IS 8 BP 1731 EP 1741 DI 10.1002/cam4.726 PG 11 WC Oncology SC Oncology GA DS6XM UT WOS:000380926600002 PM 27339860 ER PT J AU Shea, A Harish, V Afzal, Z Chijioke, J Kedir, H Dusmatova, S Roy, A Ramalinga, M Harris, B Blancato, J Verma, M Kumar, D AF Shea, Amanda Harish, Varsha Afzal, Zainab Chijioke, Juliet Kedir, Habib Dusmatova, Shahnoza Roy, Arpita Ramalinga, Malathi Harris, Brent Blancato, Jan Verma, Mukesh Kumar, Deepak TI MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics SO CANCER MEDICINE LA English DT Review DE cancer therapy; microRNA; glioblastoma multiforme ID GLIOMA STEM-CELLS; GROWTH-FACTOR RECEPTOR; OLIGONUCLEOTIDE ENHANCES CHEMOSENSITIVITY; EPITHELIAL-MESENCHYMAL TRANSITION; PROMOTES TUMOR-GROWTH; BLOOD-BRAIN-BARRIER; HIGH-GRADE GLIOMA; DOWN-REGULATION; IN-VITRO; UP-REGULATION AB Glioblastoma multiforme (GBM) is the most common and lethal cancer of the adult brain, remaining incurable with a median survival time of only 15months. In an effort to identify new targets for GBM diagnostics and therapeutics, recent studies have focused on molecular phenotyping of GBM subtypes. This has resulted in mounting interest in microRNAs (miRNAs) due to their regulatory capacities in both normal development and in pathological conditions such as cancer. miRNAs have a wide range of targets, allowing them to modulate many pathways critical to cancer progression, including proliferation, cell death, metastasis, angiogenesis, and drug resistance. This review explores our current understanding of miRNAs that are differentially modulated and pathologically involved in GBM as well as the current state of miRNA-based therapeutics. As the role of miRNAs in GBM becomes more well understood and novel delivery methods are developed and optimized, miRNA-based therapies could provide a critical step forward in cancer treatment. C1 [Shea, Amanda; Afzal, Zainab; Chijioke, Juliet; Kedir, Habib; Dusmatova, Shahnoza; Roy, Arpita; Ramalinga, Malathi; Kumar, Deepak] Univ Dist Columbia, Canc Res Lab, Div Sci & Math, 4200 Connecticut Ave NW, Washington, DC 20008 USA. [Harish, Varsha] Groton Sch, Groton, MA 01450 USA. [Harris, Brent] Georgetown Univ, Dept Neurol & Pathol, Washington, DC 20057 USA. [Blancato, Jan; Kumar, Deepak] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Verma, Mukesh] NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD 20850 USA. RP Kumar, D (reprint author), Univ Dist Columbia, Canc Res Lab, Div Sci & Math, 4200 Connecticut Ave NW, Washington, DC 20008 USA. EM dkumar@udc.edu FU National Cancer Institute [CA141935, CA162264, CA194730] FX This work was supported by National Cancer Institute CA141935, CA162264, CA194730. NR 334 TC 4 Z9 5 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD AUG PY 2016 VL 5 IS 8 BP 1917 EP 1946 DI 10.1002/cam4.775 PG 30 WC Oncology SC Oncology GA DS6XM UT WOS:000380926600022 PM 27282910 ER PT J AU Mafolasire, A Yao, XP Nawaf, C Suarez-Sarmiento, A Chow, WH Zhao, W Corley, D Hofmann, JN Purdue, M Adeniran, AJ Shuch, B AF Mafolasire, Abiodun Yao, Xiaopan Nawaf, Cayce Suarez-Sarmiento, Alfredo Chow, Wong-Ho Zhao, Wei Corley, Douglas Hofmann, Jonathan N. Purdue, Mark Adeniran, Adebowale J. Shuch, Brian TI Racial disparities in renal cell carcinoma: a single-payer healthcare experience SO CANCER MEDICINE LA English DT Article DE Health disparity; kidney cancer; outcome; RCC; survival ID AFRICAN-AMERICANS; KIDNEY CANCER; SOCIOECONOMIC-STATUS; HISTOLOGIC SUBTYPE; WHITE PATIENTS; RISK-FACTORS; SURVIVAL; HYPERTENSION; RACE; NEPHRECTOMY AB Significant racial disparities in survival for renal cell carcinoma (RCC) exist between white and black patients. Differences in access to care and comorbidities are possible contributors. To investigate if racial disparities persist when controlling for access to care, we analyzed data from a single-payer healthcare system. As part of a case-control study within the Kaiser Permanente Northern California system, pathologic and clinical records were obtained for RCC cases (2152 white, 293 black) diagnosed from 1998 to 2008. Patient demographics, comorbidities, tumor characteristics, and treatment status were compared. Overall survival and disease-specific survival (DSS) were calculated by the Kaplan-Meier method. A Cox proportion hazards model estimated the independent associations of race, comorbidity, and clinicopathologic variables with DSS. We found that compared to white patients, black patients were diagnosed at a younger age (median 62 vs. 66years, P<0.001), were more likely to have papillary RCC (15% vs. 5.2%, P<0.001), and had similar rates of surgical treatment (78.8% vs. 77.9%, P=0.764). On multivariate analysis, advanced American Joint Committee on Cancer (AJCC) stage, lack of surgical treatment, larger tumor size, and higher grade were predictors of worse DSS. Race was not an independent predictor of survival. Therefore, we conclude that within a single healthcare system, differences in characteristics of black and white patients with RCC persist; black patients had different comorbidities, were younger, and had decreased tumor stage. However, unlike other series, race was not an independent predictor of DSS, suggesting that survival differences in large registries may result from barriers to healthcare access and/or comorbidity rather than disease biology. C1 [Mafolasire, Abiodun; Nawaf, Cayce; Suarez-Sarmiento, Alfredo; Shuch, Brian] Yale Sch Med, Dept Urol, POB 208058, New Haven, CT 06520 USA. [Yao, Xiaopan] Yale Sch Med, Yale Ctr Analyt Sci, New Haven, CT USA. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Zhao, Wei; Corley, Douglas] Kaiser Permanente San Francisco Med Ctr, Kaiser Permanente Div Res, San Francisco, CA USA. [Hofmann, Jonathan N.; Purdue, Mark] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Adeniran, Adebowale J.] Yale Univ, Yale Sch Med, Dept Pathol, New Heaven, CT USA. RP Shuch, B (reprint author), Yale Sch Med, Dept Urol, POB 208058, New Haven, CT 06520 USA. EM Brian.shuch@yale.edu FU National Institutes of Health; NCI CTSA [KL2 TR000140]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics FX This research was supported by the National Institutes of Health, NCI CTSA Grant KL2 TR000140 (BS). This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics (MPP, JNH). NR 29 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD AUG PY 2016 VL 5 IS 8 BP 2101 EP 2108 DI 10.1002/cam4.755 PG 8 WC Oncology SC Oncology GA DS6XM UT WOS:000380926600039 PM 27228559 ER PT J AU Ardeljan, D Taylor, MS Burns, KH Boeke, JD Espey, MG Woodhouse, EC Howcroft, TK AF Ardeljan, Daniel Taylor, Martin S. Burns, Kathleen H. Boeke, Jef D. Espey, Michael Graham Woodhouse, Elisa C. Howcroft, Thomas Kevin TI Meeting Report: The Role of the Mobilome in Cancer SO CANCER RESEARCH LA English DT Editorial Material ID SOMATIC L1 RETROTRANSPOSITION; TRANSPOSABLE ELEMENTS; HUMAN BRAIN; EXPRESSION; MUTAGENESIS; DROSOPHILA; MOSAICISM; EVOLUTION; CARCINOMA; GENOMES AB Approximately half of the human genome consists of repetitive sequence attributed to the activities of mobile DNAs, including DNA transposons, RNA transposons, and endogenous retroviruses. Of these, only long interspersed elements (LINE-1 or L1) and sequences copied by LINE-1 remain mobile in our species today. Although cells restrict L1 activity by both transcriptional and posttranscriptional mechanisms, L1 derepression occurs in developmental and pathologic contexts, including many types of cancers. However, we have limited knowledge of the extent and consequences of L1 expression in premalignancies and cancer. Participants in this NIH strategic workshop considered key questions to enhance our understanding of mechanisms and roles the mobilome may play in cancer biology. (C) 2016 AACR. C1 [Ardeljan, Daniel; Burns, Kathleen H.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Ardeljan, Daniel] Johns Hopkins Univ, Sch Med, Med Scientist Training Program, Baltimore, MD USA. [Taylor, Martin S.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Burns, Kathleen H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Boeke, Jef D.] NYU, Langone Med Ctr, Inst Syst Genet, New York, NY USA. [Espey, Michael Graham; Woodhouse, Elisa C.; Howcroft, Thomas Kevin] NCI, Div Canc Biol, NIH, Rockville, MD USA. RP Woodhouse, EC (reprint author), NCI, Tumor Biol & Metastasis Branch, 9609 Med Ctr Dr,Room 6W416, Bethesda, MD 20892 USA. EM woodhousee@mail.nih.gov OI Taylor, Martin/0000-0001-5824-142X FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [R01 CA163705]; NIGMS NIH HHS [T32 GM007309, P50 GM107632] NR 29 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2016 VL 76 IS 15 BP 4316 EP 4319 DI 10.1158/0008-5472.CAN-15-3421 PG 4 WC Oncology SC Oncology GA DU6AO UT WOS:000382295300004 PM 27527733 ER PT J AU Richmond, J Robbins, A Evans, K Beck, D Kurmasheva, RT Billups, CA Carol, H Heatley, S Sutton, R Marshall, GM White, D Pimanda, J Houghton, PJ Smith, MA Lock, RB AF Richmond, Jennifer Robbins, Alissa Evans, Kathryn Beck, Dominik Kurmasheva, Raushan T. Billups, Catherine A. Carol, Hernan Heatley, Sue Sutton, Rosemary Marshall, Glenn M. White, Deborah Pimanda, John Houghton, Peter J. Smith, Malcolm A. Lock, Richard B. TI Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant SO CANCER RESEARCH LA English DT Article ID PRECLINICAL TESTING PROGRAM; ALPHA-DEPENDENT APOPTOSIS; IN-VIVO EFFICACY; T-CELL; XENOGRAFT MODELS; IAP PROTEINS; CANCER-CELLS; SOLID TUMORS; CHILDHOOD; EXPRESSION AB Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis, and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNF alpha/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of an induction-type regimen of vincristine, dexamethasone, and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment. (C) 2016 AACR. C1 [Richmond, Jennifer; Robbins, Alissa; Evans, Kathryn; Carol, Hernan; Sutton, Rosemary; Lock, Richard B.] Univ New South Wales Australia, Childrens Canc Inst, Lowy Canc Res Ctr, Sydney, NSW, Australia. [Beck, Dominik; Pimanda, John] Univ New South Wales Australia, Lowy Canc Res Ctr, Sydney, NSW, Australia. [Kurmasheva, Raushan T.; Houghton, Peter J.] Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA. [Billups, Catherine A.] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Heatley, Sue; White, Deborah] South Australia Hlth & Med Res Inst, Adelaide, SA, Australia. [Marshall, Glenn M.] Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW, Australia. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Lock, RB (reprint author), Childrens Canc Inst, POB 81, Sydney, NSW 2031, Australia. EM RLock@ccia.org.au RI Lock, Richard/G-4253-2013; OI White, Deborah/0000-0003-4844-333X FU NCI NIH HHS [N01CM42216] NR 52 TC 1 Z9 1 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2016 VL 76 IS 15 BP 4579 EP 4591 DI 10.1158/0008-5472.CAN-16-0523 PG 13 WC Oncology SC Oncology GA DU6AO UT WOS:000382295300027 PM 27302164 ER PT J AU Altan-Bonnet, N AF Altan-Bonnet, Nihal TI Extracellular vesicles are the Trojan horses of viral infection SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID HEPATITIS-C VIRUS; UNCONVENTIONAL SECRETION; CELLS; AUTOPHAGY; TRANSMISSION; EXOSOMES; PROTEIN; MEMBRANES; RNA AB Extracellular vesicles have recently emerged as a novel mode of viral propagation exploited by both enveloped and non enveloped viruses. In particular non-enveloped viruses utilize the hosts' production of extracellular vesicles to exit from cells non-lytically and to hide and manipulate the immune system. Moreover, challenging the long held idea that viruses behave as independent genetic units, extracellular vesicles enable multiple viral particles and genomes to collectively traffic in and out of cells, which can promote genetic cooperativity among viral quasispecies and enhance the fitness of the overall viral population. C1 [Altan-Bonnet, Nihal] NHLBI, Lab Host Pathogen Dynam, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Altan-Bonnet, N (reprint author), NHLBI, Lab Host Pathogen Dynam, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM nihal.altan-bonnet@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 41 TC 2 Z9 2 U1 5 U2 5 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 EI 1879-0364 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD AUG PY 2016 VL 32 BP 77 EP 81 DI 10.1016/j.mib.2016.05.004 PG 5 WC Microbiology SC Microbiology GA DU6SK UT WOS:000382344700016 PM 27232382 ER PT J AU Long, CA Zavala, F AF Long, Carole A. Zavala, Fidel TI Malaria vaccines and human immune responses SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID PLASMODIUM-FALCIPARUM MALARIA; EFFECTOR MECHANISMS; PROTECTIVE EFFICACY; ACQUIRED-IMMUNITY; VIVAX MALARIA; IMMUNIZATION; TRANSMISSION; SPOROZOITES; ANTIGENS; ANTIBODIES AB Despite reductions in malaria episodes and deaths over the past decade, there is still significant need for more effective tools to combat this serious global disease. The positive results with the Phase III trial of RTS,S directed to the circumsporozoite protein of Plasmodium falciparum have established that a vaccine against malaria can provide partial protection to children in endemic areas, but its limited efficacy and relatively short window of protection mandate that new generations of more efficacious vaccines must be sought. Evidence shows that anti parasite immune responses can control infection against other stages as well, but translating these experimental findings into vaccines for blood stages has been disappointing and clinical efforts to test a transmission blocking vaccine are just beginning. Difficulties include the biological complexity of the organism with a large array of stage-specific genes many of which in the erythrocytic stages are antigenically diverse. In addition, it appears necessary to elicit high and long-lasting antibody titers, address the redundant pathways of merozoite invasion, and still seek surrogate markers of protective immunity. Most vaccine studies have focused on a single or a few antigens with an apparent functional role, but this is likely to be too restrictive, and broad, multi-antigen, multi-stage vaccines need further investigation. Finally, novel tools and biological insights involving parasite sexual stages and the mosquito vector will provide new avenues for reducing or blocking malaria transmission. C1 [Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. [Zavala, Fidel] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Malaria Res Inst, 615 N Wolfe St, Baltimore, MD 21205 USA. RP Long, CA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM clong@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This review was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health to CAL, and F.Z. thanks the Bloomberg Family Foundation and PATH-MVI for continued support. NR 49 TC 2 Z9 2 U1 17 U2 20 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 EI 1879-0364 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD AUG PY 2016 VL 32 BP 96 EP 102 DI 10.1016/j.mib.2016.04.006 PG 7 WC Microbiology SC Microbiology GA DU6SK UT WOS:000382344700019 PM 27262417 ER PT J AU De Buck, M Gouwy, M Wang, JM Van Snick, J Proost, P Struyf, S Van Damme, J AF De Buck, Mieke Gouwy, Mieke Wang, Ji Ming Van Snick, Jacques Proost, Paul Struyf, Sofie Van Damme, Jo TI The cytokine-serum amyloid A-chemokine network SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE SAA; FPR2; Chemotaxis; Cytokines; TLR2 ID NECROSIS-FACTOR-ALPHA; C-REACTIVE PROTEIN; NF-KAPPA-B; ACUTE-PHASE RESPONSE; MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; ENDOTHELIAL-CELL INTERACTIONS; SIGNAL-TRANSDUCTION PATHWAY; INTESTINAL EPITHELIAL-CELLS; MESSENGER-RNA EXPRESSION; HIGH-DENSITY-LIPOPROTEIN AB Levels of serum amyloid A (SAA), a major acute phase protein in humans, are increased up to 1000-fold upon infection, trauma, cancer or other inflammatory events. However, the exact role of SAA in host defense is yet not fully understood. Several pro- and anti-inflammatory properties have been ascribed to SAA. Here, the regulated production of SAA by cytokines and glucocorticoids is discussed first. Secondly, the cytokine and chemokine inducing capacity of SAA and its receptor usage are reviewed. Thirdly, the direct (via FPR2) and indirect (via TLR2) chemotactic effects of SAA and its synergy with chemokines are unraveled. Altogether, a complex cytokine-SAA-chemokine network is established, in which SAA plays a key role in regulating "the inflammatory response. (C) 2015 Elsevier Ltd. All rights reserved. C1 [De Buck, Mieke; Gouwy, Mieke; Proost, Paul; Struyf, Sofie; Van Damme, Jo] Univ Leuven, KU Leuven, Dept Microbiol & Immunol, Rega Inst Med Res,Lab Mol Immunol, Minderbroedersstr 10, B-3000 Leuven, Belgium. [Wang, Ji Ming] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Van Snick, Jacques] Brussels Branch, Ludwig Canc Res, Brussels, Belgium. [Van Snick, Jacques] Catholic Univ Louvain, de Duve Inst, Brussels, Belgium. RP Van Damme, J (reprint author), Univ Leuven, KU Leuven, Dept Microbiol & Immunol, Rega Inst Med Res,Lab Mol Immunol, Minderbroedersstr 10, B-3000 Leuven, Belgium. EM mieke.debuck@rega.kuleuven.be; mieke.gouwy@rega.kuleuven.be; wangji@mail.nih.gov; jacques.vansnick@bru.licr.org; paul.proost@rega.kuleuven.be; sofie.struyf@rega.kuleuven.be; jo.vandamme@rega.kuleuven.be OI Struyf, Sofie/0000-0003-4558-0769 FU Fund for Scientific Research of Flanders (F.W.O.-Vlaanderen); Interuniversity Attraction Poles Program; Belgian Science Policy Office (I.A.P. project) [P7/40]; Concerted Research Actions (G.O.A.) of the Regional Government of Flanders [2013/015] FX The authors would like to thank the Fund for Scientific Research of Flanders (F.W.O.-Vlaanderen), the Interuniversity Attraction Poles Program initiated by the Belgian Science Policy Office (I.A.P. project P7/40) and the Concerted Research Actions (G.O.A., 2013/015) of the Regional Government of Flanders for financial support. The stimulatory discussions with Prof. G. Opdenakker and Prof. P. Matthys are much appreciated. NR 142 TC 3 Z9 3 U1 6 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 EI 1879-0305 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD AUG PY 2016 VL 30 SI SI BP 55 EP 69 DI 10.1016/j.cytogfr.2015.12.010 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DU7QL UT WOS:000382409600006 PM 26794452 ER PT J AU Welsh, KJ Kirkman, MS Sacks, DB AF Welsh, Kerry J. Kirkman, M. Sue Sacks, David B. TI Role of Glycated Proteins in the Diagnosis and Management of Diabetes: Research Gaps and Future Directions SO DIABETES CARE LA English DT Article ID SERUM FRUCTOSAMINE CONCENTRATION; HEMOGLOBIN A(1C) MEASUREMENT; BLOOD-GLUCOSE CONTROL; ET-AL. SRAGE; END-PRODUCTS; CARDIOVASCULAR-DISEASE; MICROVASCULAR COMPLICATIONS; SKIN AUTOFLUORESCENCE; CLINICAL-USEFULNESS; FOLLOW-UP C1 [Welsh, Kerry J.; Sacks, David B.] NIH, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. [Kirkman, M. Sue] Univ N Carolina, Dept Med, Chapel Hill, NC USA. RP Sacks, DB (reprint author), NIH, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. EM sacksdb@mail.nih.gov FU National Institutes of Health Clinical Center Intramural Program FX Work in the laboratory of D.B.S. is supported by the National Institutes of Health Clinical Center Intramural Program. NR 96 TC 7 Z9 7 U1 9 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2016 VL 39 IS 8 BP 1299 EP 1306 DI 10.2337/dc15-2727 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT4CN UT WOS:000381427800020 PM 27457632 ER PT J AU Wing, RR Espeland, MA Clark, JM Hazuda, HP Knowler, WC Pownall, HJ Unick, J Wadden, T Wagenknecht, L AF Wing, Rena R. Espeland, Mark A. Clark, Jeanne M. Hazuda, Helen P. Knowler, William C. Pownall, Henry J. Unick, Jessica Wadden, Thomas Wagenknecht, Lynne CA Action Hlth Diabet Look AHEAD TI Association of Weight Loss Maintenance and Weight Regain on 4-Year Changes in CVD Risk Factors: the Action for Health in Diabetes (Look AHEAD) Clinical Trial SO DIABETES CARE LA English DT Article ID LIFE-STYLE INTERVENTION; BODY-WEIGHT; CARDIOVASCULAR-DISEASE; MORTALITY; MEN; INDIVIDUALS; FLUCTUATION; POPULATION; OVERWEIGHT; PREVENTION AB OBJECTIVEShort-term weight loss improves cardiovascular disease (CVD) risk factors. We sought to determine the longer-term effects of maintaining weight loss or, conversely, regaining weight.RESEARCH DESIGN AND METHODSWe used data from Action for Health in Diabetes (Look AHEAD), a randomized trial of intensive lifestyle intervention (ILI) compared to a control condition in overweight/obese individuals with type 2 diabetes. ILI participants were grouped according to weight change patterns, as follows: 1) no weight loss (3% at years 1 and 4); 2) moderate weight loss (3-8% at years 1 and 4); 3) large weight loss (8-20% at years 1 and 4); 4) moderate loss/full regain (3-8% at year 1/3% at year 4); 5) large loss/full regain (8-20% at year 1/+/- 3% year 4); and 6) large loss/partial regain (8-20% at year 1/3-8% at year 4) and changes in CVD risk factors were compared.RESULTSAdjusting for baseline differences and medication use, larger weight losses produced greater improvements in HbA(1c), systolic blood pressure, HDL cholesterol, and triglycerides at years 1 and 4 (all P 0.02). Despite maintenance of weight loss, HbA(1c) levels worsened between years 1 and 4, and remained below baseline only in those with large weight losses. We found no negative associations of losing and regaining weight relative to not having lost weight. Moreover, those who had large initial weight loss but full regain of weight had greater improvements in HbA(1c) levels at year 4 than those with smaller or no initial weight loss.CONCLUSIONSLarger initial weight loss should be encouraged in individuals with type 2 diabetes, despite the possibility of regain. C1 [Wing, Rena R.; Unick, Jessica] Miriam Hosp, Providence, RI 02906 USA. [Espeland, Mark A.; Wagenknecht, Lynne] Wake Forest Sch Med, Winston Salem, NC USA. [Clark, Jeanne M.] Johns Hopkins Univ, Baltimore, MD USA. [Hazuda, Helen P.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Knowler, William C.] NIDDK, Phoenix, AZ USA. [Pownall, Henry J.] Methodist Hosp, Res Inst, 6535 Fannin, Houston, TX 77030 USA. [Wadden, Thomas] Univ Penn, Philadelphia, PA 19104 USA. RP Wing, RR (reprint author), Miriam Hosp, Providence, RI 02906 USA. EM rwing@lifespan.org FU Department of Health and Human Services through the following cooperative agreements with the National Institutes of Health [DK-57136, DK-57149, DK-56990, DK-57177, DK-57171, DK-57151, DK-57182, DK-57131, DK-57002, DK-57078, DK-57154, DK-57178, DK-57219, DK-57008, DK-57135, DK-56992]; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; Office of Research on Women's Health; Centers for Disease Control and Prevention; Department of Veterans Affairs; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Johns Hopkins Medical Institutions Bayview General Clinical Research Center [M01-RR-02719]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center and the Massachusetts Institute of Technology General Clinical Research Center [M01-RR-01066]; University of Colorado Health Sciences Center General Clinical Research Center [M01-RR-00051]; Clinical Nutrition Research Unit [P30-DK-48520]; University of Tennessee at Memphis General Clinical Research Center [M01-RR-0021140]; University of Pittsburgh General Clinical Research Center [M01-RR-000056]; Clinical and Translational Science Award [UL1 RR 024153]; National Institutes of Health [DK-046204]; Frederic C. Bartter General Clinical Research Center [M01-RR-01346] FX This study is supported by the Department of Health and Human Services through the following cooperative agreements with the National Institutes of Health: DK-57136, DK-57149, DK-56990, DK-57177, DK-57171, DK-57151, DK-57182, DK-57131, DK-57002, DK-57078, DK-57154, DK-57178, DK-57219, DK-57008, DK-57135, and DK-56992. The following federal agencies have contributed support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; Office of Research on Women's Health; the Centers for Disease Control and Prevention; and the Department of Veterans Affairs. This research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The Indian Health Service provided personnel, medical oversight, and use of facilities. Additional support was received from The Johns Hopkins Medical Institutions Bayview General Clinical Research Center (grant M01-RR-02719), the Massachusetts General Hospital Mallinckrodt General Clinical Research Center and the Massachusetts Institute of Technology General Clinical Research Center (grant M01-RR-01066), the University of Colorado Health Sciences Center General Clinical Research Center (grant M01-RR-00051) and Clinical Nutrition Research Unit (P30-DK-48520), the University of Tennessee at Memphis General Clinical Research Center (M01-RR-0021140), the University of Pittsburgh General Clinical Research Center (M01-RR-000056), the Clinical Translational Research Center funded by a Clinical and Translational Science Award (UL1 RR 024153), a National Institutes of Health grant (DK-046204), and a Frederic C. Bartter General Clinical Research Center grant (M01-RR-01346). The following organizations have committed to make major contributions to the Look AHEAD Study: FedEx Corporation; Health Management Resources; LifeScan, Inc., a Johnson & Johnson Company; OPTIFAST of Nestle HealthCare Nutrition, Inc.; Hoffmann-La Roche Inc.; Abbott Nutrition; and Slim-Fast Brand of Unilever North America. NR 29 TC 1 Z9 1 U1 6 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2016 VL 39 IS 8 BP 1345 EP 1355 DI 10.2337/dc16-0509 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT4CN UT WOS:000381427800027 ER PT J AU Robinson, C Cochran, E Gorden, P Brown, RJ AF Robinson, Cemre Cochran, Elaine Gorden, Phillip Brown, Rebecca J. TI Management of Diabetic Ketoacidosis in Severe Insulin Resistance SO DIABETES CARE LA English DT Letter C1 [Robinson, Cemre] Natl Inst Dent & Craniofacial Res, Sect Skeletal Dis & Mineral Homeostasis, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Robinson, Cemre] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Cochran, Elaine; Gorden, Phillip; Brown, Rebecca J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Brown, RJ (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM brownrebecca@niddk.nih.gov NR 5 TC 0 Z9 0 U1 1 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2016 VL 39 IS 8 BP E116 EP E118 DI 10.2337/dc16-0635 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT4CN UT WOS:000381427800006 PM 27271188 ER PT J AU Lee-Winn, AE Reinblatt, SP Mojtabai, R Mendelson, T AF Lee-Winn, Angela E. Reinblatt, Shauna P. Mojtabai, Ramin Mendelson, Tamar TI Gender and racial/ethnic differences in binge eating symptoms in a nationally representative sample of adolescents in the United States SO EATING BEHAVIORS LA English DT Article DE Binge eating disorder; National Comorbidity Survey Adolescent Supplement (NCS-A); Gender differences; Racial/ethnic differences; Adolescents; Psychiatric epidemiology ID COMORBIDITY-SURVEY-REPLICATION; SUPPLEMENT NCS-A; DISORDER SYMPTOMS; BODY-IMAGE; ETHNIC-DIFFERENCES; PROTECTIVE FACTORS; AFRICAN-AMERICAN; YOUNG-ADULTS; RISK-FACTORS; PREVALENCE AB Objective: Binge eating disorder (BED) is the most prevalent eating disorder in the U.S. adolescent population. Both BED and subthreshold binge eating disorder (SBED) are associated with physical and mental health problems. Gender and racial/ethnic differences in prevalence of binge eating in a nationally representative sample of adolescents have been reported but have not yet been assessed in relation to individual symptoms of binge eating. We examined gender and racial/ethnic differences in endorsement of eight binge eating symptoms in a nationally representative sample of U.S. adolescents. Methods: We used data from the National Comorbidity Survey-Adolescent Supplement (NCS-A; 2001-2004), a nationally representative cross-sectional study of adolescents aged 13 to 18 years (n = 9336). We compared binge eating symptoms across gender and racial/ethnic groups using multivariable regression models. Results: Females endorsed more binge eating symptoms than males associated with loss of control ('eat when not hungry') (adjusted prevalence ratio [aPR] = 1.18, 95% confidence interval [CI] = 1.02, 1.37, p = 0.024) and distress (e.g., 'afraid of weight gain while binge eating' [aPR] = 3.29, CI = 2.43, 4.47, p < 0.001). Racial/ethnic minorities displayed different patterns of binge eating symptoms than non-Hispanic Whites. Hispanics reported being more 'afraid of weight gain while binge eating' (aPR = 2.05, CI = 1.25, 3.37, p = 0.006) than non-Hispanic Blacks. Discussion: Our findings suggest significant gender and racial/ethnic differences in binge eating symptom presentation. Future work should explore reasons for these gender and racial/ethnic differences and consider these differences when determining how best to prevent and treat binge eating in adolescents. Published by Elsevier Ltd. C1 [Lee-Winn, Angela E.; Mojtabai, Ramin; Mendelson, Tamar] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, 624 North Broadway, Baltimore, MD 21205 USA. [Reinblatt, Shauna P.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Child & Adolescent Psychiat, 550 North Broadway, Baltimore, MD 21205 USA. RP Lee-Winn, AE (reprint author), Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd 7B13, Rockville, MD 20892 USA. EM aleewin1@jhu.edu; sreinbl1@jhmi.edu; rmojtab1@jhu.edu; tmendel1@jhu.edu FU U.S. National Institutes of Health, National Institute of Mental Health (NIMH) [K23MH083000] FX S. Reinblatt received research support from the U.S. National Institutes of Health, National Institute of Mental Health (NIMH) for manuscript preparation (K23MH083000). The NIMH had no role in the study design, collection, analysis or interpretation of the data and the decision to submit the paper for publication. NR 56 TC 1 Z9 1 U1 13 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1471-0153 EI 1873-7358 J9 EAT BEHAV JI Eat. Behav. PD AUG PY 2016 VL 22 BP 27 EP 33 DI 10.1016/j.eatbeh.2016.03.021 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DT1PN UT WOS:000381254700006 PM 27085166 ER PT J AU Lee-Winn, AE Townsend, L Reinblatt, SP Mendelson, T AF Lee-Winn, Angela E. Townsend, Lisa Reinblatt, Shauna P. Mendelson, Tamar TI Associations of neuroticism-impulsivity and coping with binge eating in a nationally representative sample of adolescents in the United States SO EATING BEHAVIORS LA English DT Article DE Binge eating disorder; National Comorbidity Survey: Adolescent Supplement (NCS-A); Personality; Coping; Adolescents; Psychiatric epidemiology ID COMORBIDITY-SURVEY-REPLICATION; SUPPLEMENT NCS-A; NEGATIVE URGENCY; BIG 5; COMMUNITY SAMPLE; BULIMIA-NERVOSA; COLLEGE-WOMEN; DAILY STRESS; DISORDERS; PERSONALITY AB Objective: Binge eating behavior is a public health concern due to its negative physical and mental health consequences. Little is known about the interplay of personality traits, coping styles, and binge eating in the general adolescent population. We examined the associations among the combination of neuroticism and impulsivity (NI), maladaptive coping styles (poor problem solving, distraction, and escape-avoidance), and lifetime prevalence of binge eating in a nationally representative sample of U.S. adolescents. We also explored coping as a moderator of the NI-lifetime binge eating association and gender as a moderator of the NI-coping associations and coping-lifetime binge eating associations. Methods: We used data from the National Comorbidity Survey: Adolescent Supplement (NCS-A: 2001-2004), a cross-sectional nationally representative study of adolescents aged 13 to 18 years (n = 10,028). We studied the associations of NI and coping with lifetime binge eating using multivariate regression models. Results: High NI was significantly associated with all three coping styles, especially escape-avoidance (beta = 3.96, confidence interval [CI] = 3.62, 4.29, p < 0.001). Gender was a significant moderator of the NI - distraction coping association (beta = -0.68, CI = -1.33,-0.03, p = 0.041), indicating a stronger association inmales (beta = 1.20, CI = 0.81, 1.58, p < 0.001) than females (beta = 0.53, CI = 0.02, 1.03, p = 0.042). Lifetime prevalence of binge eating was 1.13 times higher with increased escape-avoidance coping (CI = 1.10, 1.18, p < 0.001). Discussion: Our findings indicate significant associations among high NI, increased escape-avoidance coping, and higher lifetime prevalence of binge eating in adolescents. Findings of our study have potential to inform development of interventions that target modification of maladaptive personality traits and coping styles to reduce problematic eating. Published by Elsevier Ltd. C1 [Lee-Winn, Angela E.; Townsend, Lisa; Mendelson, Tamar] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, 624 North Broadway Hampton House, Baltimore, MD 21205 USA. [Reinblatt, Shauna P.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Child & Adolescent Psychiat, 550 North Broadway,Room 206D, Baltimore, MD 21205 USA. RP Lee-Winn, AE (reprint author), Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd 7B13, Rockville, MD 20892 USA. EM aleewin1@jhu.edu; ltownse8@jhu.edu; sreinbl1@jhmi.edu; tmendel1@jhu.edu FU U.S. National Institutes of Health, National Institute of Mental Health (NIMH) [K23MH083000] FX S. Reinblatt received research support from the U.S. National Institutes of Health, National Institute of Mental Health (NIMH) for manuscript preparation (K23MH083000). The NIMH had no role in the study design, collection, analysis or interpretation of the data and the decision to submit the paper for publication. NR 97 TC 0 Z9 0 U1 13 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1471-0153 EI 1873-7358 J9 EAT BEHAV JI Eat. Behav. PD AUG PY 2016 VL 22 BP 133 EP 140 DI 10.1016/j.eatbeh.2016.06.009 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DT1PN UT WOS:000381254700025 PM 27289518 ER PT J AU Kelly, NR Shomaker, LB Radin, RM Thompson, KA Cassidy, OL Brady, S Mehari, R Courville, AB Chen, KY Galescu, OA Tanofsky-Kraff, M Yanovski, JA AF Kelly, Nichole R. Shomaker, Lauren B. Radin, Rachel M. Thompson, Katherine A. Cassidy, Omni L. Brady, Sheila Mehari, Rim Courville, Amber B. Chen, Kong Y. Galescu, Ovidiu A. Tanofsky-Kraff, Marian Yanovski, Jack A. TI Associations of sleep duration and quality with disinhibited eating behaviors in adolescent girls at-risk for type 2 diabetes SO EATING BEHAVIORS LA English DT Article DE Binge eating; Eating in the absence of hunger; Obesity; Sleep; Sleepiness ID EXCESSIVE DAYTIME SLEEPINESS; POSITIVE ENERGY-BALANCE; OBESE CHILDREN; YOUNG-ADULTS; POOR SLEEP; DEPRESSIVE SYMPTOMS; AFFECTIVE-DISORDERS; INSULIN-RESISTANCE; EMOTION REGULATION; SCHOOL-CHILDREN AB Objectives: Short sleep duration and daytime sleepiness have been associated with an increased risk for the onset of type 2 diabetes in adults. There has been far less attention to the characterization of sleep in adolescents at-risk for diabetes or to the possible behavioral mechanisms, such as disinhibited eating, through which sleep may affect metabolic functioning. Methods: We evaluated the associations of sleep duration and daytime sleepiness with a multi- modal assessment of disinhibited eating in 119 adolescent girls at-risk for type 2 diabetes based upon being overweight/obese and having a family history of diabetes. Girls also endorsed mild-to-moderate depressive symptoms. Adolescents reported sleep duration and daytime sleepiness with the Sleep Habits Survey and Children's Sleep Habits Questionnaire. They were administered a series of successive test meals to measure total energy intake and eating in the absence of hunger (EAH). Adolescent binge eating was assessed with the Eating Disorder Examination interview. Results: Accounting for age, race, puberty, body composition, depressive symptoms, and perceived stress, reported sleep duration was positively related to test meal total energy intake (p = 0.04), but not to EAH. Adjusting for the same covariates, daytime sleepiness was associated with a greater odds of objective binge eating in the previous month (p = 0.009). Conclusions: In adolescent girls at-risk for type 2 diabetes, reported sleep characteristics are associated with disinhibited eating behaviors that have been linked to excessive weight and adverse metabolic outcomes. Future studies are called for to evaluate these links using objective measures of sleep. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Kelly, Nichole R.; Shomaker, Lauren B.; Radin, Rachel M.; Thompson, Katherine A.; Cassidy, Omni L.; Brady, Sheila; Mehari, Rim; Galescu, Ovidiu A.; Tanofsky-Kraff, Marian; Yanovski, Jack A.] Natl Inst Child Hlth & Human Dev NICHD, Sect Growth & Obes, NIH, DHHS, 10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. [Kelly, Nichole R.; Radin, Rachel M.; Cassidy, Omni L.; Tanofsky-Kraff, Marian] Uniformed Serv Univ Hlth Sci, Dept Def, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Shomaker, Lauren B.] Colorado State Univ, Dept Human Dev & Family Studies, 410 Pitkin St,Campus Delivery 1570, Ft Collins, CO 80523 USA. [Courville, Amber B.] NIH Clin Ctr, Dept Nutr, DHHS, 10 Ctr Dr,MSC 1078, Bethesda, MD 20892 USA. [Chen, Kong Y.] Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, NIH, DHHS, 10 Ctr Dr, Bethesda, MD 20814 USA. RP Shomaker, LB (reprint author), Colorado State Univ, Dept Human Dev & Family Studies, 410 Pitkin St,Campus Delivery 1570, Ft Collins, CO 80523 USA. EM Lauren.Shomaker@colostate.edu OI Chen, Kong/0000-0002-0306-1904 FU NICHD, NIH Intramural Research Program Grant from NICHD [K99/R00HD069516, 1ZIAHD000641]; NIH Bench to Bedside Program; Office of Disease Prevention, NIH; Office of Behavioral and Social Sciences Research FX Supported by K99/R00HD069516 (PI: Shomaker) from NICHD, NIH Intramural Research Program Grant 1ZIAHD000641 (PI: Yanovski) from NICHD with supplemental funding from the NIH Bench to Bedside Program (PIs: Yanovski, Tanofsky-Kraff, Shomaker), the Office of Disease Prevention, NIH (PI: Yanovski), and the Office of Behavioral and Social Sciences Research (PI: Yanovski). NR 78 TC 0 Z9 0 U1 4 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1471-0153 EI 1873-7358 J9 EAT BEHAV JI Eat. Behav. PD AUG PY 2016 VL 22 BP 149 EP 155 DI 10.1016/j.eatbeh.2016.06.019 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DT1PN UT WOS:000381254700028 PM 27289521 ER PT J AU Poirier, MC AF Poirier, Miriam C. TI Linking DNA adduct formation and human cancer risk in chemical carcinogenesis SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Review DE chemical carcinogen; DNA adduct; molecular dosimetry; molecular cancer epidemiology ID WHITE BLOOD-CELLS; HEPATOCELLULAR-CARCINOMA PATIENTS; PERIPHERAL MONONUCLEAR-CELLS; PARAFFIN-EMBEDDED TISSUES; ARISTOLOCHIC ACID; MASS-SPECTROMETRY; LUNG-CANCER; ENVIRONMENTAL-POLLUTANTS; XERODERMA-PIGMENTOSUM; UROTHELIAL CANCER AB Over two centuries ago, Sir Percival Pott, a London surgeon, published a pioneering treatise showing that soot exposure was the cause of high incidences of scrotal cancers occurring in young men who worked as chimney sweeps. Practicing at a time when cellular pathology was not yet recognized, Sir Percival nonetheless observed that the high incidence and short latency of the chimney sweep cancers, was fundamentally different from the rare scrotal cancers typically found in elderly men. Furthermore, his diagnosis that the etiology of these cancers was related to chimney soot exposure, was absolutely accurate, conceptually novel, and initiated the field of occupational cancer epidemiology. After many intervening years of research focused on mechanisms of chemical carcinogenesis, briefly described here, it is clear that DNA damage, or DNA adduct formation, is necessary but not sufficient for tumor induction, and that many additional factors contribute to carcinogenesis. This review includes a synopsis of carcinogen-induced DNA adduct formation in experimental models and in the human population, with particular attention paid to molecular dosimetry and molecular cancer epidemiology. Environ. Mol. Mutagen. 57:499-507, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, NIH, Bldg 37,Rm 4032,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, NIH, Bldg 37,Rm 4032,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM poirierm@exchange.nih.gov NR 82 TC 0 Z9 0 U1 6 U2 6 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 AUG PY 2016 VL 57 IS 7 BP 499 EP 507 DI 10.1002/em.22030 PG 9 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DV0DC UT WOS:000382587200001 PM 27346877 ER PT J AU Liu, YM Park, ES Gibbons, AT Shide, ED Divi, RL Woodward, RA Poirier, MC AF Liu, Yongmin Park, Eunwoo Shim Gibbons, Alexander T. Shide, Eric D. Divi, Rao L. Woodward, Ruth A. Poirier, Miriam C. TI Mitochondrial compromise in 3-year old patas monkeys exposed in utero to human-equivalent antiretroviral therapies SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE zidovudine; lamivudine; abacavir; nevirapine; mitochondrial DNA; Seahorse analyzer ID REVERSE-TRANSCRIPTASE INHIBITORS; HIV-UNINFECTED CHILDREN; GENOTOXICITY; TOXICITY; CARCINOGENICITY; DYSFUNCTION; ZIDOVUDINE; MOTHERS; DRUGS; NRTIS AB Antiretroviral (ARV) drug therapy, given during pregnancy for prevention of mother-to-child transmission of human immunodeficiency virus 1 (HIV-1), induces fetal mitochondrial dysfunction in some children. However, the persistence/reversibility of that dysfunction is unclear. Here we have followed Erythrocebus patas (patas) monkey offspring for up to 3years of age (similar in development to a 15-year old human) after exposure of the dams to human-equivalent in utero ARV exposure protocols. Pregnant patas dams (3-5/exposure group) were given ARV drug combinations that included zidovudine (AZT)/lamivudine (3TC)/abacavir (ABC), or AZT/3TC/nevirapine (NVP), for the last 10weeks (50%) of gestation. Infants kept for 1 and 3years also received drug for the first 6weeks of life. In offpsring at birth, 1 and 3years of age mitochondrial morphology, examined by electron microscopy (EM), was compromised compared to the unexposed controls. Mitochondrial DNA (mtDNA), measured by hybrid capture chemiluminescence assay (HCCA) was depleted in hearts of patas exposed to AZT/3TC/NVP at all ages (P<0.05), but not in those exposed to AZT/3TC/ABC at any age. Compared to unexposed controls, mitochondrial reserve capacity oxygen consumption rate (OCR by Seahorse) in cultured bone marrow mesenchymal fibroblasts from 3-year-old patas offspring was approximate to 50% reduced in AZT/3TC/ABC-exposed patas (P<0.01), but not in AZT/3TC/NVP-exposed patas. Overall the data show that 3-year-old patas sustain persistent mitochondrial dysfunction as a result of perinatal ARV drug exposure. Environ. Mol. Mutagen. 57:526-534, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Liu, Yongmin; Park, Eunwoo Shim; Gibbons, Alexander T.; Shide, Eric D.; Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, CCR,NIH, Madison, WI USA. [Divi, Rao L.] NCI, Methods & Technol Branch, DCCPS, NIH, Madison, WI USA. [Woodward, Ruth A.] NIH, Shared Anim Facil, Anim Ctr, Madison, WI USA. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, NIH, Bldg 37,Rm 4032,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM poir-ierm@exchange.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH [ZIA-BC 010770] FX The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. We wish to thank Alexandra Michalowski for statistical help. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, under project number ZIA-BC 010770. NR 33 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2016 VL 57 IS 7 BP 526 EP 534 DI 10.1002/em.22033 PG 9 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DV0DC UT WOS:000382587200004 PM 27452341 ER PT J AU Ma, YS Persuitte, GM Andrews, C Hovey, KM LaMonte, MJ Culver, AL Manson, JE Phillips, LS Liu, SM Eaton, C Martin, LW Howard, BV Balasubramanian, R Bird, CE Ockene, IS Sturgeon, SR Ockene, JK Tinker, L Nassir, R Rossouw, J AF Ma, Yunsheng Persuitte, Gioia M. Andrews, Christopher Hovey, Kathleen M. LaMonte, Michael J. Culver, Annie L. Manson, JoAnn E. Phillips, Lawrence S. Liu, Simin Eaton, Charles Martin, Lisa W. Howard, Barbara V. Balasubramanian, Raji Bird, Chloe E. Ockene, Ira S. Sturgeon, Susan R. Ockene, Judith K. Tinker, Lesley Nassir, Rami Rossouw, Jacques TI Impact of incident diabetes on atherosclerotic cardiovascular disease according to statin use history among postmenopausal women SO EUROPEAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Epidemiology; Diabetes; Drug-related problem; Cardiovascular disease ID HEALTHY EATING INDEX; 27 RANDOMIZED-TRIALS; PRIMARY PREVENTION; METABOLIC SYNDROME; INDIVIDUAL DATA; DIET QUALITY; SELF-REPORTS; METAANALYSIS; THERAPY; RISK AB To compare impact of incident diabetes on atherosclerotic cardiovascular disease (ASCVD) risk among postmenopausal women according to statin use. Prospective data from 120,499 postmenopausal women without prevalent diabetes or cardiovascular disease at baseline from the Women's Health Initiative were used. Incident diabetes was self-reported annually and defined as treatment with pills or injectable medication for diabetes. Current statin use was determined at enrollment and years 1, 3, 6, 9 and 13.5 in the three clinical trial arms, and at baseline, year 3, and 13.5 for the observational study. The primary outcome was incident ASCVD events, self-reported annually and adjudicated by blinded local and central physicians. Incident diabetes and statin use status were fitted as time-varying covariates in Cox regression models to assess ASCVD risk during an average follow-up of 13.6 years. For those not on statins at the time of diabetes diagnosis, there was a 42 % increased risk of ASCVD [hazard ratio (HR) 1.42, 95 % CI 1.28-1.58] among women with incident diabetes versus those without diabetes. Among women on statins, there was a 39 % increased risk of ASCVD (HR 1.39, 95 % CI 1.12-1.74) in women with incident diabetes versus those without diabetes. The increased ASCVD risk due to diabetes was similar between women before or after initiating statins (P = 0.89). Whether diabetes was diagnosed before or after statin use did not alter the increased risk of ASCVD associated with diabetes. Mitigating the increased incidence of diabetes in statin users could increase the ASCVD benefit-to-risk ratio of statins. C1 [Ma, Yunsheng; Culver, Annie L.; Ockene, Judith K.] Univ Massachusetts, Sch Med, Dept Med, Div Prevent & Behav Med, 55 Lake Ave North, Worcester, MA 01655 USA. [Persuitte, Gioia M.] Corrona LLC, 352 Boston Turnpike, Southborough, MA 01772 USA. [Andrews, Christopher] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. [Hovey, Kathleen M.; LaMonte, Michael J.] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY 14214 USA. [Manson, JoAnn E.] Harvard Med Sch, Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Phillips, Lawrence S.] Emory Univ, Div Endocrinol, Atlanta, GA 30322 USA. [Liu, Simin] Brown Univ, Sch Publ Hlth, Providence, RI 02903 USA. [Eaton, Charles] Brown Univ, Sch Med, Dept Family Med, Providence, RI 02912 USA. [Martin, Lisa W.] George Washington Univ, Sch Med & Hlth Sci, Div Cardiol, Washington, DC 20037 USA. [Howard, Barbara V.] MedStar Res Inst, Hyattsville, MD 20782 USA. [Balasubramanian, Raji; Sturgeon, Susan R.] Univ Massachusetts Amherst, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. [Bird, Chloe E.] RAND Corp, Santa Monica, CA 90407 USA. [Ockene, Ira S.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiovasc Med, Worcester, MA 01655 USA. [Tinker, Lesley] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Nassir, Rami] Univ Calif Davis, Dept Biochem & Mol Med, Davis, CA 95616 USA. [Rossouw, Jacques] NHLBI, Womens Hlth Initiat Branch, Bldg 10, Bethesda, MD 20892 USA. RP Ma, YS (reprint author), Univ Massachusetts, Sch Med, Dept Med, Div Prevent & Behav Med, 55 Lake Ave North, Worcester, MA 01655 USA. EM Yunsheng.Ma@umassmed.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; [5R01HL122241-02] FX Y.M. and G.M.P wrote the manuscript and researched data. A.L.C., J.E.M., L.S.P., S.L., C.E., M.L., L.W.M, B.V.H, R.B., C.E.B., I.S.O., S.R.S., J.K.O., L.T, R.N., and J.R. contributed to the discussion and reviewed and edited the manuscript. C.A. and K.H performed data analyses and reviewed and edited the manuscript. The Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Our investigation also was supported in part by 5R01HL122241-02. A list of WHI investigators is available in Supplementary Data online. The authors thank the principal investigators of all WHI clinical centers and the data coordinating center for their contribution to the study. They are also indebted to the dedicated and committed participants of the WHI. NR 28 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0393-2990 EI 1573-7284 J9 EUR J EPIDEMIOL JI Eur. J. Epidemiol. PD AUG PY 2016 VL 31 IS 8 BP 747 EP 761 DI 10.1007/s10654-016-0153-7 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DV1QE UT WOS:000382695100004 PM 27188186 ER PT J AU Silverman, DT Attfield, MD Blair, AE Lubin, JH Stewart, PA Vermeulen, R AF Silverman, Debra T. Attfield, Michael D. Blair, Aaron E. Lubin, Jay H. Stewart, Patricia A. Vermeulen, Roel TI Re: "The hidden impact of a healthy-worker effect on the results of the Diesel Exhaust in Miners Study" SO EUROPEAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID LUNG-CANCER; MORTALITY; COHORT C1 [Silverman, Debra T.; Blair, Aaron E.; Stewart, Patricia A.; Vermeulen, Roel] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rm 6E142,9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Attfield, Michael D.] NIOSH, Surveillance Branch, Div Resp Dis Studies, Morgantown, WV USA. [Lubin, Jay H.] NCI, Biostat Branch, Div Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA USA. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. RP Silverman, DT (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rm 6E142,9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM silvermd@mail.nih.gov RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 NR 6 TC 1 Z9 2 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0393-2990 EI 1573-7284 J9 EUR J EPIDEMIOL JI Eur. J. Epidemiol. PD AUG PY 2016 VL 31 IS 8 BP 805 EP 806 DI 10.1007/s10654-016-0188-9 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DV1QE UT WOS:000382695100010 PM 27518301 ER PT J AU Nussinov, R Tsai, CJ Jang, H AF Nussinov, Ruth Tsai, Chung-Jung Jang, Hyunbum TI Independent and core pathways in oncogenic KRAS signaling SO EXPERT REVIEW OF PROTEOMICS LA English DT Editorial Material DE KRAS; K-Ras4B; lung cancer; pancreatic cancer; Ras pathways; cell cycle; Ras effectors; PI3K; Raf; Ras isoforms ID ENGINEERED MOUSE MODELS; BETA-CATENIN ACTIVATION; REGULATES C-MYC; CELL-CYCLE; PANCREATIC-CANCER; LUNG-CANCER; K-RAS; HYPERVARIABLE REGION; TARGETED THERAPIES; TUMOR INITIATION C1 [Nussinov, Ruth; Tsai, Chung-Jung; Jang, Hyunbum] NCI, Basic Sci Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res,Canc & Inflammat Prog, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res,Canc & Inflammat Prog, Frederick, MD 21701 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, Tel Aviv, Israel. EM NussinoR@helix.nih.gov FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E] NR 86 TC 1 Z9 1 U1 4 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1478-9450 EI 1744-8387 J9 EXPERT REV PROTEOMIC JI Expert Rev. Proteomics PD AUG PY 2016 VL 13 IS 8 BP 711 EP 716 DI 10.1080/14789450.2016.1209417 PG 6 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DU6ZS UT WOS:000382363700002 PM 27389825 ER PT J AU Hernandez, L Kim, MK Lyle, LT Bunch, KP House, CD Ning, F Noonan, AM Annunziata, CM AF Hernandez, Lidia Kim, Marianne K. Lyle, L. Tiffany Bunch, Kristen P. House, Carrie D. Ning, Franklin Noonan, Anne M. Annunziata, Christina M. TI Characterization of ovarian cancer cell lines as in vivo models for preclinical studies SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian cancer; Xenografts; Cell lines; Mouse model ID CARCINOMA; GENE; METASTASIS; EXPRESSION; RESISTANCE; VITRO; MICE AB Objective. The value of cell lines for pre-clinical work lies in choosing those with similar characteristics. Selection of cell lines is typically based on patient history, histological subtype at diagnosis, mutation patterns, or signaling pathways. Although recent studies established consensus regarding molecular characteristics of ovarian cancer cell lines, data on in vivo tumorigenicity remains only sporadically available, impeding translation of in vitro work to xenograft models. Methods. We introduced 18 ovarian cancer cell lines into athymic nude mice through subcutaneous, intraperitoneal, and ovary intrabursal routes, and observed tumor development over 6 weeks. We also profiled cell line gene expression and identified differentially expressed gene sets based on their ability to form tumors in the subcutaneous or intraperitoneal locations. Representative cell lines were further subjected to proteomic analyses. Results. Ovarian cancer cell lines showed variable ability to grow in mice when implanted subcutaneous, intraperitoneal, or intrabursal. While some cell lines grew well in both SC and IP locations, others showed a strong propensity to grow in one location only. Gene expression profiles suggested that cell lines showing preference for IP growth had gene expression patterns more similar to primary tumors. Conclusions. We report the tumorigenicity of 17 human ovarian cancer cell lines and one mouse cell line in three distinct anatomical locations, and associated gene networks. Growth patterns and histopathology, linked to molecular characteristics, provide a valuable resource to the research community, and better guide the choice of cell lines for in vitro studies to translate efficiently into xenograft testing. Published by Elsevier Inc. C1 [Hernandez, Lidia; Kim, Marianne K.; Lyle, L. Tiffany; Bunch, Kristen P.; House, Carrie D.; Ning, Franklin; Noonan, Anne M.; Annunziata, Christina M.] NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Bunch, Kristen P.] Walter Reed Natl Mil Med Ctr, Dept Gynecol Oncol, Bethesda, MD USA. [Noonan, Anne M.] Ohio State Univ, Dept Internal Med, Div Med Oncol, Columbus, OH 43210 USA. RP Annunziata, CM (reprint author), 10 Ctr Dr,Room 4B54, Bethesda, MD 20892 USA. EM annunzic@mail.nih.gov RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 FU National Cancer Institute Intramural Research Program [ZIA BC 011054] FX We thank Elena Kuznetsova and Geneti Gaga for the excellent surgical expertise during intrabursal injections. This work was funded by the National Cancer Institute Intramural Research Program (CMA, #ZIA BC 011054).The authors declare no conflict of interest. NR 40 TC 0 Z9 0 U1 4 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2016 VL 142 IS 2 BP 332 EP 340 DI 10.1016/j.ygyno.2016.05.028 PG 9 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DS4EH UT WOS:000380733700022 PM 27235858 ER PT J AU Laurent, C Fabiani, B Do, C Tchernonog, E Cartron, G Gravelle, P Amara, N Malot, S Palisoc, MM Copie-Bergman, C Glehen, AT Copin, MC Brousset, P Pittaluga, S Jaffe, ES Coppo, P AF Laurent, Camille Fabiani, Bettina Do, Catherine Tchernonog, Emmanuelle Cartron, Guillaume Gravelle, Pauline Amara, Nadia Malot, Sandrine Palisoc, Maryknoll Mawanay Copie-Bergman, Christiane Glehen, Alexandra Traverse Copin, Marie-Christine Brousset, Pierre Pittaluga, Stefania Jaffe, Elaine S. Coppo, Paul TI Immune-checkpoint expression in Epstein-Barr virus positive and negative plasmablastic lymphoma: a clinical and pathological study in 82 patients SO HAEMATOLOGICA LA English DT Article ID B-CELL LYMPHOMA; DEATH-LIGAND 1; INDOLEAMINE 2,3-DIOXYGENASE; FOLLICULAR LYMPHOMA; HODGKINS LYMPHOMA; EBV INFECTION; ORAL-CAVITY; BLOCKADE; DISORDERS; RITUXIMAB AB Plasmablastic lymphoma is a rare and aggressive diffuse large B-cell lymphoma commonly associated with Epstein-Barr virus co-infection that most often occurs in the context of human immunodeficiency virus infection. Therefore, its immune escape strategy may involve the upregulation of immune-checkpoint proteins allowing the tumor immune evasion. However, the expression of these molecules was poorly studied in this lymphoma. We have investigated 82 plasmablastic lymphoma cases of whom half were Epstein-Barr virus positive. Although they harbored similar pathological features, Epstein-Barr virus positive plasmablastic lymphomas showed a significant increase in MYC gene rearrangement and had a better 2-year event-free survival than Epstein-Barr virus negative cases (P=0.049). Immunostains for programmed cell death-1, programmed cell death-ligand 1, indole 2,3-dioxygenase and dendritic cell specific C-type lectin showed a high or moderate expression by the microenvironment cells in 60%-72% of cases, whereas CD163 was expressed in almost all cases. Tumor cells also expressed programmed cell death-1 and its ligand in 22.5% and 5% of cases, respectively. Both Epstein-Barr virus positive and negative plasmablastic lymphomas exhibited a high immune-checkpoint score showing that it involves several pathways of immune escape. However, Epstein-Barr virus positive lymphomas exhibited a higher expression of programmed cell death-1 and its ligand in both malignant cells and microenvironment as compared to Epstein-Barr virus negative cases. In conclusion, plasmablastic lymphoma expresses immune-checkpoint proteins through both malignant cells and the tumor microenvironment. The expression of programmed cell death-1 and its ligand constitutes a strong rationale for testing monoclonal antibodies in this often chemoresistant disease. C1 [Laurent, Camille; Gravelle, Pauline; Amara, Nadia; Brousset, Pierre] Inst Univ Canc Oncopole, Dept Pathol, Toulouse, France. [Laurent, Camille; Gravelle, Pauline; Brousset, Pierre] Ctr Rech Cancerol Toulouse Purpan, INSERM, U1037, Toulouse, France. [Fabiani, Bettina] Hop St Antoine, AP HP, Dept Pathol, Paris, France. [Do, Catherine] Columbia Univ, Inst Canc Genet, New York, NY USA. [Tchernonog, Emmanuelle; Cartron, Guillaume] Hop Gui Chauliac St Eloi, Serv Hematol, Montpellier, France. [Malot, Sandrine; Coppo, Paul] Hop St Antoine, AP HP, Serv Hematol, Paris, France. [Malot, Sandrine; Coppo, Paul] AP HP, Ctr Reference Microangiopathies Thrombot, Paris, France. [Palisoc, Maryknoll Mawanay; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. [Copie-Bergman, Christiane] Grp Hosp Henri Mondor Albert Chenevier, AP HP, Dept Pathol, Creteil, France. [Glehen, Alexandra Traverse] Ctr Hosp Lyon Sud, Dept Pathol, Lyon, France. [Copin, Marie-Christine] Ctr Hosp Lille, Dept Pathol, Lille, France. [Coppo, Paul] Univ Paris 06, F-75252 Paris 05, France. [Coppo, Paul] Inst Gustave Roussy, INSERM, U1170, Villejuif, France. RP Laurent, C (reprint author), Inst Univ Canc Oncopole, Dept Pathol, Toulouse, France.; Laurent, C (reprint author), Ctr Rech Cancerol Toulouse Purpan, INSERM, U1037, Toulouse, France. EM laurent.c@chu-toulouse.fr RI GRAVELLE, PAULINE/D-1405-2015 OI GRAVELLE, PAULINE/0000-0002-0462-5652 NR 50 TC 5 Z9 5 U1 4 U2 5 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD AUG PY 2016 VL 101 IS 8 BP 976 EP 984 DI 10.3324/haematol.2016.141978 PG 9 WC Hematology SC Hematology GA DU1BT UT WOS:000381941900021 PM 27175027 ER PT J AU Teerlink, CC Leongamornlert, D Dadaev, T Thomas, A Farnham, J Stephenson, RA Riska, S McDonnell, SK Schaid, DJ Catalona, WJ Zheng, SL Cooney, KA Ray, AM Zuhlke, KA Lange, EM Giles, GG Southey, MC Fitzgerald, LM Rinckleb, A Luedeke, M Maier, C Stanford, JL Ostrander, EA Kaikkonen, EM Sipeky, C Tammela, T Schleutker, J Wiley, KE Isaacs, SD Walsh, PC Isaacs, WB Xu, JF Cancel-Tassin, G Cussenot, O Mandal, D Laurie, C Laurie, C Thibodeau, SN Eeles, RA Kote-Jarai, Z Cannon-Albright, L AF Teerlink, Craig C. Leongamornlert, Daniel Dadaev, Tokhir Thomas, Alun Farnham, James Stephenson, Robert A. Riska, Shaun McDonnell, Shannon K. Schaid, Daniel J. Catalona, William J. Zheng, S. Lilly Cooney, Kathleen A. Ray, Anna M. Zuhlke, Kimberly A. Lange, Ethan M. Giles, Graham G. Southey, Melissa C. Fitzgerald, Liesel M. Rinckleb, Antje Luedeke, Manuel Maier, Christiane Stanford, Janet L. Ostrander, Elaine A. Kaikkonen, Elina M. Sipeky, Csilla Tammela, Teuvo Schleutker, Johanna Wiley, Kathleen E. Isaacs, Sarah D. Walsh, Patrick C. Isaacs, William B. Xu, Jianfeng Cancel-Tassin, Geraldine Cussenot, Olivier Mandal, Diptasri Laurie, Cecelia Laurie, Cathy Thibodeau, Stephen N. Eeles, Rosalind A. Kote-Jarai, Zsofia Cannon-Albright, Lisa CA PRACTICAL Consortium Int TI Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21 SO HUMAN GENETICS LA English DT Article ID RISK-ASSOCIATED LOCI; SUSCEPTIBILITY LOCI; GERMLINE MUTATIONS; GENETIC-VARIATION; SEQUENCING DATA; MULTIPLE LOCI; VARIANTS; METAANALYSIS; DISEASE; AGGRESSIVENESS AB Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies < 1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus. C1 [Teerlink, Craig C.; Thomas, Alun; Farnham, James; Cannon-Albright, Lisa] Univ Utah, Dept Internal Med, Sch Med, Salt Lake City, UT 84108 USA. [Leongamornlert, Daniel; Dadaev, Tokhir; Eeles, Rosalind A.; Kote-Jarai, Zsofia] Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England. [Stephenson, Robert A.] Univ Utah, Dept Urol, Sch Med, Salt Lake City, UT 84132 USA. [Stephenson, Robert A.] Univ Utah, Dept Surg, Sch Med, Salt Lake City, UT 84132 USA. [Stephenson, Robert A.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Riska, Shaun; McDonnell, Shannon K.; Schaid, Daniel J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Catalona, William J.; Zheng, S. Lilly] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Cooney, Kathleen A.; Ray, Anna M.; Zuhlke, Kimberly A.] Univ Michigan, Dept Internal Med, Sch Med, Ann Arbor, MI 48109 USA. [Cooney, Kathleen A.; Ray, Anna M.; Zuhlke, Kimberly A.] Univ Michigan, Dept Urol, Sch Med, Ann Arbor, MI 48109 USA. [Lange, Ethan M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Lange, Ethan M.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Giles, Graham G.; Fitzgerald, Liesel M.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3004, Australia. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. [Rinckleb, Antje; Luedeke, Manuel] Univ Hosp Ulm, Dept Urol, D-53179 Ulm, Germany. [Maier, Christiane] Univ Ulm, Inst Human Genet, D-89081 Ulm, Germany. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Kaikkonen, Elina M.; Sipeky, Csilla] Univ Turku, Dept Med Biochem & Genet, FIN-20520 Turku, Finland. [Tammela, Teuvo] Univ Tampere, Dept Urol, Tampere 33520, Finland. [Tammela, Teuvo] Tampere Univ Hosp, Tampere 33520, Finland. [Schleutker, Johanna] Turku Univ Hosp, Dept Med Genet, Tyks Microbiol & Genet, Turku 20520, Finland. [Wiley, Kathleen E.; Isaacs, Sarah D.; Walsh, Patrick C.; Isaacs, William B.] Johns Hopkins Univ, Brady Urol Inst, Baltimore, MD 21287 USA. [Xu, Jianfeng] NorthShore Univ Hlth Syst, Program Personalized Canc Care, Evanston, IL 60201 USA. [Cancel-Tassin, Geraldine; Cussenot, Olivier] Hop Tenon, AP HP, CeRePP, F-75020 Paris, France. [Mandal, Diptasri] Louisiana State Univ, Dept Genet, Hlth Sci Ctr, New Orleans, LA 70112 USA. [Laurie, Cecelia; Laurie, Cathy] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Cannon-Albright, Lisa] Vet Affairs Med Ctr, George E Wahlen Dept, Salt Lake City, UT 84148 USA. RP Teerlink, CC (reprint author), Univ Utah, Dept Internal Med, Sch Med, Salt Lake City, UT 84108 USA. EM craig.teerlink@utah.edu OI Teerlink, Craig/0000-0002-1992-2326; Farnham, James/0000-0002-8213-949X; Leongamornlert, Daniel/0000-0002-3486-3168; albright, lisa/0000-0003-2602-3668; Giles, Graham/0000-0003-4946-9099; Thomas, Alun/0000-0001-5650-7044; Ostrander, Elaine/0000-0001-6075-9738; Cancel-Tassin, Geraldine/0000-0002-9583-6382 FU National Cancer Institute [U01 CA 89600]; Center for Inherited Disease Research [HHSN268201200008I]; NIH [R01 CA080122, R01 CA056678, R01 CA092579]; Fred Hutchinson Cancer Research Center; Prostate Cancer Foundation; European Community [223175 (HEALTH-F2-2009-223175)]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112-the GAME-ON initiative]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Institute of Health Research; Royal Marsden NHS Foundation Trust; Prostate Cancer UK FX This research was supported by the National Cancer Institute Grant U01 CA 89600 (Support for the ICPCG), and a grant from the Center for Inherited Disease Research supported the genotyping aspect of the study (contract no. HHSN268201200008I; PI Cannon-Albright). The Geneva Coordinating Center at the University of Washington conducted quality control aspects of the study and submitted public facing data to the database of Genotypes and Phenotypes (dbGaP) at the National Center for Biotechnology Information. The authors acknowledge the Keith and Susan Warshaw Fund, the Maurice Warshaw Fund, the C. Scott Watkins Fund, and the Tennity Family Fund. The FHCRC portion of the study was supported by NIH grants R01 CA080122, R01 CA056678, and R01 CA092579, Fred Hutchinson Cancer Research Center and the Prostate Cancer Foundation. Funding for the iCOGS infrastructure (PRACTICAL data) came from the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112-the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Biomedical Research Centre at the Institute of Cancer Research (UK) acknowledges the support of the National Institute of Health Research, the Royal Marsden NHS Foundation Trust, and Prostate Cancer UK. NR 51 TC 0 Z9 0 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD AUG PY 2016 VL 135 IS 8 BP 923 EP 938 DI 10.1007/s00439-016-1690-6 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA DR7DR UT WOS:000380060700009 PM 27262462 ER PT J AU Del Gobbo, LC Imamura, F Aslibekyan, S Marklund, M Virtanen, JK Wennberg, M Yakoob, MY Chiuve, SE dela Cruz, L Frazier-Wood, AC Fretts, AM Guallar, E Matsumoto, C Prem, K Tanaka, T Wu, JHY Zhou, X Helmer, C Ingelsson, E Yuan, JM Barberger-Gateau, P Campos, H Chaves, PHM Djousse, L Giles, GG Gomez-Aracena, J Hodge, AM Hu, FB Jansson, JH Johansson, I Khaw, KT Koh, WP Lemaitre, RN Lind, L Luben, RN Rimm, EB Riserus, U Samieri, C Franks, PW Siscovick, DS Stampfer, M Steffen, LM Steffen, BT Tsai, MY van Dam, RM Voutilainen, S Willett, WC Woodward, M Mozaffarian, D AF Del Gobbo, Liana C. Imamura, Fumiaki Aslibekyan, Stella Marklund, Matti Virtanen, Jyrki K. Wennberg, Maria Yakoob, Mohammad Y. Chiuve, Stephanie E. dela Cruz, Luicito Frazier-Wood, Alexis C. Fretts, Amanda M. Guallar, Eliseo Matsumoto, Chisa Prem, Kiesha Tanaka, Tosh Wu, Jason H. Y. Zhou, Xia Helmer, Catherine Ingelsson, Erik Yuan, Jian-Min Barberger-Gateau, Pascale Campos, Hannia Chaves, Paulo H. M. Djousse, Luc Giles, Graham G. Gomez-Aracena, Jose Hodge, Allison M. Hu, Frank B. Jansson, Jan-Hakan Johansson, Ingegerd Khaw, Kay-Tee Koh, Woon-Puay Lemaitre, Rozenn N. Lind, Lars Luben, Robert N. Rimm, Eric B. Riserus, Ulf Samieri, Cecilia Franks, Paul W. Siscovick, David S. Stampfer, Meir Steffen, Lyn M. Steffen, Brian T. Tsai, Michael Y. van Dam, Rob M. Voutilainen, Sari Willett, Walter C. Woodward, Mark Mozaffarian, Dariush CA Cohorts Heart Aging Res Genomic Ep Fatty Acids Outcomes Res Consortiu TI omega-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease Pooling Project of 19 Cohort Studies SO JAMA INTERNAL MEDICINE LA English DT Article ID ALPHA-LINOLENIC ACID; LONG-CHAIN N-3; CARDIOVASCULAR-DISEASE; CONTROLLED-TRIALS; FISH CONSUMPTION; ADIPOSE-TISSUE; BREAST-CANCER; DOSE-RESPONSE; RISK-FACTORS; DIETARY AB IMPORTANCE The role of omega-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers. OBJECTIVE To evaluate biomarkers of seafood-derived eicosapentaenoic acid (EPA; 20: 5 omega-3), docosapentaenoic acid (DPA; 22: 5 omega-3), and docosahexaenoic acid (DHA; 22: 6 omega-3) and plant-derived alpha-linolenic acid (ALA; 18: 3 omega-3) for incident CHD. DATA SOURCES A global consortium of 19 studies identified by November 2014. STUDY SELECTION Available prospective (cohort, nested case-control) or retrospective studies with circulating or tissue omega-3 biomarkers and ascertained CHD. DATA EXTRACTION AND SYNTHESIS Each study conducted standardized, individual-level analysis using harmonized models, exposures, outcomes, and covariates. Findings were centrally pooled using random-effects meta-analysis. Heterogeneity was examined by age, sex, race, diabetes, statins, aspirin, omega-6 levels, and FADS desaturase genes. MAIN OUTCOMES AND MEASURES Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI). RESULTS The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with omega-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue. Median age at baseline was 59 years (range, 18-97 years), and 28 660 (62.8%) were male. In continuous (per 1-SD increase) multivariable-adjusted analyses, the omega-3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses. CONCLUSIONS AND RELEVANCE On the basis of available studies of free-living populations globally, biomarker concentrations of seafood and plant-derived omega-3 fatty acids are associated with a modestly lower incidence of fatal CHD. C1 [Del Gobbo, Liana C.; Yakoob, Mohammad Y.; Ingelsson, Erik] Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA. [Imamura, Fumiaki] Univ Cambridge, Sch Clin Med, Epidemiol Unit, Med Res Council,Inst Metab Sci, Cambridge, England. [Aslibekyan, Stella] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL USA. [Marklund, Matti; Riserus, Ulf] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden. [Virtanen, Jyrki K.; Voutilainen, Sari] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Joensuu, Finland. [Wennberg, Maria; Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Chiuve, Stephanie E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Chiuve, Stephanie E.; Rimm, Eric B.; Stampfer, Meir; Willett, Walter C.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [dela Cruz, Luicito; Hodge, Allison M.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Frazier-Wood, Alexis C.] ARS, USDA, Childrens Nutr Res Ctr, Baylor Coll Med, Houston, TX USA. [Fretts, Amanda M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Guallar, Eliseo; Woodward, Mark] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Matsumoto, Chisa] Tokyo Med Univ, Div Cardiol, Tokyo, Japan. [Matsumoto, Chisa; Djousse, Luc] Brigham & Womens Hosp, Div Aging, 75 Francis St, Boston, MA 02115 USA. [Matsumoto, Chisa; Djousse, Luc; Hu, Frank B.; Rimm, Eric B.; Stampfer, Meir; Willett, Walter C.] Harvard Med Sch, Boston, MA USA. [Prem, Kiesha; Koh, Woon-Puay; van Dam, Rob M.] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Tanaka, Tosh] NIA, Translat Gerontol Branch, Bethesda, MD 20892 USA. [Wu, Jason H. Y.; Woodward, Mark] Univ Sydney, George Inst Global Hlth, Sydney Med Sch, Sydney, NSW, Australia. [Zhou, Xia; Steffen, Lyn M.; Steffen, Brian T.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Helmer, Catherine; Barberger-Gateau, Pascale; Samieri, Cecilia] Inst Sante Publ Epidemiol & Dev, Inst Natl Sante & Rech Med, Ctr Inst Natl Sante & Rech Med Epidemiol Biostat, Bordeaux, France. [Helmer, Catherine; Barberger-Gateau, Pascale; Samieri, Cecilia] Univ Bordeaux, Inst Sante Publ Epidemiol & Dev, Ctr Inst Natl Sante & Rech Med Epidemiol Biostat, Bordeaux, France. [Ingelsson, Erik; Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Yuan, Jian-Min] Univ Pittsburgh, Div Canc Control & Populat Sci, Inst Canc, Pittsburgh, PA USA. [Yuan, Jian-Min] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Campos, Hannia; Hu, Frank B.; Rimm, Eric B.; Stampfer, Meir; van Dam, Rob M.; Willett, Walter C.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Chaves, Paulo H. M.] Florida Int Univ, Benjamin Leon Ctr Geriatr Res & Educ, Miami, FL 33199 USA. [Gomez-Aracena, Jose] Univ Malaga, Dept Prevent Med, Malaga, Spain. [Hu, Frank B.; Rimm, Eric B.; Stampfer, Meir; Willett, Walter C.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Johansson, Ingegerd] Umea Univ, Dept Odontol, Umea, Sweden. [Khaw, Kay-Tee; Luben, Robert N.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Koh, Woon-Puay] Duke NUS Grad Med Sch Singapore, Singapore, Singapore. [Lemaitre, Rozenn N.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Franks, Paul W.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Lund, Sweden. [Siscovick, David S.] New York Acad Med, New York, NY USA. [Tsai, Michael Y.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [van Dam, Rob M.] Natl Univ Singapore, Dept Med, Yong Loo Lin Sch Med, Singapore, Singapore. [van Dam, Rob M.] Natl Univ Hlth Syst, Singapore, Singapore. [Woodward, Mark] Univ Oxford, George Inst Global Hlth, Nuffield Dept Publ Hlth, Oxford, England. [Mozaffarian, Dariush] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. RP Del Gobbo, LC (reprint author), Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA. EM delgobbo@stanford.edu RI HELMER, Catherine/I-6581-2015; Samieri, Cecilia/E-3334-2014; Djousse, Luc/F-5033-2017 OI HELMER, Catherine/0000-0002-5169-7421; Samieri, Cecilia/0000-0001-9809-7506; Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, R01HL081549, UM1 CA167552, R01 HL35464, AA11181, HL35464, CA55075, HL60712, P30 DK46200, UM1 CA186107, R01 CA49449, R01 HL034594, P01CA87969, R01HL034594, R01HL088521, UM1 CA182876, R01CA 144034, UL1RR025005]; National Institute on Aging [R01AG023629]; Dutch Ministry of Health; Cancer Research Switzerland [AKT76]; Swiss National Science Foundation [32-9257-87]; Medical Research Council; Medical Research Council Epidemiology Unit [MC_UU_12015/5]; Intramural Research Program of the National Institutes of Health [N01-AG-916413, N01-AG821336, 263 MD 9164 13, 263 MD 821336]; Academy of Finland, Helsinki, Finland [1041086, 41471]; VicHealth; Australia's National Health and Medical Research Council [209057, 251553, 504711]; Swedish Cancer Society; Swedish Research Council; National Cancer Institute [R21 HL088081, CA-34944, CA-40360, CA-097193]; Fondation pour la Recherche Medicale; Caisse Nationale Maladie des Travailleurs Salaries; Direction Generale de la Sante; Institut de la Longevite; Conseils Regionaux d'Aquitaine et Bourgogne; Fondation de France; Ministry of Research-Institut National de la Sante et de la Recherche Medicale Programme Cohortes et collections de donnees biologiques; grant COGINUT from the Agence Nationale de la Recherche [ANR-06-PNRA-005]; grant FCS from the Fondation Plan Alzheimer; Caisse Nationale pour la Solidarite et l'Autonomie; Scottish Health Department Chief Scientist Organization; British Heart Foundation; FP Fleming Trust; Singapore National Medical Research Council [NMRC 1270/2010]; Swedish Research Council for Health, Working Life and Welfare; Uppsala City Council; National Institutes of Health Roadmap for Medical Research; National Institute of Neurological Disorders and Stroke; Commission of the European Communities; Cancer Research UK; Italian Ministry of Health [ICS 110.1\RS97.71]; Cancer Council Victoria; MGEN; Fondation Plan Alzheimer; [N01HC85082]; [N01HC85083]; [N01HC85086]; [U01HL080295]; [N01-HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [UL1-TR-001079]; [UL1-TR000040]; [N02-HL-64278]; [HL-34595]; [HL-26490]; [N01HC85081] FX The Atherosclerosis Risk in Communities study was performed as a collaborative study supported by contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, and R01HL086694 from the National Heart, Lung, and Blood Institute; contract U01HG004402 from the National Human Genome Research Institute; and contract HHSN268200625226C from the National Institutes of Health. We thank the staff and participants of the Atherosclerosis Risk in Communities study for their important contributions. Infrastructure was partly supported by grant UL1RR025005, a component of the National Institutes of Health and National Institutes of Health Roadmap for Medical Research. The Cardiovascular Health Study (CHS) was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grant U01HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by grant R01AG023629 from the National Institute on Aging. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI. org. The Costa Rican adult study was supported by grant R01HL081549 from the National Institutes of Health. The European Study on Antioxidants, Myocardial Infarction and Cancer was supported by the Commission of the European Communities, as a Concerted Action within Directorate General-XII, with additional support from Directorate General-V Europe against Cancer. The national studies were financed by the Dutch Ministry of Health. Ulster Cancer Foundation and Milk Intervention Board, grant AKT76 from Cancer Research Switzerland, grant 32-9257-87 from the Swiss National Science Foundation, The Spanish Fondo de Investigaciones Sanitarias and Ministry of Science and Education, and German Federal Health Office. EPIC-Norfolk was funded by grants from Medical Research Council and Cancer Research UK. Dr Imamura received support from grant MC_UU_12015/5 from the Medical Research Council Epidemiology Unit. The Health Professionals Follow-up Study (HPFS) was supported by grants UM1 CA167552, R01 HL35464, AA11181, HL35464, CA55075, HL60712, and P30 DK46200 from the National Institutes of Health. The InChianti study was supported by grant ICS 110.1\RS97.71 as a targeted project by the Italian Ministry of Health and in part by contracts N01-AG-916413, N01-AG821336, 263 MD 9164 13, and 263 MD 821336 from the Intramural Research Program of the National Institutes of Health. The Kuopio Ischaemic Heart Disease Risk Factor Study was supported by grants 41471 and 1041086 from the Academy of Finland, Helsinki, Finland. The Melbourne Collaborative Cohort Study recruitment was funded by VicHealth and Cancer Council Victoria and was further supported by grants 209057, 251553, and 504711 from Australia's National Health and Medical Research Council and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. The Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with MESA investigators.; Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, and UL1-TR000040 from the National Heart, Lung, and Blood Institute. Funding for SHARe genotyping was provided by contract N02-HL-64278 from the National Heart, Lung, and Blood Institute. Genotyping was performed at Affymetrix and the Broad Institute of Harvard and MIT using the Affymetrix Genome-Wide Human SNP Array 6.0. The Northern Sweden Health and Disease Studies I and II were supported by the Swedish Cancer Society and the Swedish Research Council. The Nurses Health Study was supported by research grants UM1 CA186107, R01 CA49449, R01 HL034594, P01CA87969, R01HL034594, and R01HL088521 from the National Institutes of Health. The Physician's Health Study was supported by grants R21 HL088081, CA-34944, CA-40360, and CA-097193 from the National Cancer Institute and grants HL-26490 and HL-34595 from the National Heart, Lung, and Blood Institute. The Three-City study was conducted under a partnership agreement between the Institut National de la Sante et de la Recherche Medicale, the University Bordeaux 2 Victor Segalen, and Sanofi. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The Three-City study was also supported by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, MGEN, Institut de la Longevite, Conseils Regionaux d'Aquitaine et Bourgogne, Fondation de France, Ministry of Research-Institut National de la Sante et de la Recherche Medicale Programme Cohortes et collections de donnees biologiques, grant COGINUT ANR-06-PNRA-005 from the Agence Nationale de la Recherche, grant FCS 2009-2012 from the Fondation Plan Alzheimer, and the Caisse Nationale pour la Solidarite et l'Autonomie. Dr Samieri was sponsored by a grant from the Fondation Plan Alzheimer. The Scottish Heart Health Extended Cohort study was funded by the Scottish Health Department Chief Scientist Organization, British Heart Foundation, and FP Fleming Trust. The Singapore Chinese Health Study was supported by grant NMRC 1270/2010 from the Singapore National Medical Research Council and grants R01CA 144034 and UM1 CA182876 from the National Institutes of Health. The Uppsala Longitudinal Studies of Adult Men 50 and 70 were funded by the Swedish Research Council for Health, Working Life and Welfare, Uppsala City Council, and Swedish Research Council. NR 58 TC 9 Z9 9 U1 11 U2 16 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG PY 2016 VL 176 IS 8 BP 1155 EP 1166 DI 10.1001/jamainternmed.2016.2925 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DT0AN UT WOS:000381145000027 PM 27357102 ER PT J AU Chen, SC Pearson, SD AF Chen, Stephanie C. Pearson, Steven D. TI Policy Framework for Covering Preventive Services Without Cost Sharing Saving Lives and Saving Money? SO JAMA INTERNAL MEDICINE LA English DT Review ID VALUE-BASED INSURANCE; TASK-FORCE AB The US Affordable Care Act mandates that private insurers cover a list of preventive services without cost sharing. The list is determined by 4 expert committees that evaluate the overall health effect of preventive services. We analyzed the process by which the expert committees develop their recommendations. Each committee uses different criteria to evaluate preventive services and none of the committees consider cost systematically. We propose that the existing committees adopt consistent evidence review methodologies and expand the scope of preventive services reviewed and that a separate advisory committee be established to integrate economic considerations into the final selection of free preventive services. The comprehensive framework and associated criteria are intended to help policy makers in the future develop a more evidence-based, consistent, and ethically sound approach. C1 [Chen, Stephanie C.; Pearson, Steven D.] NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Pearson, Steven D.] Inst Clin & Econ Review, Boston, MA USA. RP Pearson, SD (reprint author), Dept Bioeth, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. EM pearsonsd@cc.nih.gov FU Intramural Research Program at the National Institutes of Health (NIH) FX This research is supported by the Intramural Research Program at the National Institutes of Health (NIH). NR 20 TC 2 Z9 2 U1 3 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG PY 2016 VL 176 IS 8 BP 1185 EP 1189 DI 10.1001/jamainternmed.2016.3052 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA DT0AN UT WOS:000381145000031 PM 27366833 ER PT J AU Griffith, LM Cowan, MJ Notarangelo, LD Kohn, DB Puck, JM Shearer, WT Burroughs, LM Torgerson, TR Decaluwe, H Haddad, E AF Griffith, Linda M. Cowan, Morton J. Notarangelo, Luigi D. Kohn, Donald B. Puck, Jennifer M. Shearer, William T. Burroughs, Lauri M. Torgerson, Troy R. Decaluwe, Helene Haddad, Elie TI Primary Immune Deficiency Treatment Consortium (PIDTC) update SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Allogeneic hematopoietic cell transplantation; gene therapy; primary immunodeficiency; clinical trial ID SEVERE COMBINED IMMUNODEFICIENCY; STEM-CELL TRANSPLANTATION; WISKOTT-ALDRICH-SYNDROME; CHRONIC GRANULOMATOUS-DISEASE; CLASS-SWITCH RECOMBINATION; GENE-THERAPY; HEMATOLOGIC MALIGNANCIES; NEUROCOGNITIVE FUNCTION; SEVERE INFECTIONS; T-CELLS AB The Primary Immune Deficiency Treatment Consortium (PIDTC) is a collaboration of 41 North American centers studying therapy for rare primary immune deficiency diseases (PIDs), including severe combined immune deficiency (SCID), Wiskott-Aldrich syndrome (WAS), and chronic granulomatous disease (CGD). An additional 3 European centers have partnered with the PIDTC to study CGD. Natural history protocols of the PIDTC analyze outcomes of treatment for rare PIDs in multicenter longitudinal retrospective, prospective, and cross-sectional studies. Since 2009, participating centers have enrolled more than 800 subjects on PIDTC protocols for SCID, and enrollment in the studies on WAS and CGD is underway. Four pilot projects have been funded, and 12 junior investigators have received fellowship awards. Important publications of the consortium describe the outcomes of hematopoietic cell transplantation for SCID during 2000-2009, diagnostic criteria for SCID, and the pilot project of newborn screening for SCID in the Navajo Nation. The PIDTC Annual Scientific Workshops provide an opportunity to strengthen collaborations with junior investigators, patient advocacy groups, and international colleagues. Funded by the National Institute of Allergy and Infectious Diseases and the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, the PIDTC has recently received renewal for another 5 years. Here we review accomplishments of the group, projects underway, highlights of recent workshops, and challenges for the future. C1 [Griffith, Linda M.] NIAID, Div Allergy Immunol & Transplantat, NIH, 5601 Fishers Ln,Rm 7D49, Bethesda, MD 20892 USA. [Cowan, Morton J.; Puck, Jennifer M.] Univ Calif San Francisco, Div Allergy Immunol & Blood & Marrow Transplantat, Dept Pediat, San Francisco, CA 94143 USA. [Cowan, Morton J.; Puck, Jennifer M.] Univ Calif San Francisco, UCSF Benioff Childrens Hosp, San Francisco, CA 94143 USA. [Notarangelo, Luigi D.] Harvard Med Sch, Childrens Hosp, Div Immunol, Boston, MA USA. [Notarangelo, Luigi D.] Harvard Med Sch, Harvard Stem Cell Inst, Boston, MA USA. [Kohn, Donald B.] Univ Calif Los Angeles, Dept Microbiol, Los Angeles, CA 90024 USA. [Kohn, Donald B.] Univ Calif Los Angeles, Dept Immunol & Mol Genet, Los Angeles, CA 90024 USA. [Kohn, Donald B.] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Shearer, William T.] Texas Childrens Hosp, Baylor Coll Med, Pediat Allergy & Immunol, Houston, TX 77030 USA. [Burroughs, Lauri M.] Univ Washington, Fred Hutchinson Canc Res Ctr, Sch Med, Pediat Hematol Oncol, Seattle, WA 98195 USA. [Torgerson, Troy R.] Univ Washington, Sch Med, Seattle Childrens Res Inst, Pediat Rheumatol, Seattle, WA USA. [Decaluwe, Helene; Haddad, Elie] Univ Montreal, Mother & Child Ste Justine Hosp, Pediat Immunol & Pediat, Montreal, PQ H3C 3J7, Canada. RP Griffith, LM (reprint author), NIAID, Div Allergy Immunol & Transplantat, NIH, 5601 Fishers Ln,Rm 7D49, Bethesda, MD 20892 USA. EM LGriffith@niaid.nih.gov OI Decaluwe, Helene/0000-0001-6617-0633 FU Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID); Intramural Research Program of the NIAID; Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Md [U54-AI082973, U54-NS064808, U01-TR001263, R13-AI094943]; Immune Deficiency Foundation, Towson, Md; Jeffrey Modell Foundation, New York, NY; David Center, Texas Children's Hospital, Houston, Tex; John P. McGovern Foundation, Houston, Tex; Seattle Cancer Care Alliance, Seattle, Wash; Seattle Children's Research Institute and Seattle Children's Hospital, Seattle, Wash; AbbVie, St-Laurent, Quebec, Canada; ADMA Biologics, Ramsey, NJ; Baxalta, Deerfield, Ill; Bristol-Myers Squibb Canada, St-Laurent, Quebec, Canada; CSL Behring, King of Prussia, Pa; CSL Behring, Ottawa, Ontario, Canada; GRI-FOLS Canada, Mississauga, Ontario, Canada; Horizon Pharma USA, Deerfield, Ill; Miltenyi Biotec, Auburn, Calif; Octapharma Canada, Toronto, Ontario, Canada; Otsuka Canada Pharmaceutical, St-Laurent, Quebec, Canada; Sigma-Tau Pharmaceuticals, Gaithersburg, Md; ORDR, NCATS; Division of Allergy Immunology and Transplantation (DAIT), NIAID FX Supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID); the Intramural Research Program of the NIAID; and the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Md: U54-AI082973 (PI: M. J. Cowan), U54-NS064808 and U01-TR001263 (PI: J. P. Krischer), and R13-AI094943 (PIs: M. J. Cowan, L. D. Notarangelo). The workshops were also supported in part by the Immune Deficiency Foundation, Towson, Md; the Jeffrey Modell Foundation, New York, NY; the David Center, Texas Children's Hospital, Houston, Tex; the John P. McGovern Foundation, Houston, Tex; Seattle Cancer Care Alliance, Seattle, Wash; Seattle Children's Research Institute and Seattle Children's Hospital, Seattle, Wash; AbbVie, St-Laurent, Quebec, Canada; ADMA Biologics, Ramsey, NJ; Baxalta, Deerfield, Ill; Bristol-Myers Squibb Canada, St-Laurent, Quebec, Canada; CSL Behring, King of Prussia, Pa; CSL Behring, Ottawa, Ontario, Canada; GRI-FOLS Canada, Mississauga, Ontario, Canada; Horizon Pharma USA, Deerfield, Ill; Miltenyi Biotec, Auburn, Calif; Octapharma Canada, Toronto, Ontario, Canada; Otsuka Canada Pharmaceutical, St-Laurent, Quebec, Canada; and Sigma-Tau Pharmaceuticals, Gaithersburg, Md. The Primary Immune Deficiency Treatment Consortium (PIDTC) is a part of the Rare Diseases Clinical Research Network (RDCRN) of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), and is sponsored by the ORDR, NCATS, and the Division of Allergy Immunology and Transplantation (DAIT), NIAID. The opinions expressed are those of the authors and do not represent the position of the NIAID, the ORDR, the NCATS, the NIH, or the US Government. NR 57 TC 2 Z9 2 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2016 VL 138 IS 2 BP 375 EP 385 DI 10.1016/j.jaci.2016.01.051 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA DS5PY UT WOS:000380835800006 PM 27262745 ER PT J AU Mendola, P Wallace, M Hwang, BS Liu, DP Robledo, C Mannisto, T Sundaram, R Sherman, S Ying, Q Grantz, KL AF Mendola, Pauline Wallace, Maeve Hwang, Beom Seuk Liu, Danping Robledo, Candace Mannisto, Tuija Sundaram, Rajeshwari Sherman, Seth Ying, Qi Grantz, Katherine L. TI Preterm birth and air pollution: Critical windows of exposure for women with asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; pregnancy; preterm birth; air pollution ID TIME-SERIES-ANALYSIS; PREGNANCY OUTCOMES; PARTICULATE MATTER; CHILDREN BORN; COHORT; PARTICLES; RISK; PRECONCEPTION; PENNSYLVANIA; METAANALYSIS AB Ambient air pollutants may increase preterm birth (PTB) risk, but critical exposure windows are uncertain. The interaction of asthma and pollutant exposure is rarely studied. Objective: We sought to assess the interaction of maternal asthma and air pollutant exposures in relation to PTB risk. Methods: Electronic medical records for 223,502 US deliveries were linked with modified Community Multiscale Air Quality model outputs. Logistic regression with generalized estimating equations estimated the odds ratio and 95% CIs for PTB on the basis of the interaction of maternal asthma and particulate matter with aerodynamic diameter of less than 2.5 microns and particulate matter with aerodynamic diameter of less than 10 microns, ozone (O-3), nitrogen oxides (NOx), sulfur dioxide (SO2), and carbon monoxide (CO) per interquartile range. For each gestational week 23 to 36, exposures among women who delivered were compared with those remaining pregnant. Three-month preconception, whole pregnancy, weeks 1 to 28, and the last 6 weeks of gestation averages were also evaluated. Results: On assessing PTB by gestational week, we found that significant asthma interactions were sporadic before 30 weeks but more common during weeks 34 to 36, with higher risk among mothers with asthma for NOx, CO, and SO2 exposure and an inverse association with O-3 in week 34. Odds of PTB were significantly higher among women with asthma for CO and NOx exposure preconception and early in pregnancy. In the last 6 weeks of pregnancy, PTB risk associated with particulate matter with aerodynamic diameter of less than 10 microns was higher among women with asthma. Conclusions: Mothers with asthma may experience a higher risk for PTB after exposure to traffic-related pollutants such as CO and NOx, particularly for exposures 3-months preconception and in the early weeks of pregnancy. C1 [Mendola, Pauline; Wallace, Maeve; Hwang, Beom Seuk; Liu, Danping; Sundaram, Rajeshwari; Grantz, Katherine L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, 6100 Execut Blvd,Rm 7B03F, Rockville, MD 20852 USA. [Robledo, Candace] Univ North Texas, Hlth Sci Ctr, Dept Behav & Community Hlth, Ft Worth, TX USA. [Mannisto, Tuija] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Oulu, Finland. [Mannisto, Tuija] Northern Finland Lab Ctr Nordlab, Oulu, Finland. [Mannisto, Tuija] Univ Oulu, Dept Clin Chem, Oulu, Finland. [Sherman, Seth] Emmes Corp, Rockville, MD USA. [Ying, Qi] Texas A&M Univ, Zachary Dept Civil Engn, College Stn, TX USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, 6100 Execut Blvd,Rm 7B03F, Rockville, MD 20852 USA. EM pauline.mendola@nih.gov OI Mannisto, Tuija/0000-0002-6382-9153; Mendola, Pauline/0000-0001-5330-2844; Sundaram, Rajeshwari/0000-0002-6918-5002; Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Air Quality and Reproductive Health Study [HHSN275200800002I, HHSN27500008]; [HHSN267200603425C] 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 (NICHD), including funding for the Consortium on Safe Labor (Contract No. HHSN267200603425C) and the Air Quality and Reproductive Health Study (Contract No. HHSN275200800002I, Task Order No. HHSN27500008). This article has been cleared for publication by the NICHD, but the funding source had no role in the design, analysis, interpretation, or writing of the manuscript. Disclosure of potential conflict of interest: T. Mannisto has received grants from Laboratoriolaaketieteen edistamissaatio and Paulo Foundation. NR 42 TC 1 Z9 1 U1 8 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2016 VL 138 IS 2 BP 432 EP + DI 10.1016/j.jaci.2015.12.1309 PG 14 WC Allergy; Immunology SC Allergy; Immunology GA DS5PY UT WOS:000380835800013 PM 26944405 ER PT J AU Hsu, AP West, RR Calvo, KR Cuellar-Rodriguez, J Parta, M Kelly, SJ Ganson, NJ Hershfield, MS Holland, SM Hickstein, DD AF Hsu, Amy P. West, Robert R. Calvo, Katherine R. Cuellar-Rodriguez, Jennifer Parta, Mark Kelly, Susan J. Ganson, Nancy J. Hershfield, Michael S. Holland, Steven M. Hickstein, Dennis D. TI Adenosine deaminase type 2 deficiency masquerading as GATA2 deficiency: Successful hematopoietic stem cell transplantation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID EOSINOPHILIC ESOPHAGITIS; ELIMINATION DIET; MONOMAC SYNDROME; ADA2; MUTATIONS; IDENTIFICATION; VASCULOPATHY; CHILDREN; FOODS C1 [Hsu, Amy P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [West, Robert R.; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Calvo, Katherine R.] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Cuellar-Rodriguez, Jennifer] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Infect Dis, Mexico City, DF, Mexico. [Parta, Mark] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD USA. [Kelly, Susan J.; Ganson, Nancy J.; Hershfield, Michael S.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Hershfield, Michael S.] Duke Univ, Sch Med, Dept Biochem, Durham, NC USA. RP Hickstein, DD (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. EM hicksted@mail.nih.gov FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS [Z99 AI999999]; NCI NIH HHS [HHSN261200800001E] NR 12 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2016 VL 138 IS 2 BP 628 EP 630 DI 10.1016/j.jaci.2016.03.016 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA DS5PY UT WOS:000380835800047 PM 27130863 ER PT J AU Olfson, M King, M Schoenbaum, M AF Olfson, Mark King, Marissa Schoenbaum, Michael TI Stimulant Treatment of Young People in the United States SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; MENTAL-HEALTH-CARE; IMMEDIATE-RELEASE METHYLPHENIDATE; COMMUNITY SAMPLE; ADHD SYMPTOMS; US CHILDREN; SERVICE USE; TRENDS; PRESCHOOLERS AB Objective: To describe national stimulant treatment patterns among young people focusing on patient age and prescribing specialty. Methods: Stimulant prescriptions to patients aged 3-24 were analyzed from the 2008 IMS LifeLink LRx Longitudinal Prescription database (n = 3,147,352), which includes 60% of all U.S. retail pharmacies. A subset of young people from 2009 with service claims (n = 197,654) were also analyzed. Denominators were adjusted to generalize estimates to the U.S. population. Population percentages filling >= 1 stimulant prescription during the study year by sex and age group (younger children, 3-5 years; older children, 6-12 years; adolescents, 13-18 years; and young adults, 19-24 years) were determined. Percentages prescribed stimulants by psychiatrists, child and adolescent psychiatrists, pediatricians, and other physicians were also determined along with percentages that were treated for a long or short duration; coprescribed other psychotropic medications; used psychosocial services; and received clinical psychiatric diagnoses. Results: Population percentages with any stimulant use varied across younger children (0.4%), older children (4.5%), adolescents (4.0%), and young adults (1.7%). Among children and adolescents, males were over twice as likely as females to receive stimulants. Percentages of stimulant-treated young people with >= 1 stimulant prescription from a child and adolescent psychiatrist varied from younger children (19.1%), older children (17.1%), and adolescents (18.2%) to young adults (10.1%), and these percentages increased among those who were also prescribed other psychotropic medications: young children (31.0%), older children (37.9%), adolescents (35.1%), and young adults (15.8%). Antipsychotics were the most commonly coprescribed class to stimulant-treated younger (15.0%) and older children (11.8%), while antidepressants were most commonly coprescribed to adolescents (17.5%) and young adults (23.9%). Conclusions: Stimulant treatment peaks during middle childhood, especially for boys. For young people treated with stimulants, including younger children, low rates of treatment by child and adolescent psychiatrists highlight difficulties with access to specialty mental health services. C1 [Olfson, Mark] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Olfson, Mark] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [King, Marissa] Yale Sch Management, New Haven, CT USA. [Schoenbaum, Michael] NIMH, Off Sci Policy Planning & Commun, NIH, Bethesda, MD 20892 USA. RP Olfson, M (reprint author), Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Dept Psychiat, 1051 Riverside Dr, New York, NY 10032 USA. EM mo49@cumc.columbia.edu FU National Institutes of Health; New York State Psychiatric Institute FX This research was funded by contracts from the National Institutes of Health to Yale University (M.K.) and Columbia University (M.O.). M.O. is also supported by the New York State Psychiatric Institute. NR 41 TC 0 Z9 0 U1 4 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD AUG PY 2016 VL 26 IS 6 BP 520 EP 526 DI 10.1089/cap.2015.0228 PG 7 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA DU6FA UT WOS:000382308300005 PM 26982632 ER PT J AU Hotchkiss, L Donkervoort, S Leach, ME Mohassel, P Bharucha-Goebel, DX Bradley, N Nguyen, D Hu, Y Gurgel-Giannetti, J Bonnemann, CG AF Hotchkiss, Leslie Donkervoort, Sandra Leach, Meganne E. Mohassel, Payam Bharucha-Goebel, Diana X. Bradley, Nathaniel Nguyen, David Hu, Ying Gurgel-Giannetti, Juliana Bonnemann, Carsten G. TI Novel De Novo Mutations in KIF1A as a Cause of Hereditary Spastic Paraplegia With Progressive Central Nervous System Involvement SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE hereditary spastic paraplegia; neuromuscular disorders; KIF1A; genetics ID MOTOR DOMAIN; PARAPARESIS; NEUROPATHY; KINESIN AB Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of disorders characterized by lower extremity spasticity and weakness. Recently, the first de novo mutations in KIF1A were identified in patients with an early-onset severe form of complicated hereditary spastic paraplegia. We report two additional patients with novel de novo mutations in KIF1A, hereby expanding the genetic spectrum of KIF1A-related hereditary spastic paraplegia. Both children presented with spastic paraplegia and additional findings of optic nerve atrophy, structural brain abnormalities, peripheral neuropathy, cognitive/language impairment, and never achieved ambulation. In particular, we highlight the progressive nature of cerebellar involvement as captured on sequential magnetic resonance images (MRIs), thus linking the neurodegenerative and spastic paraplegia phenotypes. Exome sequencing in patient 1 and patient 2 identified novel heterozygous missense mutations in KIF1A at c.902G>A (p.R307Q) and c.595G>A (p.G199 R), respectively. Therefore, our report contributes to expanding the genotypic and phenotypic spectrum of hereditary spastic paraplegia caused by mutations in KIF1A. C1 [Hotchkiss, Leslie; Donkervoort, Sandra; Leach, Meganne E.; Mohassel, Payam; Bharucha-Goebel, Diana X.; Bradley, Nathaniel; Nguyen, David; Hu, Ying; Bonnemann, Carsten G.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Hotchkiss, Leslie] Weill Cornell Med Coll, New York, NY USA. [Leach, Meganne E.; Bharucha-Goebel, Diana X.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Gurgel-Giannetti, Juliana] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. RP Bonnemann, CG (reprint author), NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, Neurogenet Branch, NIH, Bldg 35 Porter NRC,Room 2A-116, Bethesda, MD 20892 USA. EM carsten.bonnemann@nih.gov FU NIH FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: All funding was provided by NIH. NR 12 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD AUG PY 2016 VL 31 IS 9 BP 1114 EP 1119 DI 10.1177/0883073816639718 PG 6 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA DS7DN UT WOS:000380943100003 PM 27034427 ER PT J AU Cherkassky, L Morello, A Villena-Vargas, J Feng, Y Dimitrov, DS Jones, DR Sadelain, M Adusumilli, PS AF Cherkassky, Leonid Morello, Aurore Villena-Vargas, Jonathan Feng, Yang Dimitrov, Dimiter S. Jones, David R. Sadelain, Michel Adusumilli, Prasad S. TI Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ANTIBODY-LIKE IMMUNORECEPTORS; ANTITUMOR-ACTIVITY; MESOTHELIN OVEREXPRESSION; ANTI-PD-1 ANTIBODY; PANCREATIC-CANCER; ADVANCED MELANOMA; HIGH-AFFINITY; CHIMERIC TCR; SOLID TUMORS; LUNG-CANCER AB Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies. C1 [Cherkassky, Leonid; Morello, Aurore; Villena-Vargas, Jonathan; Sadelain, Michel; Adusumilli, Prasad S.] Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, New York, NY 10021 USA. [Cherkassky, Leonid; Morello, Aurore; Villena-Vargas, Jonathan; Jones, David R.; Adusumilli, Prasad S.] Mem Sloan Kettering Canc Ctr, Dept Surg, Thorac Serv, New York, NY 10021 USA. [Feng, Yang; Dimitrov, Dimiter S.] NCI, Prot Interact Sect, Expt Immunol Lab, Canc & Inflammat Program,Ctr Canc Res,NIH, Frederick, MD 21701 USA. RP Adusumilli, PS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Surg, Thorac Serv, Ctr Cell Engn, 1275 York Ave, New York, NY 10065 USA. EM adusumip@mskcc.org FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH); NIH [P30 CA008748, P50 CA086438-13]; US Department of Defense [PR101053, LC110202, BC132124]; Commonwealth Foundation for Cancer Research; Experimental Therapeutics Center; Stand Up To Cancer - Cancer Research Institute Cancer Immunology Translational Cancer research grant [SU2C-AACR-DT1012]; DallePezze Foundation; Derfner Foundation; American College of Surgeons resident research scholarship; ETC Edythe Griffinger Fellowship Program FX The authors' laboratory work was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), grants from the NIH (P30 CA008748 and P50 CA086438-13), the US Department of Defense (PR101053, LC110202, and BC132124), Mr. William H. Goodwin and Alice Goodwin, the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center, a Stand Up To Cancer - Cancer Research Institute Cancer Immunology Translational Cancer research grant (SU2C-AACR-DT1012), the DallePezze Foundation, the Derfner Foundation, the American College of Surgeons resident research scholarship, and the ETC Edythe Griffinger Fellowship Program. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. We thank David Sewell and Alex Torres of the Memorial Sloan Kettering Cancer Center (MSK) Thoracic Surgery Service for their editorial assistance. We also thank Nina Lampen and Laurent Schmitt for the electron microscopy image. NR 71 TC 14 Z9 14 U1 9 U2 13 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 AUG 1 PY 2016 VL 126 IS 8 BP 3130 EP 3144 DI 10.1172/JCI83092 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DU1BZ UT WOS:000381943000032 PM 27454297 ER PT J AU Liangpunsakul, S Gao, B AF Liangpunsakul, Suthat Gao, Bin TI Alcohol and fat promote steatohepatitis: a critical role for fat-specific protein 27/CIDEC SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Article DE Liver Diseases; Alcoholic; Fatty Liver ID ADIPOSE TRIGLYCERIDE LIPASE; ADIPOCYTE-SPECIFIC GENE; HEPATIC STEATOSIS; INSULIN SENSITIVITY; LIPID-METABOLISM; CIDE PROTEINS; LIVER-DISEASE; PATHOGENESIS; EXPRESSION; FSP27 AB Alcoholic liver disease (ALD) is a major public health problem worldwide and is the leading cause of end-stage liver disease. While the ultimate control of ALD will require the prevention of alcohol abuse, better understanding of the mechanisms of alcohol-induced liver injury may lead to treatments of fatty liver, alcoholic hepatitis, and prevention or delay of occurrence of cirrhosis. The elucidation and the discovery of several new concepts in ALD pathogenesis have raised our understanding on the complex mechanisms and the potential in developing the new strategies for therapeutic benefits. In this review, we provide the most up-to-date information on the basic molecular mechanisms focusing on the role of fat-specific protein 27/CIDEC in the pathogenesis of ALD. C1 [Liangpunsakul, Suthat] Indiana Univ Sch Med, Div Gastroenterol & Hepatol, Dept Med, Indianapolis, IN 46202 USA. [Liangpunsakul, Suthat] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Liangpunsakul, Suthat] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Liangpunsakul, Suthat] Richard L Roudebush Vet Adm Med Ctr, Indianapolis, IN USA. [Gao, Bin] NIAAA, Lab Liver Dis, Rockville, MD 20852 USA. RP Liangpunsakul, S (reprint author), Div Gastroenterol & Hepatol, 550 N Univ Blvd,UH 4100, Indianapolis, IN 46202 USA. EM sliangpu@iupui.edu FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health; VA Merit Award [1I01CX000361]; NIH [U01AA021840]; US DOD [W81XWH-12-1-0497] FX This work was supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (to BG), VA Merit Award 1I01CX000361, NIH U01AA021840, US DOD W81XWH-12-1-0497 (to SL). NR 34 TC 0 Z9 0 U1 7 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD AUG PY 2016 VL 64 IS 6 BP 1078 EP 1081 DI 10.1136/jim-2016-000204 PG 4 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA DV0BJ UT WOS:000382582300002 PM 27342423 ER PT J AU Henderson, BW Gentry, EG Rush, T Troncoso, JC Thambisetty, M Montine, TJ Herskowitz, JH AF Henderson, Benjamin W. Gentry, Erik G. Rush, Travis Troncoso, Juan C. Thambisetty, Madhav Montine, Thomas J. Herskowitz, Jeremy H. TI Rho-associated protein kinase 1 (ROCK1) is increased in Alzheimer's disease and ROCK1 depletion reduces amyloid- levels in brain SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Alzheimer's disease; amyloid-; mild cognitive impairment; Rho kinase; ROCK1; ROCK2 ID BETA PRODUCTION; GROWTH CONE; PHOSPHORYLATION; DEGENERATION; INHIBITION; MECHANISM; SYNAPSE; MICE AB Alzheimer's disease (AD) is the leading cause of dementia and mitigating amyloid- (A) levels may serve as a rational therapeutic avenue to slow AD progression. Pharmacologic inhibition of the Rho-associated protein kinases (ROCK1 and ROCK2) is proposed to curb A levels, and mechanisms that underlie ROCK2s effects on A production are defined. How ROCK1 affects A generation remains a critical barrier. Here, we report that ROCK1 protein levels were elevated in mild cognitive impairment due to AD (MCI) and AD brains compared to controls. A42 oligomers marginally increased ROCK1 and ROCK2 protein levels in neurons but strongly induced phosphorylation of Lim kinase 1 (LIMK1), suggesting that A42 activates ROCKs. RNAi depletion of ROCK1 or ROCK2 suppressed endogenous A40 production in neurons, and A40 levels were reduced in brains of ROCK1 heterozygous knock-out mice compared to wild-type littermate controls. ROCK1 knockdown decreased amyloid precursor protein (APP), and treatment with bafilomycin accumulated APP levels in neurons depleted of ROCK1. These observations suggest that reduction of ROCK1 diminishes A levels by enhancing APP protein degradation. Collectively, these findings support the hypothesis that both ROCK1 and ROCK2 are therapeutic targets to combat A production in AD. C1 [Henderson, Benjamin W.; Gentry, Erik G.; Rush, Travis; Herskowitz, Jeremy H.] Univ Alabama Birmingham, Ctr Neurodegenerat & Expt Therapeut, Birmingham, AL USA. [Henderson, Benjamin W.; Gentry, Erik G.; Rush, Travis; Herskowitz, Jeremy H.] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL USA. [Troncoso, Juan C.] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. [Troncoso, Juan C.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Thambisetty, Madhav] NIA, Unit Clin & Translat Neurosci, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Montine, Thomas J.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Herskowitz, Jeremy H.] Univ Alabama Birmingham, Dept Neurobiol, Birmingham, AL USA. RP Herskowitz, JH (reprint author), Univ Alabama Birmingham, Ctr Neurodegenerat & Expt Therapeut, Dept Neurol, 1825 Univ Blvd, Birmingham, AL 35294 USA.; Herskowitz, JH (reprint author), Univ Alabama Birmingham, Ctr Neurodegenerat & Expt Therapeut, Dept Neurobiol, 1825 Univ Blvd, Birmingham, AL 35294 USA. EM jhersko@uab.edu FU National Institutes of Health through NIA [AG043552-05]; New Investigator Research Grant from the Alzheimer's Association [2015-NIRG-339422]; Viral Vector Core of the Emory Neuroscience NINDS Core Facilities grant [P30NS055077]; Johns Hopkins University Alzheimer's Disease Research Center NIH [AG05146, AG05136]; Intramural Research Program of the NIH, National Institute on Aging FX This work was supported by the National Institutes of Health through NIA AG043552-05 to J.H.H. This work was also supported by a New Investigator Research Grant 2015-NIRG-339422 from the Alzheimer's Association to J.H.H. This research project was supported in part by the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities grant, P30NS055077, the Johns Hopkins University Alzheimer's Disease Research Center NIH AG05146 to Dr Juan Troncoso, and AG05136 to T.J.M. We are grateful to participants in the Baltimore Longitudinal Study of Aging for their invaluable contribution. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. We thank Drs James Lah, Allan Levey, and Erik Roberson for helpful discussions and Dr Jeremy Day's lab for technical assistance. The authors have no conflict of interest to declare. NR 24 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 IS 4 BP 525 EP 531 DI 10.1111/jnc.13688 PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU8ZZ UT WOS:000382507300004 PM 27246255 ER PT J AU Hediger, ML Fuchs, KM Grantz, KL Grewal, J Kim, S Gore-Langton, RE Louis, GMB D'Alton, ME Albert, PS AF Hediger, Mary L. Fuchs, Karin M. Grantz, Katherine L. Grewal, Jagteshwar Kim, Sungduk Gore-Langton, Robert E. Louis, Germaine M. Buck D'Alton, Mary E. Albert, Paul S. TI Ultrasound Quality Assurance for Singletons in the National Institute of Child Health and Human Development Fetal Growth SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE obstetrics; obstetric ultrasound; quality assurance; quality control; reliability; ultrasound ID REPRODUCIBILITY; RELIABILITY; BIOMETRY AB Objectives-To report on the ultrasound quality assurance program for the National Institute of Child Health and Human Development Fetal Growth Studies and describe both its advantages and generalizability. Methods-After training on an ultrasound system and software, research sonographers were expected to capture blank (unmeasured) images in triplicate for crown-rump length, biparietal diameter, head circumference, abdominal circumference, and femur length. A primary expert sonographer was designated and validated. A 5% sample (n = 740 of 14,785 scans) was randomly selected in 3 distinct rounds from within strata of maternal body mass index (round 1 only), gestational age, and research site. Unmeasured images were extracted from selected scans and measured with the ultrasound software by an expert sonographer. Correlations and coefficients of variation (CVs) were calculated, and the within-measurement standard deviation (ie, technical error of the measurement), was calculated. Results-The reliability between the site sonographers and the expert was high, with correlations exceeding 0.99 for all dimensions in all rounds. The CV % values showed low variability, with the percentage differences being less than 2%, except for abdominal circumference in rounds 2 and 3, in which it averaged about 3%. Correlations remained high (> 0.90) with increasing fetal size; there was a monotonic increase in technical errors of the measurement but without a corresponding increase in the CV %. Conclusions-Using rigorous procedures for training sonographers, coupled with quality assurance oversight, we determined that the measurements acquired longitudinally for singletons are both accurate and reliable for establishment of an ultrasound standard for fetal growth. C1 [Hediger, Mary L.; Grantz, Katherine L.; Grewal, Jagteshwar; Kim, Sungduk; Louis, Germaine M. Buck; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. [Fuchs, Karin M.; D'Alton, Mary E.] Columbia Univ, Dept Obstet & Gynecol, Med Ctr, New York, NY USA. [Gore-Langton, Robert E.] Emmes Corp, Rockville, MD USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Off Director, Div Intramural Populat Hlth Res, 6710B Rockledge Dr,MSC 7004, Rockville, MD 20817 USA. EM louisg@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural program [HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275200800003IC, HHSN275200800014C, HHSN275200800012C, HHSN275200800028C, HHSN275201000009C]; American Recovery and Reinvestment Act FX We thank the principal investigators at the clinical sites for their support and the site sonographers for their good and careful work. The principal investigators were: Anthony Sciscione, DO (Christiana Care Health System, Newark, DE); Deborah A. Wing, MD, MBA (University of California, Irvine, Long Beach Memorial Medical Center, Long Beach, CA; and Fountain Valley Regional Hospital and Medical Center, Fountain Valley, CA); William A. Grobman, MD, MBA (Northwestern University Feinberg School of Medicine, Chicago, IL); Roger B. Newman, MD (Medical University of South Carolina, Charleston, SC); Ronald Wapner, MD (Columbia University Medical Center, New York, NY); Daniel Skupski, MD (New York Hospital Queens, Flushing, NY); Angela C. Ranzini, MD (St Peter's University Hospital, New Brunswick, NJ); John Owen, MD, MSPH (University of Alabama at Birmingham, Birmingham, AL); Edward K. Chien, MD (Women and Infants Hospital of Rhode Island, Providence, RI); and Sabrina Craigo, MD (Tufts Medical Center, Boston, MA). We also thank Patricia Morgan, RDMS, who served as the primary expert sonographer, and George Bega, MD, who served as a backup expert for quality assurance (QA), for their contributions. Matthew Beyers (The Emmes Corporation) was instrumental in setting up the image management system to conduct the QA, and Scott McCrimmon (The Emmes Corporation) contributed his invaluable technical expertise in image management. This research was supported by funding through the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural program (contracts HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275200800003IC, HHSN275200800014C, HHSN275200800012C, HHSN275200800028C, and HHSN275201000009C) and included funding through the American Recovery and Reinvestment Act of 2009. NR 20 TC 0 Z9 0 U1 2 U2 2 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD AUG 1 PY 2016 VL 35 IS 8 BP 1725 EP 1733 DI 10.7863/ultra.15.09087 PG 9 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA DU9HJ UT WOS:000382527000013 PM 27353072 ER PT J AU Lee, JH Gamarel, KE Bryant, KJ Zaller, ND Operario, D AF Lee, Ji Hyun Gamarel, Kristi E. Bryant, Kendall J. Zaller, Nickolas D. Operario, Don TI Discrimination, Mental Health, and Substance Use Disorders Among Sexual Minority Populations SO LGBT HEALTH LA English DT Article DE discrimination; gender; mental health; sexual minorities; substance use ID UNITED-STATES; GENDER-DIFFERENCES; BISEXUAL ADULTS; PERCEIVED DISCRIMINATION; STRUCTURAL STIGMA; ALCOHOL-USE; STRESS; GAY; PREVALENCE; ABUSE AB Purpose: Sexual minority (lesbian, gay, bisexual) populations have a higher prevalence of mental health and substance use disorders compared to their heterosexual counterparts. Such disparities have been attributed, in part, to minority stressors, including distal stressors such as discrimination. However, few studies have examined associations between discrimination, mental health, and substance use disorders by gender among sexual minority populations. Methods: We analyzed data from 577 adult men and women who self-identified as lesbian, gay, or bisexual and participated in Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Six questions assessed discrimination due to sexual orientation. Weighted multivariable logistic regression examined associations between experiences of sexual orientation discrimination and both mental health and substance use disorders. Analyses were conducted separately for sexual minority men and women, adjusting for sociodemographic covariates. Results: Sexual minority men who ever experienced discrimination (57.4%) reported higher odds of any lifetime drug use disorder and cannabis use disorder compared to sexual minority men who never experienced discrimination. Sexual minority women who ever experienced discrimination (42.9%) reported higher odds of any lifetime mood disorder and any lifetime anxiety disorder compared to sexual minority women who never experienced discrimination. Conclusion: The findings suggest that discrimination is differentially associated with internalizing (mental health) and externalizing (substance use) disorders for sexual minority men and women. These findings indicate a need to consider how homophobia and heteronormative discrimination may contribute to distinct health outcomes for lesbian and bisexual women compared with gay and bisexual men. C1 [Lee, Ji Hyun; Operario, Don] Brown Univ, Sch Publ Hlth, 121 South Main St, Providence, RI 02906 USA. [Gamarel, Kristi E.] Brown Univ, Dept Psychiat & Human Behav, Warren Alpert Med Sch, Providence, RI 02912 USA. [Bryant, Kendall J.] NIAAA, Rockville, MD 20852 USA. [Zaller, Nickolas D.] Univ Arkansas, Fay W Boozman Coll Publ Hlth, Little Rock, AR 72204 USA. RP Operario, D (reprint author), Brown Univ, Sch Publ Hlth, 121 South Main St, Providence, RI 02906 USA. EM don_operario@brown.edu FU National Institute on Alcohol Abuse and Alcoholism [U24-AA022000, P01-AA019072]; National Institute of Mental Health [T32-MH07878] FX Funding was provided by the National Institute on Alcohol Abuse and Alcoholism (grants U24-AA022000 and P01-AA019072) and National Institute of Mental Health (grant T32-MH07878). NR 41 TC 0 Z9 0 U1 6 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2325-8292 EI 2325-8306 J9 LGBT HEALTH JI LGBT Health PD AUG PY 2016 VL 3 IS 4 BP 258 EP 265 DI 10.1089/lgbt.2015.0135 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DT4XM UT WOS:000381484700004 PM 27383512 ER PT J AU Avtanski, DB Nagalingam, A Tomaszewski, JE Risbood, P Difillippantonio, MJ Saxena, NK Malhotra, SV Sharma, D AF Avtanski, Dimiter B. Nagalingam, Arumugam Tomaszewski, Joseph E. Risbood, Prabhakar Difillippantonio, Michael J. Saxena, Neeraj K. Malhotra, Sanjay V. Sharma, Dipali TI Indolo-pyrido-isoquinolin based alkaloid inhibits growth, invasion and migration of breast cancer cells via activation of p53-miR34a axis SO MOLECULAR ONCOLOGY LA English DT Article DE p53; miR34a; Indolo-pyrido-isoquinolin based alkaloid; Breast cancer; EMT; Invasion ID EPITHELIAL-MESENCHYMAL TRANSITION; TUMOR-SUPPRESSOR; IN-VIVO; P53 FUNCTION; STEM-CELLS; MUTANT P53; MDM2; RESTORATION; PROMOTES; METASTASIS AB The tumor suppressor p53 plays a critical role in suppressing cancer growth and progression and is an attractive target for the development of new targeted therapies. We synthesized several indolo-pyrido-isoquinolin based alkaloids to activate p53 function and examined their therapeutic efficacy using NCI-60 screening. Here, we provide molecular evidence that one of these compounds, 11-methoxy-2,3,4,13-tetrahydro-1H-indolo [2',3':3,4]pyrido[1,2-b]isoquinolin-6-ylium-bromide (termed P18 or NSC-768219) inhibits growth and clonogenic potential of cancer cells. P18 treatment results in downregulation of mesenchymal markers and concurrent upregulation of epithelial markers as well as inhibition of migration and invasion. Experimental epithelial mesenchymal-transition (EMT) induced by exposure to TGF beta/TNF alpha is also completely reversed by P18. Importantly, P18 also inhibits mammosphere-formation along with a reduction in the expression of sternness factors, Oct4, Nanog and Sox2. We show that P18 induces expression, phosphorylation and accumulation of p53 in cancer cells. P18-mediated induction of p53 leads to increased nuclear localization and elevated expression of p53 target genes. Using isogenic cancer cells differing only in p53 status, we show that p53 plays an important role in P18 mediated alteration of mesenchymal and epithelial genes, inhibition of migration and invasion of cancer cells. Furthermore, P18 increases miR-34a expression in p53-dependent manner and miR-34a is integral for P18-mediated inhibition of growth, invasion and mammosphere-formation. miR-34a mimics potentiate P18 efficacy while miR-34a antagomirs antagonize P18. Collectively, these data provide evidence that P18 may represent a promising therapeutic strategy for the inhibition of growth and progression of breast cancer and p53-miR-34a axis is important for P18 function. (C) 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Avtanski, Dimiter B.; Nagalingam, Arumugam; Sharma, Dipali] Johns Hopkins Univ, Sch Med, Dept Oncol, 1650 Orleans St,CRB 1,Rm 145, Baltimore, MD 21231 USA. [Avtanski, Dimiter B.; Nagalingam, Arumugam; Sharma, Dipali] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21231 USA. [Tomaszewski, Joseph E.; Risbood, Prabhakar; Difillippantonio, Michael J.] NCI, Div Canc Treatment & Diag, NIH, Rockville, MD 20852 USA. [Sharma, Dipali] Johns Hopkins, Grad Program Cellular & Mol Med, Baltimore, MD 21231 USA. [Saxena, Neeraj K.] Univ Maryland, Sch Med, Dept Med, 660 W Redwood St,Howard Hall,Rm 301, Baltimore, MD 21201 USA. [Malhotra, Sanjay V.] Stanford Univ, Dept Radiat Oncol, Palo Alto, CA 94304 USA. [Malhotra, Sanjay V.] Stanford Univ, Stanford Canc Inst, Palo Alto, CA 94304 USA. RP Sharma, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, 1650 Orleans St,CRB 1,Rm 145, Baltimore, MD 21231 USA.; Saxena, NK (reprint author), Univ Maryland, Sch Med, Dept Med, 660 W Redwood St,Howard Hall,Rm 301, Baltimore, MD 21201 USA.; Sharma, D (reprint author), Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, 1650 Orleans St,CRB 1,Rm 145, Baltimore, MD 21231 USA.; Malhotra, SV (reprint author), Stanford Univ, Div Radiat & Canc Biol, Radiat Oncol, Palo Alto, CA USA. EM nsaxena@medicine.umaryland.edu; smalhotra@stanford.edu; dsharma7@jhmi.edu FU NIDDK NIH [K01DK077137, R03DK089130]; NCI NIH [R21CA185943, R01CA131294, R21CA155686]; Avon Foundation; NCI; NIH [HHSN261200800001E]; Breast Cancer Research Foundation (BCRF) [90047965] FX This work was supported by NIDDK NIH, K01DK077137, R03DK089130 and NCI NIH R21CA185943 (to NKS); NCI NIH R01CA131294, NCI NIH R21CA155686, Avon Foundation, NCI, NIH contract no. HHSN261200800001E (to SVM), Breast Cancer Research Foundation (BCRF) 90047965 (to DS). NR 52 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1574-7891 EI 1878-0261 J9 MOL ONCOL JI Mol. Oncol. PD AUG PY 2016 VL 10 IS 7 BP 1118 EP 1132 DI 10.1016/j.molonc.2016.04.003 PG 15 WC Oncology SC Oncology GA DU1FC UT WOS:000381952600013 PM 27259808 ER PT J AU Arthur, KC Calvo, A Price, TR Geiger, JT Chio, A Traynor, BJ AF Arthur, Karissa C. Calvo, Andrea Price, T. Ryan Geiger, Joshua T. Chio, Adriano Traynor, Bryan J. TI Projected increase in amyotrophic lateral sclerosis from 2015 to 2040 SO NATURE COMMUNICATIONS LA English DT Article ID MOTOR-NEURON DISEASE; EPIDEMIOLOGY; ALS; PREVALENCE AB Although amyotrophic lateral sclerosis (ALS) is relatively rare, the socioeconomic significance of the disease is extensive. It is therefore vital to project the epidemiologic trend of ALS. To date, there have been few published studies attempting to estimate the number and distribution of ALS cases in the upcoming years. Here we show that the number of ALS cases across the globe will increase from 222,801 in 2015 to 376,674 in 2040, representing an increase of 69%. This increase is predominantly due to ageing of the population, particularly among developing nations. This projection is likely an underestimate due to improving healthcare and economic conditions. The results should be used to inform healthcare policy to more efficiently allocate healthcare resources. C1 [Arthur, Karissa C.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Arthur, Karissa C.] Commonwealth Med Coll, Scranton, PA 18509 USA. [Calvo, Andrea; Chio, Adriano] Univ Turin, Rita Levi Montalcini Dept Neurosci, I-10124 Turin, Italy. [Calvo, Andrea; Chio, Adriano] Neurosci Inst Torino, I-10124 Turin, Italy. [Price, T. Ryan] NIA, Stat Genet Grp, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Geiger, Joshua T.] NINDS, Neurodegenerat Dis Res Unit, Neurogenet Lab, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Traynor, Bryan J.] Johns Hopkins Univ, Dept Neurol, Brain Sci Inst, Baltimore, MD 21205 USA. RP Traynor, BJ (reprint author), NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA.; Traynor, BJ (reprint author), Johns Hopkins Univ, Dept Neurol, Brain Sci Inst, Baltimore, MD 21205 USA. EM traynorb@mail.nih.gov FU Intramural Research Program of the US National Institutes of Health (NIH), National Institute on Aging [Z01-AG000949-02]; National Institute of Neurological Disorders and Stroke; NIH; European Community's Health Seventh Framework Programme [259867]; Joint Programme-Neurodegenerative Disease Research (Italian Ministry of Education and University) (Strength Project) FX This work was supported in part by the Intramural Research Program of the US National Institutes of Health (NIH), National Institute on Aging (Z01-AG000949-02) and National Institute of Neurological Disorders and Stroke. This research was made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute and the Colgate-Palmolive Company, as well as other private donors. For a complete list, please visit the Foundation website at http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. This work was supported in part by the European Community's Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867), the Joint Programme-Neurodegenerative Disease Research (Italian Ministry of Education and University) (Strength Project) and the Vialli and Mauro Foundation for ALS (grant no. 4). NR 37 TC 0 Z9 0 U1 12 U2 12 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 AUG PY 2016 VL 7 AR 12408 DI 10.1038/ncomms12408 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5MA UT WOS:000381526100001 PM 27510634 ER PT J AU Lamprecht, DA Finin, PM Rahman, MA Cumming, BM Russell, SL Jonnala, SR Adamson, JH Steyn, AJC AF Lamprecht, Dirk A. Finin, Peter M. Rahman, Md Aejazur Cumming, Bridgette M. Russell, Shannon L. Jonnala, Surendranadha R. Adamson, John H. Steyn, Adrie J. C. TI Turning the respiratory flexibility of Mycobacterium tuberculosis against itself SO NATURE COMMUNICATIONS LA English DT Article ID MULTIDRUG-RESISTANT TUBERCULOSIS; ESCHERICHIA-COLI; CORYNEBACTERIUM-GLUTAMICUM; CYTOCHROME BD; CLINICAL CANDIDATE; ENERGY-METABOLISM; N-ACETYLCYSTEINE; GLYCOLYTIC FLUX; ATP HOMEOSTASIS; CLOFAZIMINE AB The Mycobacterium tuberculosis (Mtb) electron transport chain (ETC) has received significant attention as a drug target, however its vulnerability may be affected by its flexibility in response to disruption. Here we determine the effect of the ETC inhibitors bedaquiline, Q203 and clofazimine on the Mtb ETC, and the value of the ETC as a drug target, by measuring Mtb's respiration using extracellular flux technology. We find that Mtb's ETC rapidly reroutes around inhibition by these drugs and increases total respiration to maintain ATP levels. Rerouting is possible because Mtb rapidly switches between terminal oxidases, and, unlike eukaryotes, is not susceptible to back pressure. Increased ETC activity potentiates clofazimine's production of reactive oxygen species, causing rapid killing in vitro and in a macrophage model. Our results indicate that combination therapy targeting the ETC can be exploited to enhance killing of Mtb. C1 [Lamprecht, Dirk A.; Finin, Peter M.; Rahman, Md Aejazur; Cumming, Bridgette M.; Russell, Shannon L.; Adamson, John H.; Steyn, Adrie J. C.] KwaZulu Natal Res Inst TB & HIV K RITH, K RITH Tower Bldg,Level 3,719 Umbilo Rd, ZA-4001 Durban, South Africa. [Finin, Peter M.] Univ Pittsburgh, Dept Internal Med, 1218 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. [Jonnala, Surendranadha R.] NIAID, TB Res Sect, NIH, 6610 Rockledge Dr, Bethesda, MD 20817 USA. [Steyn, Adrie J. C.] Univ Alabama Birmingham, Dept Microbiol, 1720 2nd Ave South, Birmingham, AL 35294 USA. [Steyn, Adrie J. C.] Univ Alabama Birmingham, Ctr AIDS Res, 1720 2nd Ave South, Birmingham, AL 35294 USA. [Steyn, Adrie J. C.] Univ Alabama Birmingham, Ctr Free Rad Biol, 1720 2nd Ave South, Birmingham, AL 35294 USA. RP Steyn, AJC (reprint author), KwaZulu Natal Res Inst TB & HIV K RITH, K RITH Tower Bldg,Level 3,719 Umbilo Rd, ZA-4001 Durban, South Africa.; Steyn, AJC (reprint author), Univ Alabama Birmingham, Dept Microbiol, 1720 2nd Ave South, Birmingham, AL 35294 USA.; Steyn, AJC (reprint author), Univ Alabama Birmingham, Ctr AIDS Res, 1720 2nd Ave South, Birmingham, AL 35294 USA.; Steyn, AJC (reprint author), Univ Alabama Birmingham, Ctr Free Rad Biol, 1720 2nd Ave South, Birmingham, AL 35294 USA. EM asteyn@uab.edu FU Strategic Health Innovation Partnerships (SHIP) Unit of the South African Medical Research Council; South African Department of Science and Technology; National Institutes of Health Grant [R01AI058131]; Department of Defence Award [W81XWH-13-1-0149]; UAB Centres for AIDS Research and Free Radical Biology; UKZN CHS; K-RITH; Victor Daitz Information Gateway, an initiative of the Victor Daitz Foundation; University of KwaZulu-Natal FX We thank Dr William Jacobs for Mtb mc26230, Dr Helena Boshoff for the Mtb cydKO mutant (generated in the lab of Dr Valerie Mizrahi) and qcrB SNP strains, and Dr Digby Warner for BDQ. Research reported in this publication was supported by the Strategic Health Innovation Partnerships (SHIP) Unit of the South African Medical Research Council with funds received from the South African Department of Science and Technology. Part of this work is supported by the National Institutes of Health Grant R01AI058131, Department of Defence Award W81XWH-13-1-0149 and the UAB Centres for AIDS Research and Free Radical Biology to AJCS. AJCS is a Burroughs Welcome Investigator in the Pathogenesis of Infectious Diseases. DAL received support from the UKZN CHS and K-RITH. PMF was a Howard Hughes Medical Institute Medical Research Fellow. Open access publication of this article has been made possible through support from the Victor Daitz Information Gateway, an initiative of the Victor Daitz Foundation and the University of KwaZulu-Natal. NR 61 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2016 VL 7 AR 12393 DI 10.1038/ncomms12393 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5LY UT WOS:000381525900001 PM 27506290 ER PT J AU Benveniste, O Rider, LG AF Benveniste, Olivier Rider, Lisa G. CA ENMC Myositis Outcomes Study Grp TI 213th ENMC International Workshop: Outcome measures and clinical trial readiness in idiopathic inflammatory myopathies, Heemskerk, The Netherlands, 18-20 September 2015 SO NEUROMUSCULAR DISORDERS LA English DT Article ID QUALITY-OF-LIFE; INCLUSION-BODY MYOSITIS; CUTANEOUS ASSESSMENT-TOOL; TERM-FOLLOW-UP; DERMATOMYOSITIS DISEASE AREA; INTERSTITIAL LUNG-DISEASE; FUNCTIONAL RATING-SCALE; ADULT MUSCLE DISEASE; JUVENILE DERMATOMYOSITIS; PULMONARY-FIBROSIS C1 [Benveniste, Olivier] Hop La Pitie Salpetriere, AP HP, Dept Med Interne & Immunol Clin, DHU I2B, Paris, France. [Benveniste, Olivier] Univ Paris 04, UPMC, INSERM, U974, Paris, France. [Rider, Lisa G.] NIEHS, Environm Autoimmun Grp, Clin Res Branch, NIH, Bldg 10,Rm 4-2352,10 Ctr Dr,MSC 1301, Bethesda, MD 20892 USA. RP Rider, LG (reprint author), NIEHS, Environm Autoimmun Grp, Clin Res Branch, NIH, Bldg 10,Rm 4-2352,10 Ctr Dr,MSC 1301, Bethesda, MD 20892 USA.; Benveniste, O (reprint author), Hop La Pitie Salpetriere, Dept Med Interne & Immunol Clin, 47 Blvd Hop, F-75013 Paris, France. EM olivier.benveniste@aphp.fr; riderl@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458 FU European Neuromuscular Centre (ENMC); Association Francaise contre les Myopathies (France); Deutsche Gesellschaft fur Muskelkranke (Germany); Muscular Dystrophy Campaign (UK); Muskelsvindfonden (Denmark); Prinses Beatrix Fonds (The Netherlands); Schweizerische Stiftung fur die Erforschung der Muskelkrankheiten (Switzerland); Telethon Foundation (Italy); Spierziekten Nederland (The Netherlands); Finnish Neuromuscular Association (Finland); Myositis UK; Myositis Association; AstraZeneca; aTyr Pharmaceuticals; LFB Group; MedImmune; intramural research program of the National Institutes of Health, National Institute of Environmental Health Sciences FX This workshop was made possible with the financial support of the European Neuromuscular Centre (ENMC) and its main sponsors: Association Francaise contre les Myopathies (France), Deutsche Gesellschaft fur Muskelkranke (Germany), Muscular Dystrophy Campaign (UK), Muskelsvindfonden (Denmark), Prinses Beatrix Fonds (The Netherlands), Schweizerische Stiftung fur die Erforschung der Muskelkrankheiten (Switzerland), Telethon Foundation (Italy), Spierziekten Nederland (The Netherlands) and Associated members, and the Finnish Neuromuscular Association (Finland). The workshop received supplementary funding from Myositis UK, The Myositis Association, AstraZeneca, aTyr Pharmaceuticals, LFB Group, and MedImmune. This work was supported in part by the intramural research program of the National Institutes of Health, National Institute of Environmental Health Sciences. The views expressed are those of the authors and not necessarily those of the US government, the (UK) National Health Service (NHS), the NIHR, or the (UK) Department of Health. We thank Drs. James Katz and Lisa Christopher-Stine for critical reading of the manuscript. NR 103 TC 1 Z9 1 U1 5 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD AUG PY 2016 VL 26 IS 8 BP 523 EP 534 DI 10.1016/j.nmd.2016.05.014 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT5TK UT WOS:000381545300009 PM 27312023 ER PT J AU Melani, C Roschewski, M AF Melani, Christopher Roschewski, Mark TI Molecular Monitoring of Cell-Free Circulating Tumor DNA in Non-Hodgkin Lymphoma SO ONCOLOGY-NEW YORK LA English DT Review ID RESIDUAL DISEASE DETECTION; CANCER-PATIENTS; FOLLICULAR LYMPHOMA; NUCLEIC-ACIDS; THERAPY; REMISSION; RITUXIMAB; BLOOD; PET; ERA AB The ability to precisely monitor the effectiveness of therapy for non-Hodgkin lymphoma has important clinical implications. In patients with curable lymphomas, such as diffuse large B-cell lymphoma, the eradication of all disease is necessary for cure. In patients with incurable lymphomas, such as follicular lymphoma and mantle cell lymphoma, deep and durable remissions are associated with improvements in survival. Radiographic imaging modalities such as computed tomography and positron emission tomography are the current gold standard for monitoring therapy, but they are fundamentally limited by radiation risks, costs, lack of tumor specificity, and inability to detect disease at the molecular level. Novel sequencing-based methods can detect circulating tumor DNA (ctDNA) in the peripheral blood with great sensitivity, which opens new opportunities for molecular monitoring before, during, and after therapy. Beyond monitoring, ctDNA can also be used as a "liquid biopsy" to assess for molecular changes after therapy that may identify treatment-resistant clones. ctDNA is an emerging tool that may transform our ability to offer precision therapy in non-Hodgkin lymphoma. C1 [Melani, Christopher] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Roschewski, Mark] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room 4N-115, Bethesda, MD 20892 USA. RP Roschewski, M (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Room 4N-115, Bethesda, MD 20892 USA. EM mark.roschewski@nih.gov FU intramural research program of the National Institutes of Health FX The authors acknowledge support from the intramural research program of the National Institutes of Health, especially Wyndham Wilson, Kieron Dunleavy, and the rest of the research team. NR 40 TC 1 Z9 1 U1 5 U2 5 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 AUG PY 2016 VL 30 IS 8 BP 731 EP 738 PG 8 WC Oncology SC Oncology GA DT4LN UT WOS:000381452700008 ER PT J AU Hoyme, HE Kalberg, WO Elliott, AJ Blankenship, J Buckley, D Marais, AS Manning, MA Robinson, LK Adam, MP Abdul-Rahman, O Jewett, T Coles, CD Chambers, C Jones, KL Adnams, CM Shah, PE Riley, EP Charness, ME Warren, KR May, PA AF Hoyme, H. Eugene Kalberg, Wendy O. Elliott, Amy J. Blankenship, Jason Buckley, David Marais, Anna-Susan Manning, Melanie A. Robinson, Luther K. Adam, Margaret P. Abdul-Rahman, Omar Jewett, Tamison Coles, Claire D. Chambers, Christina Jones, Kenneth L. Adnams, Colleen M. Shah, Prachi E. Riley, Edward P. Charness, Michael E. Warren, Kenneth R. May, Philip A. TI Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders SO PEDIATRICS LA English DT Article ID MATERNAL RISK-FACTORS; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; PALPEBRAL FISSURE LENGTH; PREGNANCY RECOGNITION; HEAD CIRCUMFERENCE; BIRTH-DEFECTS; NEUROBEHAVIORAL PROFILE; FULL SPECTRUM; BRAIN VOLUME; SOUTH-AFRICA AB The adverse effects of prenatal alcohol exposure constitute a continuum of disabilities (fetal alcohol spectrum disorders [FASD]). In 1996, the Institute of Medicine established diagnostic categories delineating the spectrum but not specifying clinical criteria by which diagnoses could be assigned. In 2005, the authors published practical guidelines operationalizing the Institute of Medicine categories, allowing for standardization of FASD diagnoses in clinical settings. The purpose of the current report is to present updated diagnostic guidelines based on a thorough review of the literature and the authors' combined expertise based on the evaluation of >10 000 children for potential FASD in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism-funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence. The guidelines were formulated through conference calls and meetings held at National Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific areas addressed include the following: precise definition of documented prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder; revised diagnostic criteria for alcohol-related birth defects; an updated comprehensive research dysmorphology scoring system; and a new lip/philtrum guide for the white population, incorporating a 45-degree view. The guidelines reflect consensus among a large and experienced cadre of FASD investigators in the fields of dysmorphology, epidemiology, neurology, psychology, developmental/behavioral pediatrics, and educational diagnostics. Their improved clarity and specificity will guide clinicians in accurate diagnosis of infants and children prenatally exposed to alcohol. C1 [Hoyme, H. Eugene; Elliott, Amy J.; May, Philip A.] Sanford Res, Sioux Falls, SD USA. [Hoyme, H. Eugene; Elliott, Amy J.; May, Philip A.] Univ South Dakota, Dept Pediat, Sanford Sch Med, Sioux Falls, SD USA. [Hoyme, H. Eugene] Univ Arizona, Coll Med, Ctr Appl Genet & Genom, Tucson, AZ USA. [Hoyme, H. Eugene] Univ Arizona, Coll Med, Dept Pediat, Tucson, AZ USA. [Kalberg, Wendy O.; Blankenship, Jason; Buckley, David; May, Philip A.] Univ New Mexico, Ctr Alcoholism Substance Abuse & Addict, Albuquerque, NM 87131 USA. [Marais, Anna-Susan] Univ Stellenbosch, Fac Med & Hlth Sci, Stellenbosch, South Africa. [Manning, Melanie A.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Manning, Melanie A.] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA. [Robinson, Luther K.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Pediat, Buffalo, NY 14260 USA. [Adam, Margaret P.] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Abdul-Rahman, Omar] Univ Mississippi, Sch Med, Dept Pediat, Jackson, MS 39216 USA. [Jewett, Tamison] Wake Forest Univ, Sch Med, Dept Pediat, Winston Salem, NC 27109 USA. [Coles, Claire D.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. [Chambers, Christina; Jones, Kenneth L.] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA. [Adnams, Colleen M.] Univ Cape Town, Fac Hlth Sci, Dept Psychiat & Mental Hlth, Cape Town, South Africa. [Shah, Prachi E.] Univ Michigan, Sch Med, Dept Pediat & Communicable Dis, Ann Arbor, MI USA. [Riley, Edward P.] San Diego State Univ, Dept Psychol, San Diego, CA 92182 USA. [Charness, Michael E.] Harvard Med Sch, Dept Neurol, VA Boston Healthcare Syst, Boston, MA USA. [Charness, Michael E.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Warren, Kenneth R.] NIAAA, Bethesda, MD USA. [May, Philip A.] Univ N Carolina, Dept Nutr, Gillings Sch Global Publ Hlth, Inst Nutr Res, Chapel Hill, NC USA. RP Hoyme, HE (reprint author), Sanford Hlth, Genet & Genom Med, POB 5039, Sioux Falls, SD 57117 USA. EM gene.hoyme@sanfordhealth.org FU National Institutes of Health (NIH): National Institute on Alcohol Abuse and Alcoholism [R01 AA11685, R01/U01 AA01115134, U01 AA019879-01/NIH-NIAAA]; Oxnard Foundation, Newport Beach, CA; National Institutes of Health (NIH) FX This project was funded by the National Institutes of Health (NIH): National Institute on Alcohol Abuse and Alcoholism grants R01 AA11685, R01/U01 AA01115134, and U01 AA019879-01/NIH-NIAAA (Collaboration on Fetal Alcohol Spectrum Disorders Prevalence); and by the Oxnard Foundation, Newport Beach, CA. Funded by the National Institutes of Health (NIH). NR 112 TC 4 Z9 4 U1 19 U2 20 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD AUG PY 2016 VL 138 IS 2 AR e20154256 DI 10.1542/peds.2015-4256 PG 18 WC Pediatrics SC Pediatrics GA DS7ZP UT WOS:000381002500017 ER PT J AU McKinney, CO Hahn-Holbrook, J Chase-Lansdale, PL Ramey, SL Krohn, J Reed-Vance, M Raju, TNK Shalowitz, MU AF McKinney, Chelsea O. Hahn-Holbrook, Jennifer Chase-Lansdale, P. Lindsay Ramey, Sharon L. Krohn, Julie Reed-Vance, Maxine Raju, Tonse N. K. Shalowitz, Madeleine U. CA Community Child Hlth Res Network TI Racial and Ethnic Differences in Breastfeeding SO PEDIATRICS LA English DT Article ID UNITED-STATES; DURATION; INITIATION; ACCULTURATION; DISPARITIES; DEPRESSION; HOSPITALS; COUNTRIES; CHILDREN; PROGRESS AB OBJECTIVES: Breastfeeding rates differ among racial/ethnic groups in the United States. Our aim was to test whether racial/ethnic disparities in demographic characteristics, hospital use of infant formula, and family history of breastfeeding mediated racial/ethnic gaps in breastfeeding outcomes. METHODS: We analyzed data from the Community and Child Health Network study (N = 1636). Breastfeeding initiation, postnatal intent to breastfeed, and breastfeeding duration were assessed postpartum. Hierarchical linear modeling was used to estimate relative odds of breastfeeding initiation, postnatal intent, and duration among racial/ethnic groups and to test the candidate mediators of maternal age, income, household composition, employment, marital status, postpartum depression, preterm birth, smoking, belief that "breast is best," family history of breastfeeding, in-hospital formula introduction, and WIC participation. RESULTS: Spanish-speaking Hispanic mothers were most likely to initiate (91%), intend (92%), and maintain (mean duration, 17.1 weeks) breastfeeding, followed by English-speaking Hispanic mothers (initiation 90%, intent 88%; mean duration, 10.4 weeks) and white mothers (initiation 78%, intent 77%; mean duration, 16.5 weeks); black mothers were least likely to initiate (61%), intend (57%), and maintain breastfeeding (mean duration, 6.4 weeks). Demographic variables fully mediated disparities between black and white mothers in intent and initiation, whereas demographic characteristics and in-hospital formula feeding fully mediated breastfeeding duration. Family breastfeeding history and demographic characteristics helped explain the higher breastfeeding rates of Hispanic mothers relative to white and black mothers. CONCLUSIONS: Hospitals and policy makers should limit in-hospital formula feeding and consider family history of breastfeeding and demographic characteristics to reduce racial/ethnic breastfeeding disparities. C1 [McKinney, Chelsea O.; Shalowitz, Madeleine U.] NorthShore Univ HealthSyst, Dept Pediat, 1001 Univ Pl,Suite 348, Evanston, IL 60201 USA. [McKinney, Chelsea O.; Shalowitz, Madeleine U.] Res Inst, 1001 Univ Pl,Suite 348, Evanston, IL 60201 USA. [Hahn-Holbrook, Jennifer] Chapman Univ, Crean Coll Hlth & Behav Sci, Orange, CA USA. [Chase-Lansdale, P. Lindsay] Northwestern Univ, Inst Policy Res, Evanston, IL USA. [Ramey, Sharon L.] Virginia Tech, Caril Res Inst, Roanoke, VA USA. [Krohn, Julie] Lake Cty Hlth Dept, Waukegan, IL USA. [Krohn, Julie] Ctr Community Hlth, Waukegan, IL USA. [Reed-Vance, Maxine] Baltimore Hlth Start Inc, Baltimore, MD USA. [Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Rockville, MD USA. [Shalowitz, Madeleine U.] Univ Chicago, Pritzker Sch Med, Dept Pediat, Chicago, IL USA. RP McKinney, CO (reprint author), NorthShore Univ HealthSyst, Dept Pediat, 1001 Univ Pl,Suite 348, Evanston, IL 60201 USA.; McKinney, CO (reprint author), Res Inst, 1001 Univ Pl,Suite 348, Evanston, IL 60201 USA. EM chelseaomckinney@gmail.com FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [UHD44207, U HD44219, UHD44226, U HD44245, U HD44253, U HD54791, U HD54019, UHD44226-05S1, U HD44245-06S1, R03 HD59584]; National Institute for Nursing Research [U NR008929]; National Institutes of Health (NIH) FX All phases of this study were supported by grants to the Community and Child Health Network through cooperative agreements with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UHD44207, U HD44219, UHD44226, U HD44245, U HD44253, U HD54791, U HD54019, UHD44226-05S1, U HD44245-06S1, and R03 HD59584) and the National Institute for Nursing Research (U NR008929). Funded by the National Institutes of Health (NIH). NR 36 TC 1 Z9 1 U1 6 U2 10 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD AUG PY 2016 VL 138 IS 2 AR e20152388 DI 10.1542/peds.2015-2388 PG 11 WC Pediatrics SC Pediatrics GA DS7ZP UT WOS:000381002500004 ER PT J AU Freund, J May, RM Yang, EJ Li, HC McCullen, M Zhang, B Lenvik, T Cichocki, F Anderson, SK Kambayashi, T AF Freund, Jacquelyn May, Rebecca M. Yang, Enjun Li, Hongchuan McCullen, Matthew Zhang, Bin Lenvik, Todd Cichocki, Frank Anderson, Stephen K. Kambayashi, Taku TI Activating Receptor Signals Drive Receptor Diversity in Developing Natural Killer Cells SO PLOS BIOLOGY LA English DT Article ID NK CELLS; ADAPTER PROTEIN; DENDRITIC CELLS; LY49 RECEPTORS; MISSING-SELF; BONE-MARROW; IN-VIVO; MHC; EXPRESSION; REPERTOIRE AB It has recently been appreciated that NK cells exhibit many features reminiscent of adaptive immune cells. Considerable heterogeneity exists with respect to the ligand specificity of individual NK cells and as such, a subset of NK cells can respond, expand, and differentiate into memory-like cells in a ligand-specific manner. MHC I-binding inhibitory receptors, including those belonging to the Ly49 and KIR families, are expressed in a variegated manner, which creates ligand-specific diversity within the NK cell pool. However, how NK cells determine which inhibitory receptors to express on their cell surface during a narrow window of development is largely unknown. In this manuscript, we demonstrate that signals from activating receptors are critical for induction of Ly49 and KIR receptors during NK cell development; activating receptor-derived signals increased the probability of the Ly49 bidirectional Pro1 promoter to transcribe in the forward versus the reverse direction, leading to stable expression of Ly49 receptors in mature NK cells. Our data support a model where the balance of activating and inhibitory receptor signaling in NK cells selects for the induction of appropriate inhibitory receptors during development, which NK cells use to create a diverse pool of ligand-specific NK cells. C1 [Freund, Jacquelyn; May, Rebecca M.; Yang, Enjun; Kambayashi, Taku] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Li, Hongchuan; Anderson, Stephen K.] Leidos Biomed Res Inc, Frederick Natl Lab, Basic Sci Program, Frederick, MD USA. [McCullen, Matthew; Anderson, Stephen K.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Zhang, Bin; Lenvik, Todd; Cichocki, Frank] Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Box 736 UMHC, Minneapolis, MN 55455 USA. RP Kambayashi, T (reprint author), Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA. EM taku.kambayashi@uphs.upenn.edu OI McCullen, Matthew/0000-0001-9138-1483 FU National Cancer Institute (NCI), National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NIH, NCI, Center for Cancer Research; NIH [R01HL111501, R01HL107589, T32-AI055428] FX This project has been funded in part with federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under contract HHSN261200800001E, the Intramural Research Program of the NIH, NCI, Center for Cancer Research and by NIH grants R01HL111501 (TK), R01HL107589 (TK), T32-AI055428 (JF) http://www.nhlbi.nih.gov/. The funders had no role in the study design, data collection, and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 1 Z9 1 U1 2 U2 2 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 AUG PY 2016 VL 14 IS 8 AR e1002526 DI 10.1371/journal.pbio.1002526 PG 18 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA DU7LM UT WOS:000382395700002 PM 27500644 ER PT J AU Hartford, SA Chittela, R Ding, X Vyas, A Martin, B Burkett, S Haines, DC Southon, E Tessarollo, L Sharan, SK AF Hartford, Suzanne A. Chittela, Rajanikant Ding, Xia Vyas, Aradhana Martin, Betty Burkett, Sandra Haines, Diana C. Southon, Eileen Tessarollo, Lino Sharan, Shyam K. TI Interaction with PALB2 Is Essential for Maintenance of Genomic Integrity by BRCA2 SO PLOS GENETICS LA English DT Article ID BREAST-CANCER; HOMOLOGOUS RECOMBINATION; HETEROZYGOUS MUTATIONS; NUCLEAR-ORGANIZATION; EMBRYONIC LETHALITY; GERMLINE MUTATION; DNA-REPLICATION; MOUSE MODEL; MICE; SUSCEPTIBILITY AB Human breast cancer susceptibility gene, BRCA2, encodes a 3418-amino acid protein that is essential for maintaining genomic integrity. Among the proteins that physically interact with BRCA2, Partner and Localizer of BRCA2 (PALB2), which binds to the N-terminal region of BRCA2, is vital for its function by facilitating its subnuclear localization. A functional redundancy has been reported between this N-terminal PALB2-binding domain and the C-terminal DNA-binding domain of BRCA2, which undermines the relevance of the interaction between these two proteins. Here, we describe a genetic approach to examine the functional significance of the interaction between BRCA2 and PALB2 by generating a knock-in mouse model of Brca2 carrying a single amino acid change (Gly25Arg, Brca2G25R) that disrupts this interaction. In addition, we have combined Brca2G25R homozygosity as well as hemizygosity with Palb2 and Trp53 heterozygosity to generate an array of genotypically and phenotypically distinct mouse models. Our findings reveal defects in body size, fertility, meiotic progression, and genome stability, as well as increased tumor susceptibility in these mice. The severity of the phenotype increased with a decrease in the interaction between BRCA2 and PALB2, highlighting the significance of this interaction. In addition, our findings also demonstrate that hypomorphic mutations such as Brca2G25R have the potential to be more detrimental than the functionally null alleles by increasing genomic instability to a level that induces tumorigenesis, rather than apoptosis. C1 [Hartford, Suzanne A.; Chittela, Rajanikant; Ding, Xia; Vyas, Aradhana; Burkett, Sandra; Southon, Eileen; Tessarollo, Lino; Sharan, Shyam K.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Martin, Betty; Haines, Diana C.; Southon, Eileen] NCI, Leidos Biomed Inc, Frederick, MD 21701 USA. [Chittela, Rajanikant] Bhabha Atom Res Ctr, Bombay, Maharashtra, India. RP Sharan, SK (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. EM sharans@mail.nih.gov FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, US National Institutes of Health [HHSN261200800001E] FX This research was sponsored by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, US National Institutes of Health under Contract No. HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2016 VL 12 IS 8 AR e1006236 DI 10.1371/journal.pgen.1006236 PG 27 WC Genetics & Heredity SC Genetics & Heredity GA DU7LA UT WOS:000382394500033 PM 27490902 ER PT J AU Lavender, CA Cannady, KR Hoffman, JA Trotter, KW Gilchrist, DA Bennett, BD Burkholder, AB Burd, CJ Fargo, DC Archer, TK AF Lavender, Christopher A. Cannady, Kimberly R. Hoffman, Jackson A. Trotter, Kevin W. Gilchrist, Daniel A. Bennett, Brian D. Burkholder, Adam B. Burd, Craig J. Fargo, David C. Archer, Trevor K. TI Downstream Antisense Transcription Predicts Genomic Features That Define the Specific Chromatin Environment at Mammalian Promoters SO PLOS GENETICS LA English DT Article ID FACTOR-BINDING; RNA EXOSOME; ELEMENTS; GENE; SEQUENCES; EXPRESSION; VERTEBRATE; DROSOPHILA; INITIATION; RESOLUTION AB Antisense transcription is a prevalent feature at mammalian promoters. Previous studies have primarily focused on antisense transcription initiating upstream of genes. Here, we characterize promoter-proximal antisense transcription downstream of gene transcription starts sites in human breast cancer cells, investigating the genomic context of downstream antisense transcription. We find extensive correlations between antisense transcription and features associated with the chromatin environment at gene promoters. Antisense transcription downstream of promoters is widespread, with antisense transcription initiation observed within 2 kb of 28% of gene transcription start sites. Antisense transcription initiates between nucleosomes regularly positioned downstream of these promoters. The nucleosomes between gene and downstream antisense transcription start sites carry histone modifications associated with active promoters, such as H3K4me3 and H3K27ac. This region is bound by chromatin remodeling and histone modifying complexes including SWI/SNF subunits and HDACs, suggesting that antisense transcription or resulting RNA transcripts contribute to the creation and maintenance of a promoter-associated chromatin environment. Downstream antisense transcription overlays additional regulatory features, such as transcription factor binding, DNA accessibility, and the downstream edge of promoter-associated CpG islands. These features suggest an important role for antisense transcription in the regulation of gene expression and the maintenance of a promoter-associated chromatin environment. C1 [Lavender, Christopher A.; Cannady, Kimberly R.; Hoffman, Jackson A.; Trotter, Kevin W.; Gilchrist, Daniel A.; Archer, Trevor K.] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Lavender, Christopher A.; Bennett, Brian D.; Burkholder, Adam B.; Fargo, David C.] NIEHS, Integrat Bioinformat, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Burd, Craig J.] Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA. [Burd, Craig J.] Ohio State Univ, Wexner Med Ctr, Columbus, OH USA. [Gilchrist, Daniel A.] NHGRI, Bethesda, MD 20892 USA. RP Archer, TK (reprint author), NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.; Fargo, DC (reprint author), NIEHS, Integrat Bioinformat, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM fargod@niehs.nih.gov; archer1@niehs.nih.gov RI Burd, Craig/D-9500-2017; OI Burd, Craig/0000-0002-6899-6751 FU Intramural Research Program of the NIH - National Institute of Environmental Health Sciences [Z01 ES071006-15] FX This research was supported by the Intramural Research Program of the NIH - National Institute of Environmental Health Sciences [Z01 ES071006-15; nih.gov]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 2 Z9 2 U1 3 U2 3 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 AUG PY 2016 VL 12 IS 8 AR e1006224 DI 10.1371/journal.pgen.1006224 PG 21 WC Genetics & Heredity SC Genetics & Heredity GA DU7LA UT WOS:000382394500026 ER PT J AU Lo, CL Lossie, AC Liang, TB Liu, YL Xuei, XL Lumeng, L Zhou, FC Muir, WM AF Lo, Chiao-Ling Lossie, Amy C. Liang, Tiebing Liu, Yunlong Xuei, Xiaoling Lumeng, Lawrence Zhou, Feng C. Muir, William M. TI High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model SO PLOS GENETICS LA English DT Article ID QUANTITATIVE TRAIT LOCI; CORTICOTROPIN-RELEASING-FACTOR; ESTIMATING F-STATISTICS; FALSE DISCOVERY RATE; WIDE ASSOCIATION; LINKAGE DISEQUILIBRIUM; POPULATION-STRUCTURE; NATURAL-SELECTION; PROTEIN FUNCTION; DRUG-ADDICTION AB Investigations on the influence of nature vs. nurture on Alcoholism (Alcohol Use Disorder) in human have yet to provide a clear view on potential genomic etiologies. To address this issue, we sequenced a replicated animal model system bidirectionally-selected for alcohol preference (AP). This model is uniquely suited to map genetic effects with high reproducibility, and resolution. The origin of the rat lines (an 8-way cross) resulted in small haplotype blocks (HB) with a corresponding high level of resolution. We sequenced DNAs from 40 samples (10 per line of each replicate) to determine allele frequencies and HB. We achieved similar to 46X coverage per line and replicate. Excessive differentiation in the genomic architecture between lines, across replicates, termed signatures of selection (SS), were classified according to gene and region. We identified SS in 930 genes associated with AP. The majority (50%) of the SS were confined to single gene regions, the greatest numbers of which were in promoters (284) and intronic regions (169) with the least in exon's (4), suggesting that differences in AP were primarily due to alterations in regulatory regions. We confirmed previously identified genes and found many new genes associated with AP. Of those newly identified genes, several demonstrated neuronal function involved in synaptic memory and reward behavior, e.g. ion channels (Kcnf1, Kcnn3, Scn5a), excitatory receptors (Grin2a, Gria3, Grip1), neurotransmitters (Pomc), and synapses (Snap29). This study not only reveals the polygenic architecture of AP, but also emphasizes the importance of regulatory elements, consistent with other complex traits. C1 [Lo, Chiao-Ling; Lossie, Amy C.; Liang, Tiebing; Liu, Yunlong; Xuei, Xiaoling; Lumeng, Lawrence; Zhou, Feng C.; Muir, William M.] Indiana Univ Sch Med, Indiana Alcohol Res Ctr, Indianapolis, IN 46202 USA. [Lo, Chiao-Ling; Zhou, Feng C.] Indiana Univ Sch Med, Dept Anat & Cell Biol, Indianapolis, IN 46202 USA. [Lossie, Amy C.; Muir, William M.] Purdue Univ, Dept Anim Sci, W Lafayette, IN 47907 USA. [Liang, Tiebing; Lumeng, Lawrence; Muir, William M.] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Liu, Yunlong] Indiana Univ Sch Med, Dept Med Genet, Indianapolis, IN 46202 USA. [Xuei, Xiaoling] Indiana Univ Sch Med, Dept Biochem, Indianapolis, IN 46202 USA. [Zhou, Feng C.] Indiana Univ Sch Med, Stark Neurosci Res Inst, Indianapolis, IN 46202 USA. [Lossie, Amy C.] NIDA, Genet Epigenet & Dev Neurosci Branch, Div Neurosci & Behav, NIH, Bethesda, MD 20892 USA. RP Zhou, FC; Muir, WM (reprint author), Indiana Univ Sch Med, Indiana Alcohol Res Ctr, Indianapolis, IN 46202 USA.; Zhou, FC (reprint author), Indiana Univ Sch Med, Dept Anat & Cell Biol, Indianapolis, IN 46202 USA.; Muir, WM (reprint author), Purdue Univ, Dept Anim Sci, W Lafayette, IN 47907 USA.; Muir, WM (reprint author), Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA.; Zhou, FC (reprint author), Indiana Univ Sch Med, Stark Neurosci Res Inst, Indianapolis, IN 46202 USA. EM imce100@iu.edu; bmuir@purdue.edu FU National Institute of Health [P60 AA07611, AA016698] FX This work was supported by the National Institute of Health P60 AA07611 and AA016698. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 86 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2016 VL 12 IS 8 AR e1006178 DI 10.1371/journal.pgen.1006178 PG 23 WC Genetics & Heredity SC Genetics & Heredity GA DU7LA UT WOS:000382394500011 PM 27490364 ER PT J AU Rijal, K Maraia, RJ AF Rijal, Keshab Maraia, Richard J. TI Active Center Control of Termination by RNA Polymerase III and tRNA Gene Transcription Levels In Vivo SO PLOS GENETICS LA English DT Article ID TRIGGER LOOP FUNCTIONS; SACCHAROMYCES-CEREVISIAE; ELONGATION COMPLEX; FISSION YEAST; DNA HYBRID; DEPENDENT TRANSCRIPTION; SUBSTRATE-SPECIFICITY; MUTATIONAL ANALYSIS; CLEAVAGE ACTIVITY; STRUCTURAL BASIS AB The ability of RNA polymerase (RNAP) III to efficiently recycle from termination to reinitiation is critical for abundant tRNA production during cellular proliferation, development and cancer. Yet understanding of the unique termination mechanisms used by RNAP III is incomplete, as is its link to high transcription output. We used two tRNA-mediated suppression systems to screen for Rpc1 mutants with gain-and loss-of termination phenotypes in S. pombe. 122 point mutation mutants were mapped to a recently solved 3.9 angstrom structure of yeast RNAP III elongation complex (EC); they cluster in the active center bridge helix and trigger loop, as well as the pore and funnel, the latter of which indicate involvement of the RNA cleavage domain of the C11 subunit in termination. Purified RNAP III from a readthrough (RT) mutant exhibits increased elongation rate. The data strongly support a kinetic coupling model in which elongation rate is inversely related to termination efficiency. The mutants exhibit good correlations of terminator RT in vitro and in vivo, and surprisingly, amounts of transcription in vivo. Because assessing in vivo transcription can be confounded by various parameters, we used a tRNA reporter with a processing defect and a strong terminator. By ruling out differences in RNA decay rates, the data indicate that mutants with the RT phenotype synthesize more RNA than wild type cells, and than can be accounted for by their increased elongation rate. Finally, increased activity by the mutants appears unrelated to the RNAP III repressor, Maf1. The results show that the mobile elements of the RNAP III active center, including C11, are key determinants of termination, and that some of the mutations activate RNAP III for overall transcription. Similar mutations in spontaneous cancer suggest this as an unforeseen mechanism of RNAP III activation in disease. C1 [Rijal, Keshab; Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Maraia, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM maraiar@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH [HD000412-28] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. The Grant number is HD000412-28. The URL of the funders website is http://data.nidb.nih.gov/reports/viewreports.taf?ipid=90327&ts=144061033 6. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 80 TC 1 Z9 1 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2016 VL 12 IS 8 AR e1006253 DI 10.1371/journal.pgen.1006253 PG 31 WC Genetics & Heredity SC Genetics & Heredity GA DU7LA UT WOS:000382394500047 ER PT J AU Shen, H Yu, XB Yang, FM Zhang, ZH Shen, JX Sun, J Choksi, S Jitkaew, S Shu, YQ AF Shen, Hua Yu, Xiaobo Yang, Fengming Zhang, Zhihua Shen, Jianxin Sun, Jin Choksi, Swati Jitkaew, Siriporn Shu, Yongqian TI Reprogramming of Normal Fibroblasts into Cancer-Associated Fibroblasts by miRNAs-Mediated CCL2/VEGFA Signaling SO PLOS GENETICS LA English DT Article ID TUMOR-GROWTH; BREAST-CANCER; STROMAL FIBROBLASTS; OVARIAN-CANCER; STEM-CELLS; MICRORNAS; ANGIOGENESIS; PROGRESSION; EXPRESSION; CARCINOMA AB Cancer-associated fibroblasts (CAFs), the most common constituent of the tumor stoma, are known to promote tumor initiation, progression and metastasis. However, the mechanism of how cancer cells transform normal fibroblasts (NFs) into CAFs is largely unknown. In this study, we determined the contribution of miRNAs in the transformation of NFs into CAFs. We found that miR-1 and miR-206 were down-regulated, whereas miR-31 was up-regulated in lung CAFs when compared with matched NFs. Importantly, modifying the expression of these three deregulated miRNAs induced a functional conversion of NFs into CAFs and vice versa. When the miRNA-reprogrammed NFs and CAFs were co-cultured with lung cancer cells (LCCs), a similar pattern of cytokine expression profiling were observed between two groups. Using a combination of cytokine expression profiling and miRNAs algorithms, we identified VEGFA/CCL2 and FOXO3a as direct targets of miR-1, miR-206 and miR-31, respectively. Importantly, systemic delivery of anti-VEGFA/CCL2 or pre-miR-1, pre-miR-206 and anti-miR-31 significantly inhibited tumor angiogenesis, TAMs accumulation, tumor growth and lung metastasis. Our results show that miRNAs-mediated FOXO3a/VEGF/CCL2 signaling plays a prominent role in LCCs-mediated NFs into CAFs, which may have clinical implications for providing novel biomarker(s) and potential therapeutic target(s) of lung cancer in the future. C1 [Shen, Hua; Yang, Fengming; Shu, Yongqian] Nanjing Med Univ, Affiliated Hosp 1, Dept Oncol, Nanjing, Jiangsu, Peoples R China. [Shen, Hua; Yang, Fengming; Shu, Yongqian] Nanjing Med Univ, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Collaborat Innovat Ctr Canc Personalized Med, Nanjing, Jiangsu, Peoples R China. [Yu, Xiaobo] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Thorac Surg, Shanghai, Peoples R China. [Zhang, Zhihua] Hebei North Univ, Affiliated Hosp 1, Dept Respirat, Zhangjiakou, Hebei Province, Peoples R China. [Shen, Jianxin] Hebei North Univ, Affiliated Hosp 1, Dept Clin Lab, Zhangjiakou, Hebei Province, Peoples R China. [Sun, Jin] Nanjing Med Univ, Affiliated Hosp 1, Dept Nucl Med, Nanjing, Jiangsu, Peoples R China. [Choksi, Swati] NIH, Bldg 10, Bethesda, MD 20892 USA. [Jitkaew, Siriporn] Chulalongkorn Univ, Fac Allied Hlth Sci, Dept Clin Chem, Bangkok, Thailand. RP Shu, YQ (reprint author), Nanjing Med Univ, Affiliated Hosp 1, Dept Oncol, Nanjing, Jiangsu, Peoples R China.; Shu, YQ (reprint author), Nanjing Med Univ, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Collaborat Innovat Ctr Canc Personalized Med, Nanjing, Jiangsu, Peoples R China. EM shuyongqian1999@126.com FU National Natural Science Foundation of China [81202032, 81172140, 81272532]; Jiangsu 233 Province Clinical Science and Technology Projects (Clinical Research Center) [BL2012008]; Priority Academic Program Development of Jiangsu Higher Education Institutions [JX10231801] FX This work was supported in part by National Natural Science Foundation of China (81202032, 81172140, 81272532); by the Jiangsu 233 Province Clinical Science and Technology Projects (Clinical Research Center, BL2012008), the Priority Academic Program Development of Jiangsu Higher Education Institutions (JX10231801). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 2 Z9 2 U1 6 U2 7 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 AUG PY 2016 VL 12 IS 8 AR e1006244 DI 10.1371/journal.pgen.1006244 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA DU7LA UT WOS:000382394500040 PM 27541266 ER PT J AU Martin, A AF Martin, Alex TI GRAPES-Grounding representations in action, perception, and emotion systems: How object properties and categories are represented in the human brain SO PSYCHONOMIC BULLETIN & REVIEW LA English DT Review DE Concepts and categories; Cognitive neuroscience of memory; Embodied cognition; Neuroimaging and memory ID AUTISM SPECTRUM DISORDERS; ANTERIOR TEMPORAL-LOBES; VENTRAL OCCIPITOTEMPORAL CORTEX; FUNCTIONAL CONNECTIVITY; MANIPULATABLE OBJECTS; COLOR KNOWLEDGE; CONCEPTUAL KNOWLEDGE; MULTIPLE SEMANTICS; SOCIAL COGNITION; NEURAL FRAMEWORK AB In this article, I discuss some of the latest functional neuroimaging findings on the organization of object concepts in the human brain. I argue that these data provide strong support for viewing concepts as the products of highly interactive neural circuits grounded in the action, perception, and emotion systems. The nodes of these circuits are defined by regions representing specific object properties (e.g., form, color, and motion) and thus are property-specific, rather than strictly modality-specific. How these circuits are modified by external and internal environmental demands, the distinction between representational content and format, and the grounding of abstract social concepts are also discussed. C1 [Martin, Alex] NIMH, Lab Brain & Cognit, Bldg 10,Room 4C-104,10 Ctr Dr MSC 1366, Bethesda, MD 20892 USA. RP Martin, A (reprint author), NIMH, Lab Brain & Cognit, Bldg 10,Room 4C-104,10 Ctr Dr MSC 1366, Bethesda, MD 20892 USA. EM alexmartin@mail.nih.gov FU National Institute of Mental Health, National Institutes of Health, Division of Intramural Research [1 ZIA MH 002588-25, NCT01031407] FX I thank Chris Baker, Alfonso Caramazza, Anjan Chatterjee, Dwight Kravitiz, Brad Mahon, and the members of my laboratory for their critical comments on earlier versions of this manuscript. This work was supported by the National Institute of Mental Health, National Institutes of Health, Division of Intramural Research (1 ZIA MH 002588-25; NCT01031407). The views expressed in this article do not necessarily represent the views of the NIMH, NIH, HHS, or the United States Government. NR 126 TC 5 Z9 5 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1069-9384 EI 1531-5320 J9 PSYCHON B REV JI Psychon. Bull. Rev. PD AUG PY 2016 VL 23 IS 4 BP 979 EP 990 DI 10.3758/s13423-015-0842-3 PG 12 WC Psychology, Mathematical; Psychology, Experimental SC Psychology GA DT0MK UT WOS:000381177500003 PM 25968087 ER PT J AU Gotts, SJ AF Gotts, Stephen J. TI Incremental learning of perceptual and conceptual representations and the puzzle of neural repetition suppression SO PSYCHONOMIC BULLETIN & REVIEW LA English DT Review DE Priming; Predictive coding; Plasticity; Sharpening; Synchrony; Semantic memory ID INFERIOR TEMPORAL CORTEX; MONKEY INFEROTEMPORAL CORTEX; PRIMATE PREFRONTAL CORTEX; OBJECT-SELECTIVE CORTEX; TERM IMPLICIT MEMORY; VISUAL-CORTEX; CATEGORY-SELECTIVITY; STIMULUS REPETITION; CORTICAL ACTIVITY; NEURONAL SYNCHRONIZATION AB Incremental learning models of long-term perceptual and conceptual knowledge hold that neural representations are gradually acquired over many individual experiences via Hebbian-like activity-dependent synaptic plasticity across cortical connections of the brain. In such models, variation in task relevance of information, anatomic constraints, and the statistics of sensory inputs and motor outputs lead to qualitative alterations in the nature of representations that are acquired. Here, the proposal that behavioral repetition priming and neural repetition suppression effects are empirical markers of incremental learning in the cortex is discussed, and research results that both support and challenge this position are reviewed. Discussion is focused on a recent fMRI-adaptation study from our laboratory that shows decoupling of experience-dependent changes in neural tuning, priming, and repetition suppression, with representational changes that appear to work counter to the explicit task demands. Finally, critical experiments that may help to clarify and resolve current challenges are outlined. C1 [Gotts, Stephen J.] NIMH, Sect Cognit Neuropsychol, Lab Brain & Cognit, NIH, Bldg 10,Rm 4C-104, Bethesda, MD 20892 USA. RP Gotts, SJ (reprint author), NIMH, Sect Cognit Neuropsychol, Lab Brain & Cognit, NIH, Bldg 10,Rm 4C-104, Bethesda, MD 20892 USA. EM gottss@mail.nih.gov FU National Institute of Mental Health, NIH, Division of Intramural Research FX The author would like to thank Alex Martin, Jay McClelland, David Plaut, Carson Chow, Gary Dell, Gary Oppenheim, and Sharon Thompson-Schill for helpful discussions, and Brad Mahon, Ken Norman, and an anonymous reviewer for insightful comments on the manuscript. The writing of this paper was supported by the National Institute of Mental Health, NIH, Division of Intramural Research. NR 196 TC 2 Z9 2 U1 15 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1069-9384 EI 1531-5320 J9 PSYCHON B REV JI Psychon. Bull. Rev. PD AUG PY 2016 VL 23 IS 4 BP 1055 EP 1071 DI 10.3758/s13423-015-0855-y PG 17 WC Psychology, Mathematical; Psychology, Experimental SC Psychology GA DT0MK UT WOS:000381177500010 PM 27294423 ER PT J AU Satyamitra, MM DiCarlo, AL Taliaferro, L AF Satyamitra, Merriline M. DiCarlo, Andrea L. Taliaferro, Lanyn TI Understanding the Pathophysiology and Challenges of Development of Medical Countermeasures for Radiation-Induced Vascular/Endothelial Cell Injuries: Report of a NIAID Workshop, August 20, 2015 SO RADIATION RESEARCH LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; THROMBIN FRAGMENT TP508; DISSEMINATED INTRAVASCULAR COAGULATION; CIRCULATING ENDOTHELIAL-CELLS; ATOMIC-BOMB SURVIVORS; IN-VIVO; PROGENITOR CELLS; SENESCENT CELLS; IONIZING-RADIATION; INDUCED APOPTOSIS AB After the events of September 11, 2001, a decade of research on the development of medical countermeasures (MCMs) to treat victims of a radiological incident has yielded two FDA-approved agents to mitigate acute radiation syndrome. These licensed agents specifically target the mitigation of radiation-induced neutropenia and infection potential, while the ramifications of the exposure event in a public health emergency incident could include the entire body, causing additional acute and/or delayed organ/tissue injuries. Anecdotal data as well as recent findings from both radiation accident survivors and animal experiments implicate radiation-induced injury or dysfunction of the vascular endothelium leading to tissue and organ injuries. There are significant gaps in our understanding of the disease processes and progression, as well as the optimum approaches to develop medical countermeasures to mitigate radiation vascular injury. To address this issue, the Radiation and Nuclear Countermeasures Program of the National Institute of Allergy and Infectious Diseases (NIAID) organized a one-day workshop to examine the current state of the science in radiation-induced vascular injuries and organ dysfunction, the natural history of the pathophysiology and the product development maturity of potential medical countermeasures to treat these injuries. Meeting presentations were followed by a NIAID-led open discussion among academic investigators, industry researchers and government agency representatives. This article provides a summary of these presentations and subsequent discussion from the workshop. (C) 2016 by Radiation Research Society C1 [Satyamitra, Merriline M.; DiCarlo, Andrea L.; Taliaferro, Lanyn] NIAID, Div Allergy Immunol & Transplantat, NIH, Rockville, MD 20852 USA. RP Satyamitra, MM (reprint author), NIAID, RNCP, DAIT, NIH, 5601 Fishers Lane,Room 7A67, Rockville, MD 20852 USA. EM merriline.satyamitra@nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 109 TC 1 Z9 1 U1 1 U2 1 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD AUG PY 2016 VL 186 IS 2 BP 99 EP 111 DI 10.1667/RR14436.1 PG 13 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA DU6DW UT WOS:000382305100001 PM 27387859 ER PT J AU Mizrachi, A Cotrim, AP Katabi, N Mitchell, JB Verheij, M Haimovitz-Friedman, A AF Mizrachi, Aviram Cotrim, Ana P. Katabi, Nora Mitchell, James B. Verheij, Marcel Haimovitz-Friedman, Adriana TI Radiation-Induced Microvascular Injury as a Mechanism of Salivary Gland Hypofunction and Potential Target for Radioprotectors SO RADIATION RESEARCH LA English DT Article ID REDOX SIGNALING PLATFORMS; ENDOTHELIAL APOPTOSIS; IONIZING-RADIATION; NECK IRRADIATION; INDUCED DAMAGE; MOUSE MODEL; CANCER; TEMPOL; PROTECTION; CERAMIDE AB Radiation therapy is commonly used to treat patients with head and neck squamous cell carcinoma (HNSCC). One of the major side effects of radiotherapy is injury to the salivary glands (SG), which is thought to be mediated by microvascular dysfunction leading to permanent xerostomia. The goal of this study was to elucidate the mechanism of radiation-induced microvasculature damage and its impact on SG function. We measured bovine aortic endothelial cell (BAEC) apoptosis and ceramide production in response to 5 Gy irradiation, either alone or with reactive oxygen species (ROS) scavengers. We then investigated the effect of a single 15 Gy radiation dose on murine SG function. BAECs exposed to 5 Gy underwent apoptosis with increased ceramide production, both prevented by ROS scavengers. Among the 15 Gy irradiated mice, there was considerable weight loss, alopecia and SG hypofunction manifested by reduced saliva production and lower lysozyme levels. All of these effects, except for the lysozyme levels, were prevented by pretreatment with ROS scavengers. Microvessel density was significantly lower in the SG of irradiated mice compared to the control group, and this effect was significantly attenuated by pretreatment with Tempol. This study demonstrates that radiation-induced SG hypofunction is to a large extent mediated by microvascular dysfunction involving ceramide and ROS generation. These findings strongly suggest that ROS scavengers may serve as potential radioprotectors of SG function in patients undergoing radiotherapy for HNSCC. (C) 2016 by Radiation Research Society C1 [Mizrachi, Aviram] Mem Sloan Kettering Canc Ctr, Dept Surg Head & Neck Serv, 1275 York Ave, New York, NY 10021 USA. [Katabi, Nora] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Haimovitz-Friedman, Adriana] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10065 USA. [Cotrim, Ana P.; Mitchell, James B.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Verheij, Marcel] Netherlands Canc Inst, Dept Radiat Oncol, Amsterdam, Netherlands. RP Haimovitz-Friedman, A (reprint author), Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10065 USA. EM a-haimovitz-friedman@ski.mskcc.org FU NIH/NCI Cancer Center Support Core Grant [P30 CA008748]; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center FX We thank Karen Reede for assistance in preparation of the manuscript and Evan Darling from the Molecular Cytology Facility for his help with the IF apoptotic staining. This study was supported in part through the NIH/NCI Cancer Center Support Core Grant (no. P30 CA008748), and by the Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center. NR 29 TC 0 Z9 0 U1 4 U2 4 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD AUG PY 2016 VL 186 IS 2 BP 189 EP 195 DI 10.1667/RR14431.1 PG 7 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA DU6DW UT WOS:000382305100008 PM 27459704 ER PT J AU Kaplan, G Lee, F Onda, M Kolyvas, E Bhardwaj, G Baker, D Pastan, I AF Kaplan, Gilad Lee, Fred Onda, Masanori Kolyvas, Emily Bhardwaj, Gaurav Baker, David Pastan, Ira TI K Protection of the Furin Cleavage Site in Low-Toxicity Immunotoxins Based on Pseudomonas Exotoxin A SO TOXINS LA English DT Article DE recombinant immunotoxin; mesothelin; Pseudomonas exotoxin A; disulfide bond ID CELL-SURFACE; RECOMBINANT IMMUNOTOXIN; TUMOR MICROENVIRONMENT; PROPROTEIN CONVERTASE; LOW IMMUNOGENICITY; ANTITUMOR-ACTIVITY; GENE-EXPRESSION; TARGETING CD22; CANCER; MESOTHELIN AB Recombinant immunotoxins (RITs) are fusions of an Fv-based targeting moiety and a toxin. Pseudomonas exotoxin A (PE) has been used to make several immunotoxins that have been evaluated in clinical trials. Immunogenicity of the bacterial toxin and off-target toxicity have limited the efficacy of these immunotoxins. To address these issues, we have previously made RITs in which the Fv is connected to domain III (PE24) by a furin cleavage site (FCS), thereby removing unneeded sequences of domain II. However, the PE24 containing RITs do not contain the naturally occurring disulfide bond around the furin cleavage sequence, because it was removed when domain II was deleted. This could potentially allow PE24 containing immunotoxins to be cleaved and inactivated before internalization by cell surface furin or other proteases in the blood stream or tumor microenvironment. Here, we describe five new RITs in which a disulfide bond is engineered to protect the FCS. The most active of these, SS1-Fab-DS3-PE24, shows a longer serum half-life than an RIT without the disulfide bond and has the same anti-tumor activity, despite being less cytotoxic in vitro. These results have significance for the production of de-immunized, low toxicity, PE24-based immunotoxins with a longer serum half-life. C1 [Kaplan, Gilad; Lee, Fred; Onda, Masanori; Kolyvas, Emily; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Bhardwaj, Gaurav; Baker, David] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Bhardwaj, Gaurav; Baker, David] Univ Washington, Inst Prot Design, Seattle, WA 98195 USA. [Baker, David] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM gilad.kaplan@nih.gov; fred.lee@nih.gov; OndaM@mail.nih.gov; emily.kolyvas@nih.gov; Gauravb@uw.edu; dabaker@uw.edu; pastani@mail.nih.gov FU Intramural Research Program of the NIH, NCI, Center for Cancer Research; Howard Hughes Medical Institute FX This work was supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research and in part by Howard Hughes Medical Institute. NR 35 TC 0 Z9 0 U1 1 U2 1 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2072-6651 J9 TOXINS JI Toxins PD AUG PY 2016 VL 8 IS 8 AR 217 DI 10.3390/toxins8080217 PG 14 WC Toxicology SC Toxicology GA DU5RK UT WOS:000382268800001 ER PT J AU Spencer, BR Johnson, B Wright, DJ Kleinman, S Glynn, SA Cable, RG AF Spencer, Bryan R. Johnson, Bryce Wright, David J. Kleinman, Steven Glynn, Simone A. Cable, Ritchard G. CA REDS-II Rise Anal Grp TI Potential impact on blood availability and donor iron status of changes to donor hemoglobin cutoff and interdonation intervals SO TRANSFUSION LA English DT Article ID STATUS EVALUATION RISE; DEFICIENCY AB BACKGROUNDA minimum male hemoglobin (Hb) level of 13.0 g/dL becomes a Food and Drug Administration requirement effective May 2016. In addition, extending whole blood (WB) interdonation intervals (IDIs) beyond 8 weeks has been considered to reduce iron depletion in repeat blood donors. This study estimates the impact these changes might have on blood availability and donor iron status. STUDY DESIGN AND METHODSSix blood centers participating in Retrovirus Epidemiology Donor Study-II (REDS-II) collected information on all donation visits from 2006 to 2009. Simulations were developed from these data using a multistage approach that first sought to adequately reproduce the patterns of donor return, Hb and ferritin levels, and outcomes of a donor's visit (successful single- or double-red blood cell donation, deferral for low Hb) observed in REDS-II data sets. Modified simulations were used to predict the potential impact on the blood supply and donor iron status under different Hb cutoff and IDI qualification criteria. RESULTSMore than 10% of WB donations might require replacement under many simulated scenarios. Longer IDIs would reduce the proportion of donors with iron depletion, but 80% of these donors may remain iron-depleted if minimal IDIs increased to 12 or 16 weeks. CONCLUSIONHigher Hb cutoffs and longer IDIs are predicted to have a potentially large impact on collections but only a modest impact on donor iron depletion. Efforts to address iron depletion should be targeted to at-risk donors, such as iron supplementation programs for frequent donors, and policy makers should try to avoid broadly restrictive donation requirements that could substantially reduce blood availability. C1 [Spencer, Bryan R.] Amer Red Cross Blood Serv, Massachusetts Reg, Dedham, MA USA. [Johnson, Bryce; Wright, David J.] Westat Corp, Rockville, MD USA. [Kleinman, Steven] Univ British Columbia, Vancouver, BC, Canada. [Glynn, Simone A.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Cable, Ritchard G.] Amer Red Cross Blood Serv, Connecticut Reg, Farmington, CT USA. RP Spencer, BR (reprint author), Amer Red Cross, Massachusetts Reg, 180 Rustcraft Rd,Suite 115, Dedham, MA 02026 USA. EM bryan.spencer@redcross.org FU National Heart, Lung, and Blood Institute [N01HB47168, N01HB47169, N01HB47170, N01HB47171, N01HB47172, N01HB 47174, N01HB47175, N01HB57181] FX This study was supported by contracts N01HB47168, N01HB47169, N01HB47170, N01HB47171, N01HB47172, N01HB 47174, N01HB47175, and N01HB57181 from the National Heart, Lung, and Blood Institute. NR 14 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD AUG PY 2016 VL 56 IS 8 BP 1994 EP 2004 DI 10.1111/trf.13663 PG 11 WC Hematology SC Hematology GA DU8ZP UT WOS:000382506100013 PM 27237451 ER PT J AU Cable, RG Brambilla, D Glynn, SA Kleinman, S Mast, AE Spencer, BR Stone, M Kiss, JE AF Cable, Ritchard G. Brambilla, Donald Glynn, Simone A. Kleinman, Steven Mast, Alan E. Spencer, Bryan R. Stone, Mars Kiss, Joseph E. CA Natl Heart Lung Blood Inst TI Effect of iron supplementation on iron stores and total body iron after whole blood donation SO TRANSFUSION LA English DT Article ID STATUS EVALUATION RISE; TRANSFERRIN RECEPTOR; NATIONAL-HEALTH; DONORS; DEFICIENCY; TRIAL AB BACKGROUNDUnderstanding the effect of blood donation and iron supplementation on iron balance will inform strategies to manage donor iron status. STUDY DESIGN AND METHODSA total of 215 donors were randomized to receive ferrous gluconate daily (37.5 mg iron) or no iron for 24 weeks after blood donation. Iron stores were assessed using ferritin and soluble transferrin receptor. Hemoglobin (Hb) iron was calculated from total body Hb. Total body iron (TBI) was estimated by summing iron stores and Hb iron. RESULTSAt 24 weeks, TBI in donors taking iron increased by 281.0 mg (95% confidence interval [CI], 223.4-338.6 mg) compared to before donation, while TBI in donors not on iron decreased by 74.1 mg (95% CI, -112.3 to -35.9; p<0.0001, iron vs. no iron). TBI increased rapidly after blood donation with iron supplementation, especially in iron-depleted donors. Supplementation increased TBI compared to controls during the first 8 weeks after donation: 367.8 mg (95% CI, 293.5-442.1) versus -24.1 mg (95% CI, -82.5 to 34.3) for donors with a baseline ferritin level of not more than 26 ng/mL and 167.8 mg (95% CI, 116.5-219.2) versus -68.1 mg (95% CI, -136.7 to 0.5) for donors with a baseline ferritin level of more than 26 ng/mL. A total of 88% of the benefit of iron supplementation occurred during the first 8 weeks after blood donation. CONCLUSIONDonors on iron supplementation replaced donated iron while donors not on iron did not. Eight weeks of iron supplementation provided nearly all of the measured improvement in TBI. Daily iron supplementation after blood donation allows blood donors to recover the iron loss from blood donation and prevents sustained iron deficiency. C1 [Cable, Ritchard G.] Amer Red Cross, 209 Farmington Ave, Farmington, CT 06032 USA. [Brambilla, Donald] RTI, Rockville, MD USA. [Glynn, Simone A.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Kleinman, Steven] Univ British Columbia, Victoria, BC, Canada. [Mast, Alan E.] BloodCtr Wisconsin, Milwaukee, WI USA. [Spencer, Bryan R.] Amer Red Cross, Dedham, MA USA. [Stone, Mars] Blood Syst Res Inst, San Francisco, CA USA. [Kiss, Joseph E.] Inst Transfus Med, Pittsburgh, PA USA. RP Cable, RG (reprint author), Amer Red Cross, 209 Farmington Ave, Farmington, CT 06032 USA. EM Ritchard.Cable@redcross.org FU NHLBI [HHSN2682011 00001I, HHSN268201100002I, HHSN268201100003I, HHSN268 201100004I, HHSN268201100005I, HHSN268201100006I] FX This work was supported by NHLBI contracts HHSN2682011 00001I, HHSN268201100002I, HHSN268201100003I, HHSN268 201100004I, HHSN268201100005I, and HHSN268201100006I. NR 16 TC 2 Z9 2 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD AUG PY 2016 VL 56 IS 8 BP 2005 EP 2012 DI 10.1111/trf.13659 PG 8 WC Hematology SC Hematology GA DU8ZP UT WOS:000382506100014 PM 27232535 ER PT J AU Vahidnia, F Stramer, SL Kessler, D Goncalez, TT Shaz, BH Leparc, G Krysztof, DE Dodd, RY Glynn, SA Custer, B AF Vahidnia, Farnaz Stramer, Susan L. Kessler, Debra Goncalez, Thelma T. Shaz, Beth H. Leparc, German Krysztof, David E. Dodd, Roger Y. Glynn, Simone A. Custer, Brian CA NHLBI Retrovirus Epidemiology TI Motivations for donating and attitudes toward screening policies in US blood donors with viral infection SO TRANSFUSION LA English DT Article ID TRANSFUSION-TRANSMISSIBLE INFECTIONS; IMMUNODEFICIENCY-VIRUS TYPE-1; RISK-FACTORS; SAO-PAULO; TEST-SEEKING; HAD SEX; MEN; BRAZIL; BEHAVIORS; QUESTIONNAIRE AB BACKGROUNDDifferences in motivating factors that contribute to the decision to donate blood between infected and uninfected donors may help to identify areas for improving donor education. STUDY DESIGN AND METHODSAs part of a risk factor study, confirmed-positive donors (cases) based on serology-only (human T-lymphotropic virus [HTLV]) or serology and nucleic acid testing (NAT) or NAT-only (human immunodeficiency virus [HIV], hepatitis B virus [HBV], hepatitis C virus [HCV]), and serology-unconfirmed, NAT-negative false-positive donors (controls) were asked about motivations and opinions toward blood donation. Test seeking was inferred if a donor answered yes to I wanted to get my test results and one of the following: blood center testing is confidential, free, more accurate than other test centers, or tests will identify problems with my blood. Cases were compared to controls using descriptive and multivariable analyses. RESULTSWhether a case or control, the most common donation reason was to help someone in need (>90% in each group). After adjusting for demographic characteristics, test seeking was not significantly associated with infection status. Test seeking was more common in first-time, younger males and nonwhite, non-Hispanic donors. Of donors with HIV, 13% considered selection policies to be unfair, compared with 1, 2, 0.5, and 6% of donors with HBV, HCV, and HTLV and controls, respectively (adjusted odds ratio for HIV cases vs. controls, 3.9; 95% confidence interval, 2.3-6.7). CONCLUSIONSMost donors give to help those in need, including HIV-positive donors. Our results establish a baseline from which additional studies can be compared focused on alternate ways to reduce noncompliance and improved messaging to ensure that high-risk potential donors understand the reasons for blood donor screening policies. C1 [Vahidnia, Farnaz; Goncalez, Thelma T.; Custer, Brian] Blood Syst Res Inst, 270 Masonic Ave, San Francisco, CA 94118 USA. [Stramer, Susan L.; Krysztof, David E.] Amer Red Cross, Gaithersburg, MD USA. [Kessler, Debra; Shaz, Beth H.] New York Blood Ctr, New York, NY 10021 USA. [Leparc, German] OneBlood, Tampa, FL USA. [Dodd, Roger Y.] Amer Red Cross, Holland Lab, Rockville, MD USA. [Glynn, Simone A.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Custer, Brian] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Vahidnia, F (reprint author), Blood Syst Res Inst, 270 Masonic Ave, San Francisco, CA 94118 USA. EM Fvahidnia@bloodsystems.org OI Vahidnia, Farnaz/0000-0003-1130-4643 FU Retrovirus Epidemiology Donor Study-II (REDS-II) - National Heart, Lung, and Blood Institute, National Institutes of Health [HHSN26820041717] FX This study was funded by Research Contract HHSN26820041717 from the Retrovirus Epidemiology Donor Study-II (REDS-II) sponsored by the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 40 TC 1 Z9 1 U1 9 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD AUG PY 2016 VL 56 IS 8 BP 2013 EP 2020 DI 10.1111/trf.13678 PG 8 WC Hematology SC Hematology GA DU8ZP UT WOS:000382506100015 PM 27351292 ER PT J AU Bingham, CR Simons-Morton, BG Pradhan, AK Li, KG Almani, F Falk, EB Shope, JT Buckley, L Ouimet, MC Albert, PS AF Bingham, C. Raymond Simons-Morton, Bruce G. Pradhan, Anuj K. Li, Kaigang Almani, Farideh Falk, Emily B. Shope, Jean T. Buckley, Lisa Ouimet, Marie Claude Albert, Paul S. TI Peer passenger norms and pressure: Experimental effects on simulated driving among teenage males SO TRANSPORTATION RESEARCH PART F-TRAFFIC PSYCHOLOGY AND BEHAVIOUR LA English DT Article DE Teen driver; Risky driving behavior; Simulated driving; Hazard perception; Social influences; Injunctive norms ID UNITED-STATES; DEVELOPMENTAL PERSPECTIVE; ADOLESCENT DRIVERS; SOCIAL-INFLUENCE; RISK PERCEPTION; CRASHES; BEHAVIOR; NOVICE; SAFETY; INVOLVEMENT AB Objective: Serious crashes are more likely when teenage drivers have teenage passengers. One likely source of this increased risk is social influences on driving performance. This driving simulator study experimentally tested the effects of peer influence (i.e., risk-accepting compared to risk-averse peer norms reinforced by pressure) on the driving risk behavior (i.e., risky driving behavior and inattention to hazards) of male teenagers. It was hypothesized that peer presence would result in greater driving risk behavior (i.e., increased driving risk and reduced latent hazard anticipation), and that the effect would be greater when the peer was risk-accepting. Methods: Fifty-three 16- and 17-year-old male participants holding a provisional U.S., State of Michigan driver license were randomized to either a risk-accepting or risk-averse condition. Each participant operated a driving simulator while alone and separately with a confederate peer passenger. The simulator world included scenarios designed to elicit variation in driving risk behavior with a teen passenger present in the vehicle. Results: Significant interactions of passenger presence (passenger present vs. alone) by risk condition (risk-accepting vs. risk-averse) were observed for variables measuring: failure to stop at yellow light intersections (Incident Rate Ratio (IRR) = 2.16; 95% confidence interval [950]= 1.06, 4.43); higher probability of overtaking (IRR = 10.17; 95CI = 1.43, 73.35); shorter left turn latency (IRR = 0.43; 95CI = 0.31, 0.60); and, failure to stop at an intersection with an occluded stop sign (IRR = 7.90; 95CI = 2.06, 30.35). In all cases, greater risky driving by participants was more likely with a risk-accepting passenger versus a risk-averse passenger present and a risk-accepting passenger present versus driving alone. Conclusions: Exposure of male teenagers to a risk-accepting confederate peer passenger who applied peer influence increased simulated risky driving behavior compared with exposure to a risk-averse confederate peer passenger or driving alone. These results are consistent with the contention that variability in teenage risky driving is in part explained by social influences. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Bingham, C. Raymond; Pradhan, Anuj K.; Almani, Farideh; Shope, Jean T.; Buckley, Lisa] Univ Michigan, Transportat Res Inst, 2091 Baxter Rd, Ann Arbor, MI 48109 USA. [Simons-Morton, Bruce G.; Li, Kaigang; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut Blvd Room 7B13M,MSC 7510, Bethesda, MD 20892 USA. [Falk, Emily B.] Univ Penn, Annenberg Sch Commun, 3620 Walnut St, Philadelphia, PA 19104 USA. [Ouimet, Marie Claude] Univ Sherbrooke, Dept Sci Sante Communautaire, 2500 Boul Univ, Sherbrooke, PQ J1K 2R1, Canada. RP Bingham, CR (reprint author), Univ Michigan, Transportat Res Inst, 2091 Baxter Rd, Ann Arbor, MI 48109 USA. EM rbingham@umich.edu OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Eunice Kennedy Shriver National Institute on Child Health and Human Development [HHSN275201000007C] FX This research was funded through contract HHSN275201000007C by the Eunice Kennedy Shriver National Institute on Child Health and Human Development. The authors have no conflicts of interest to disclose relating to this research. NR 58 TC 0 Z9 0 U1 6 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1369-8478 EI 1873-5517 J9 TRANSPORT RES F-TRAF JI Transp. Res. Pt. F-Traffic Psychol. Behav. PD AUG PY 2016 VL 41 BP 124 EP 137 DI 10.1016/j.trf.2016.06.007 PN A PG 14 WC Psychology, Applied; Transportation SC Psychology; Transportation GA DU6RZ UT WOS:000382343600014 PM 27818610 ER PT J AU Hickman, HD Pierson, TC AF Hickman, Heather D. Pierson, Theodore C. TI Zika in the Brain: New Models Shed Light on Viral Infection SO TRENDS IN MOLECULAR MEDICINE LA English DT Editorial Material AB The current Zika virus (ZIKV) outbreak is associated with high numbers of human congenital birth defects, yet it has been unclear how ZIKV infection during pregnancy causes these abnormalities. Three new mouse models now show that ZIKV crosses the placenta and replicates in the brains of fetal mice. C1 [Hickman, Heather D.; Pierson, Theodore C.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Pierson, TC (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 10 TC 0 Z9 0 U1 48 U2 57 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 EI 1471-499X J9 TRENDS MOL MED JI Trends Mol. Med PD AUG PY 2016 VL 22 IS 8 BP 639 EP 641 DI 10.1016/j.molmed.2016.06.004 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DT5NR UT WOS:000381530400005 PM 27345865 ER PT J AU Barfield, WL Plank-Bazinet, JL Clayton, JA AF Barfield, Whitney L. Plank-Bazinet, Jennifer L. Clayton, Janine Austin TI Advancement of Women in the Biomedical Workforce: Insights for Success SO ACADEMIC MEDICINE LA English DT Editorial Material AB Women continue to face unique barriers in the biomedical workforce that affect their advancement and retention in this field. The National Institutes of Health (NIH) formed the Working Group on Women in Biomedical Careers to address these issues. Through the efforts of the working group, the NIH funded 14 research grants to identify barriers or to develop and/or test interventions to support women in the biomedical workforce. The grantees that were funded through this endeavor later established the grassroots Research Partnership on Women in Biomedical Careers, and they continue to conduct research and disseminate information on the state of women in academic medicine. This Commentary explores the themes introduced in a collection of articles organized by the research partnership and published in this issue of Academic Medicine. The authors highlight the role that government plays in the advancement of women in academic medicine and highlight the findings put forward in this collection. C1 [Barfield, Whitney L.] NIH, Amer Assoc Adv Sci, Off Res Womens Hlth, Bldg 10, Bethesda, MD 20892 USA. [Plank-Bazinet, Jennifer L.; Clayton, Janine Austin] NIH, Off Res Womens Hlth, Bldg 10, Bethesda, MD 20892 USA. [Clayton, Janine Austin] NIH, Womens Hlth, Bldg 10, Bethesda, MD 20892 USA. RP Plank-Bazinet, JL (reprint author), 6707 Democracy Blvd,Suite 400, Bethesda, MD 20817 USA. EM jennifer.bazinet@nih.gov FU Intramural NIH HHS [Z99 OD999999] NR 17 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD AUG PY 2016 VL 91 IS 8 BP 1047 EP 1049 DI 10.1097/ACM.0000000000001274 PG 3 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA DS5HT UT WOS:000380813000012 PM 27306970 ER PT J AU Plank-Bazinet, JL Whittington, KB Cassidy, SKB Filart, R Cornelison, TL Begg, L Clayton, JA AF Plank-Bazinet, Jennifer L. Whittington, Kjersten Bunker Cassidy, Sara K. B. Filart, Rosemarie Cornelison, Terri L. Begg, Lisa Clayton, Janine Austin TI Programmatic Efforts at the National Institutes of Health to Promote and Support the Careers of Women in Biomedical Science SO ACADEMIC MEDICINE LA English DT Article ID INTERDISCIPLINARY RESEARCH CAREERS AB Although women have reached parity at the training level in the biological sciences and medicine, they are still significantly underrepresented in the professoriate and in mid-and senior-level life science positions. Considerable effort has been devoted by individuals and organizations across science sectors to understanding this disparity and to developing interventions in support of women's career development. The National Institutes of Health (NIH) formed the Office of Research on Women's Health (ORWH) in 1990 with the goals of supporting initiatives to improve women's health and providing opportunities and support for the recruitment, retention, reentry, and sustained advancement of women in biomedical careers. Here, the authors review several accomplishments and flagship activities initiated by the NIH and ORWH in support of women's career development during this time. These include programming to support researchers returning to the workforce after a period away (Research Supplements to Promote Reentry into Biomedical and Behavioral Research Careers), career development awards made through the Building Interdisciplinary Research Careers in Women's Health program, and trans-NIH involvement and activities stemming from the NIH Working Group on Women in Biomedical Careers. These innovative programs have contributed to advancement of women by supporting the professional and personal needs of women in science. The authors discuss the unique opportunities that accompany NIH partnerships with the scientific community, and conclude with a summary of the impact of these programs on women in science. C1 [Plank-Bazinet, Jennifer L.; Begg, Lisa; Clayton, Janine Austin] NIH, Off Res Womens Hlth, Bldg 10, Bethesda, MD 20892 USA. [Whittington, Kjersten Bunker] NIH, Amer Assoc Adv Sci, Off Res Womens Hlth, Bldg 10, Bethesda, MD 20892 USA. [Whittington, Kjersten Bunker] Reed Coll, Dept Sociol, Portland, OR 97202 USA. [Cassidy, Sara K. B.] NHGRI, NIH, Bethesda, MD 20892 USA. [Filart, Rosemarie] Penn State Univ, Milton S Hershey Med Ctr, Inpatient Consultat, Hummelstown, PA USA. [Filart, Rosemarie] Penn State Univ, Milton S Hershey Med Ctr, Res, Hummelstown, PA USA. [Filart, Rosemarie] Penn State Univ, Milton S Hershey Med Ctr, Dept Phys Med & Rehabil, Hummelstown, PA USA. [Cornelison, Terri L.] NIH, Off Res Womens Hlth, Clin Res, Bldg 10, Bethesda, MD 20892 USA. [Clayton, Janine Austin] NIH, Womens Hlth, Bldg 10, Bethesda, MD 20892 USA. RP Plank-Bazinet, JL (reprint author), 6707 Democracy Blvd,Suite 400, Bethesda, MD 20817 USA. EM jennifer.plank@nih.gov FU National Institutes of Health Office of Research on Women's Health FX National Institutes of Health Office of Research on Women's Health. NR 30 TC 6 Z9 6 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD AUG PY 2016 VL 91 IS 8 BP 1057 EP 1064 DI 10.1097/ACM.0000000000001239 PG 8 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA DS5HT UT WOS:000380813000015 PM 27191836 ER PT J AU Ginther, DK Kahn, S Schaffer, WT AF Ginther, Donna K. Kahn, Shulamit Schaffer, Walter T. TI Gender, Race/Ethnicity, and National Institutes of Health R01 Research Awards: Is There Evidence of a Double Bind for Women of Color? SO ACADEMIC MEDICINE LA English DT Article ID ETHNICITY; RACE; INVESTIGATORS; GAP; SEX AB Purpose To analyze the relationship between gender, race/ethnicity, and the probability of being awarded an R01 grant from the National Institutes of Health (NIH). Method The authors used data from the NIH Information for Management, Planning, Analysis, and Coordination grants management database for the years 2000-2006 to examine gender differences and race/ethnicity-specific gender differences in the probability of receiving an R01 Type 1 award. The authors used descriptive statistics and probit models to determine the relationship between gender, race/ethnicity, degree, investigator experience, and R01 award probability, controlling for a large set of observable characteristics. Results White women PhDs and MDs were as likely as white men to receive an R01 award. Compared with white women, Asian and black women PhDs and black women MDs were significantly less likely to receive funding. Women submitted fewer grant applications, and blacks and women who were new investigators were more likely to submit only one application between 2000 and 2006. Conclusions Differences by race/ethnicity explain the NIH funding gap for women of color, as white women have a slight advantage over men in receiving Type 1 awards. Findings of a lower submission rate for women and an increased likelihood that they will submit only one proposal are consistent with research showing that women avoid competition. Policies designed to address the racial and ethnic diversity of the biomedical workforce have the potential to improve funding outcomes for women of color. C1 [Ginther, Donna K.] Univ Kansas, Dept Econ, 1460 Jayhawk Blvd, Lawrence, KS 66045 USA. [Ginther, Donna K.] Univ Kansas, Ctr Sci Technol & Econ Policy, Lawrence, KS 66045 USA. [Ginther, Donna K.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Kahn, Shulamit] Boston Univ, Questrom Sch Business, Dept Markets Publ Policy & Law, Boston, MA 02215 USA. [Schaffer, Walter T.] NIH, Div Biomed Workforce, Off Extramural Res, Bldg 10, Bethesda, MD 20892 USA. RP Ginther, DK (reprint author), Univ Kansas, Dept Econ, 1460 Jayhawk Blvd, Lawrence, KS 66045 USA. EM dginther@ku.edu RI Ginther, Donna/F-7317-2016 OI Ginther, Donna/0000-0002-0881-7969 FU National Institutes of Health (NIH) [1R01AG36820-01]; NIH [07-6008 OD OER] FX Ginther and Kahn acknowledge financial support from a National Institutes of Health (NIH) grant (1R01AG36820-01). Schaffer was an employee of NIH, and, as a result, NIH supported this work through an NIH Evaluation Set-Aside Award (07-6008 OD OER). NR 17 TC 7 Z9 7 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD AUG PY 2016 VL 91 IS 8 BP 1098 EP 1107 DI 10.1097/ACM.0000000000001278 PG 10 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA DS5HT UT WOS:000380813000023 PM 27306969 ER PT J AU Girod, S Fassiotto, M Grewal, D Ku, MC Sriram, N Nosek, BA Valantine, H AF Girod, Sabine Fassiotto, Magali Grewal, Daisy Ku, Manwai Candy Sriram, Natarajan Nosek, Brian A. Valantine, Hannah TI Reducing Implicit Gender Leadership Bias in Academic Medicine With an Educational Intervention SO ACADEMIC MEDICINE LA English DT Article ID ASSOCIATION TEST; SEX-DIFFERENCES; WOMEN LEADERS; RACE BIAS; FACULTY; PREJUDICE; SCIENCE; MALLEABILITY; STEREOTYPES; FEMALE AB Purpose One challenge academic health centers face is to advance female faculty to leadership positions and retain them there in numbers equal to men, especially given the equal representation of women and men among graduates of medicine and biological sciences over the last 10 years. The purpose of this study is to investigate the explicit and implicit biases favoring men as leaders, among both men and women faculty, and to assess whether these attitudes change following an educational intervention. Method The authors used a standardized, 20-minute educational intervention to educate faculty about implicit biases and strategies for overcoming them. Next, they assessed the effect of this intervention. From March 2012 through April 2013, 281 faculty members participated in the intervention across 13 of 18 clinical departments. Results The study assessed faculty members' perceptions of bias as well as their explicit and implicit attitudes toward gender and leadership. Results indicated that the intervention significantly changed all faculty members' perceptions of bias (P < .05 across all eight measures). Although, as expected, explicit biases did not change following the intervention, the intervention did have a small but significant positive effect on the implicit biases surrounding women and leadership of all participants regardless of age or gender (P = .008). Conclusions These results suggest that providing education on bias and strategies for reducing it can serve as an important step toward reducing gender bias in academic medicine and, ultimately, promoting institutional change, specifically the promoting of women to higher ranks. C1 [Girod, Sabine] Stanford Univ, Sch Med, Dept Surg, Stanford, CA 94305 USA. [Girod, Sabine] Stanford Univ, Dept Otolaryngol, Sch Med, Stanford, CA 94305 USA. [Fassiotto, Magali] Stanford Univ, Sch Med, Programs & Res, Off Fac Dev & Divers, Stanford, CA 94305 USA. [Grewal, Daisy] Stanford Univ, Off Vice Provost Undergrad Educ, Stanford, CA 94305 USA. [Ku, Manwai Candy] Apple Inc, Cupertino, CA USA. [Sriram, Natarajan] Implisci, Charlottesville, VA USA. [Nosek, Brian A.] Univ Virginia, Dept Psychol, Gilmer Hall, Charlottesville, VA 22903 USA. [Nosek, Brian A.] Ctr Open Sci, Charlottesville, VA USA. [Valantine, Hannah] NIH, Sci Workforce Divers, Bldg 10, Bethesda, MD 20892 USA. [Valantine, Hannah] Stanford Univ, Stanford, CA 94305 USA. RP Valantine, H (reprint author), NIH, Off Director, 300 Rockville Pike, Rockville, MD 20850 USA. EM Hannah.valantine@nih.gov OI Nosek, Brian/0000-0001-6797-5476 FU National Institutes of Health [1UL1 RR025744-01, 1DP4GM096849-01] FX This work was supported by National Institutes of Health Clinical and Translational Science Award 1UL1 RR025744-01 and the National Institutes of Health Director's Pathfinder Award (1DP4GM096849-01). NR 49 TC 6 Z9 6 U1 17 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD AUG PY 2016 VL 91 IS 8 BP 1143 EP 1150 DI 10.1097/ACM.0000000000001099 PG 8 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA DS5HT UT WOS:000380813000028 PM 26826068 ER PT J AU Heggeness, ML Evans, L Pohlhaus, JR Mills, SL AF Heggeness, Misty L. Evans, Lisa Pohlhaus, Jennifer Reineke Mills, Sherry L. TI Measuring Diversity of the National Institutes of Health-Funded Workforce SO ACADEMIC MEDICINE LA English DT Article ID REPRESENTATION; ETHNICITY; RACE AB Purpose To measure diversity within the National Institutes of Health (NIH)-funded workforce. The authors use a relevant labor market perspective to more directly understand what the NIH can influence in terms of enhancing diversity through NIH policies. Method Using the relevant labor market (defined as persons with advanced degrees working as biomedical scientists in the United States) as the conceptual framework, and informed by accepted economic principles, the authors used the American Community Survey and NIH administrative data to calculate representation ratios of the NIH-funded biomedical workforce from 2008 to 2012 by race, ethnicity, sex, and citizenship status, and compared this against the pool of characteristic individuals in the potential labor market. Results In general, the U.S. population during this time period was an inaccurate comparison group for measuring diversity of the NIH-funded scientific workforce. Measuring accurately, we found the representation of women and traditionally underrepresented groups in NIH-supported postdoc fellowships and traineeships and mentored career development programs was greater than their representation in the relevant labor market. The same analysis found these demographic groups are less represented in the NIH-funded independent investigator pool. Conclusions Although these findings provided a picture of the current NIH-funded workforce and a foundation for understanding the federal role in developing, maintaining, and renewing diverse scientific human resources, further study is needed to identify whether junior-and early-stage investigators who are part of more diverse cohorts will naturally transition into independent NIH-funded investigators, or whether they will leave the workforce before achieving independent researcher status. C1 [Heggeness, Misty L.] US Bur Census, Longitudinal Res Evaluat & Outreach Branch, Social Econ & Housing Stat Div, Suitland, MD 20746 USA. [Heggeness, Misty L.; Evans, Lisa] NIH, Div Biomed Res Workforce, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Pohlhaus, Jennifer Reineke] Ripple Effect Commun Inc, Rockville, MD USA. [Mills, Sherry L.] NIH, Off Extramural Programs, Off Director, Bldg 10, Bethesda, MD 20892 USA. RP Heggeness, ML (reprint author), US Bur Census, 4600 Silver Hill Rd,Room 6H065, Suitland, MD 20746 USA. EM misty.l.heggeness@census.gov OI Heggeness, Misty/0000-0003-4113-7698 FU NIH FX All authors are employees or contractors of the NIH; in this way, this work was supported by the NIH. NR 23 TC 4 Z9 4 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD AUG PY 2016 VL 91 IS 8 BP 1164 EP 1172 DI 10.1097/ACM.0000000000001209 PG 9 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA DS5HT UT WOS:000380813000031 PM 27224301 ER PT J AU Appiah, D Schreiner, PJ Durant, RW Kiefe, CI Loria, C Lewis, CE Williams, OD Person, SD Sidney, S AF Appiah, Duke Schreiner, Pamela J. Durant, Raegan W. Kiefe, Catarina I. Loria, Catherine Lewis, Cora E. Williams, O. Dale Person, Sharina D. Sidney, Stephen TI Relation of longitudinal changes in body mass index with atherosclerotic cardiovascular disease risk scores in middle-aged black and white adults: the Coronary Artery Risk Development in Young Adults (CARDIA) Study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Obesity; Cardiovascular disease; Risk prediction ID HEART-DISEASE; UNITED-STATES; CEREBROVASCULAR DISEASES; OBESITY; HYPERTENSION; PREVALENCE; MORTALITY; HEALTH; TRENDS; IMPACT AB Purpose: We assessed whether longitudinal changes in body mass index (BMI) are positively associated with changes in 10-year American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease (ASCVD) risk scores in middle-aged blacks compared to whites. Methods: Data were from 1691 participants enrolled in the Coronary Artery Risk Development in Young Adults Study aged 40 years or more in 2000-2001, who had follow-up examinations 5 and 10 years later. Results: The prevalence of obesity increased from 32.3% in 2000-2001 (mean age: 42.8 years) to 41.7% in 2010-2011, higher in blacks than whites. The corresponding change in 10-year ASCVD risk was significantly higher for blacks (men: 4.5%-9.6%, women: 1.7%-5.0%) than whites (men: 2.4%-5.2%, women: 0.7%-1.6%). In 2010-2011, 57.5% of black men had ASCVD risk scores of 7.5% or more compared to white men (14.7%), black women (17.4%), and white women (1.6%). Although BMI trends were positively associated with 10-year change in ASCVD risk scores (0.07% per 1 kg/m(2) increase), it explained very little variance in risk score trends in all race sex groups. Conclusions: In middle-aged adults, longitudinal changes in BMI had little independent influence on changes in 10 -year ASCVD risk scores as its effect may be largely mediated through ASCVD risk factors already accounted for in the risk score. (C) 2016 Elsevier Inc. All rights reserved. C1 [Appiah, Duke; Schreiner, Pamela J.] Univ Minnesota, Div Epidemiol & Community Hlth, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. [Durant, Raegan W.; Lewis, Cora E.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Kiefe, Catarina I.; Person, Sharina D.] Univ Massachusetts, Quantitat Hlth Sci, Worcester, MA 01605 USA. [Loria, Catherine] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Williams, O. Dale] Florida Int Univ, Dept Biostat, Miami, FL 33199 USA. [Sidney, Stephen] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. RP Appiah, D (reprint author), Univ Minnesota, Div Epidemiol & Community Hlth, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM dappiah@umn.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005]; NHLBI [AG0005, T32HL007779] FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), an intra-agency agreement between NIA and NHLBI (AG0005). Dr. Appiah was supported by NHLBI training grant T32HL007779. NR 40 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2016 VL 26 IS 8 BP 521 EP 526 DI 10.1016/j.annepidem.2016.06.008 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DU3HU UT WOS:000382102200001 PM 27402259 ER PT J AU Withrow, DR Racey, CS Jamal, S AF Withrow, Diana R. Racey, C. Sarai Jamal, Sehar TI A critical review of methods for assessing cancer survival disparities in indigenous population SO ANNALS OF EPIDEMIOLOGY LA English DT Review DE Neoplasms; Survival analysis; Indians; North American; Oceanic Ancestry Group; Health status disparities; Health care disparities ID SQUAMOUS-CELL CARCINOMA; HISPANIC WHITE WOMEN; NEW-ZEALAND; AMERICAN-INDIANS; BREAST-CANCER; CERVICAL-CANCER; NEW-MEXICO; PROSTATE-CANCER; UNITED-STATES; LUNG-CANCER AB Purpose: An increasing cancer burden among indigenous populations has led to a growing literature about survival disparities between indigenous and nonindigenous persons. We aim to describe and appraise methods used to measure cancer survival in indigenous persons in the United States, Canada, Australia, and New Zealand. Methods: We searched Medline, Web of Science, and EMBASE for articles published between 1990 and 2015 that estimated survival in populations indigenous to one of these four countries. We gathered information about data sources, analytical methods, and the extent to which threats to validity were discussed. Results: The search retrieved 83 articles. The most common approach to survival analysis was cause specific survival (n = 49). Thirty-eight articles measured all-cause survival and 11 measured excess mortality attributable to cancer (relative survival). Three sources of information bias common to all studies (ethnic misclassification, incomplete case ascertainment, and incomplete death ascertainment) were acknowledged in a minority of articles. Conclusions: The methodological considerations we present here are shared with studies of cancer survival across other subpopulations. We urge future researchers on this and related topics to clearly describe their data sources, to justify analytic choices, and to fully discuss the potential impact of those choices on the results and interpretation. Published by Elsevier Inc. C1 [Withrow, Diana R.; Jamal, Sehar] Canc Care Ontario, Aboriginal Canc Control Unit, Prevent & Canc Control, Toronto, ON, Canada. [Withrow, Diana R.; Racey, C. Sarai] Univ Toronto, Dalla Lana Sch Publ Hlth, Dept Epidemiol, Toronto, ON, Canada. RP Withrow, DR (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 7E590, Rockville, MD 20850 USA. EM diana.withrow@nih.gov FU Canadian Institutes of Health Research Doctoral Award FX The authors acknowledge insightful comments on drafts of this article from Wendy Lou, Loraine Marrett, Diane Nishri, and Jason Pole. Caroline Cawley contributed valuable editorial expertise. D.R.W. was supported by a Canadian Institutes of Health Research Doctoral Award. The funder had no role in the preparation of this article. NR 124 TC 2 Z9 2 U1 6 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2016 VL 26 IS 8 BP 579 EP 591 DI 10.1016/j.annepidem.2016.06.007 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DU3HU UT WOS:000382102200009 PM 27431064 ER PT J AU Barnett, CF Alvarez, P Park, MH AF Barnett, Christopher F. Alvarez, Paulino Park, Myung H. TI Pulmonary Arterial Hypertension: Diagnosis and Treatment SO CARDIOLOGY CLINICS LA English DT Article DE Pulmonary arterial hypertension; Echocardiography; Right heart catheterization; Prostacyclin; Phosphodiesterase inhibitor; Endothelin antagonist ID ENDOTHELIN RECEPTOR ANTAGONIST; RANDOMIZED CONTROLLED-TRIAL; 5 INHIBITOR THERAPY; ORAL TREPROSTINIL; HEART-FAILURE; DOUBLE-BLIND; ECHOCARDIOGRAPHY; PROSTACYCLIN; MULTICENTER; MANAGEMENT AB Pulmonary arterial hypertension (PAH) is a specific, rare disease characterized by a well-described pattern of pulmonary vascular remodeling. The elevated pulmonary artery pressure in PAH results in increased right ventricular afterload, which, if untreated, leads rapidly to right ventricular failure and death. Recent marked expansion in knowledge about PAH has resulted in the development of effective therapies that improve quality of life and survival. However, delays in diagnosis and suboptimal treatment remain significant barriers to achieving optimal patient outcomes. Continued success in raising PAH awareness, earlier diagnosis, and the availability of new therapies mean a promising future for PAH patients. C1 [Barnett, Christopher F.] Medstar Heart & Vasc Inst, 110 Irving St Northwest, Washington, DC 20010 USA. [Barnett, Christopher F.] NIH, Dept Crit Care Med, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. [Alvarez, Paulino] Houston Methodist Hosp, Dept Cardiol, Methodist DeBakey Heart & Vasc Ctr, 6550 Fannin St,Smith Tower,Suite 1901, Houston, TX 77030 USA. [Park, Myung H.] Houston Methodist Hosp, Div Heart Failure & Transplant, Dept Cardiol, Methodist DeBakey Heart & Vasc Ctr, 6550 Fannin St,Smith Tower,Suite 1901, Houston, TX 77030 USA. RP Park, MH (reprint author), Houston Methodist Hosp, Div Heart Failure & Transplant, Dept Cardiol, Methodist DeBakey Heart & Vasc Ctr, 6550 Fannin St,Smith Tower,Suite 1901, Houston, TX 77030 USA. EM mhpark@houstonmethodist.org NR 40 TC 2 Z9 2 U1 6 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0733-8651 EI 1558-2264 J9 CARDIOL CLIN JI Cardiol. Clin. PD AUG PY 2016 VL 34 IS 3 BP 375 EP + DI 10.1016/j.ccl.2016.04.006 PG 16 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DT2SU UT WOS:000381331500004 PM 27443135 ER PT J AU Cragg, G AF Cragg, Gordon TI Tribute to the late Emeritus Professor Lester A Mitscher SO JOURNAL OF ANTIBIOTICS LA English DT Biographical-Item C1 [Cragg, Gordon] NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Cragg, G (reprint author), NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. EM gmcragg2@gmail.com NR 1 TC 0 Z9 0 U1 1 U2 1 PU JAPAN ANTIBIOTICS RESEARCH ASSOC PI TOKYO PA 2 20 8 KAMIOSAKI SHINAGAWA KU, TOKYO, 141, JAPAN SN 0021-8820 J9 J ANTIBIOT JI J. Antibiot. PD AUG PY 2016 VL 69 IS 8 SI SI BP 580 EP 580 DI 10.1038/ja.2016.83 PG 1 WC Biotechnology & Applied Microbiology; Immunology; Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Immunology; Microbiology; Pharmacology & Pharmacy GA DU3GS UT WOS:000382099400002 PM 27569907 ER PT J AU Newman, D AF Newman, David TI A tribute to the late Emeritus Professor Lester A Mitscher SO JOURNAL OF ANTIBIOTICS LA English DT Biographical-Item C1 [Newman, David] NCI, Nat Prod Branch, Frederick Natl Lab, Frederick, MD 21701 USA. RP Newman, D (reprint author), NCI, Nat Prod Branch, Frederick Natl Lab, Frederick, MD 21701 USA. EM djnewman664@verizon.net NR 1 TC 0 Z9 0 U1 0 U2 0 PU JAPAN ANTIBIOTICS RESEARCH ASSOC PI TOKYO PA 2 20 8 KAMIOSAKI SHINAGAWA KU, TOKYO, 141, JAPAN SN 0021-8820 J9 J ANTIBIOT JI J. Antibiot. PD AUG PY 2016 VL 69 IS 8 SI SI BP 581 EP 581 DI 10.1038/ja.2016.85 PG 1 WC Biotechnology & Applied Microbiology; Immunology; Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Immunology; Microbiology; Pharmacology & Pharmacy GA DU3GS UT WOS:000382099400003 PM 27569908 ER PT J AU Bailey, AL Lauck, M Ghai, RR Nelson, CW Heimbruch, K Hughes, AL Goldberg, TL Kuhn, JH Jasinska, AJ Freimer, NB Apetrei, C O'Connor, DH AF Bailey, Adam L. Lauck, Michael Ghai, Ria R. Nelson, Chase W. Heimbruch, Katelyn Hughes, Austin L. Goldberg, Tony L. Kuhn, Jens H. Jasinska, Anna J. Freimer, Nelson B. Apetrei, Cristian O'Connor, David H. CA Int Vervet Res Consortium TI Arteriviruses, Pegiviruses, and Lentiviruses Are Common among Wild African Monkeys SO JOURNAL OF VIROLOGY LA English DT Article ID SIMIAN HEMORRHAGIC-FEVER; GB-VIRUS-C; RESPIRATORY SYNDROME VIRUS; NEUTRALIZATION EPITOPE; GP5 ECTODOMAIN; PRIMATE; INFECTION; HOST; TRANSMISSION; PHYLOGENY AB Nonhuman primates (NHPs) are a historically important source of zoonotic viruses and are a gold-standard model for research on many human pathogens. However, with the exception of simian immunodeficiency virus (SIV) (family Retroviridae), the blood-borne viruses harbored by these animals in the wild remain incompletely characterized. Here, we report the discovery and characterization of two novel simian pegiviruses (family Flaviviridae) and two novel simian arteriviruses (family Arteriviridae) in wild African green monkeys from Zambia (malbroucks [Chlorocebus cynosuros]) and South Africa (vervet monkeys [Chlorocebus pygerythrus]). We examine several aspects of infection, including viral load, genetic diversity, evolution, and geographic distribution, as well as host factors such as age, sex, and plasma cytokines. In combination with previous efforts to characterize blood-borne RNA viruses in wild primates across sub-Saharan Africa, these discoveries demonstrate that in addition to SIV, simian pegiviruses and simian arteriviruses are widespread and prevalent among many African cercopithecoid (i.e., Old World) monkeys. IMPORTANCE Primates are an important source of viruses that infect humans and serve as an important laboratory model of human virus infection. Here, we discover two new viruses in African green monkeys from Zambia and South Africa. In combination with previous virus discovery efforts, this finding suggests that these virus types are widespread among African monkeys. Our analysis suggests that one of these virus types, the simian arteriviruses, may have the potential to jump between different primate species and cause disease. In contrast, the other virus type, the pegiviruses, are thought to reduce the disease caused by human immunodeficiency virus (HIV) in humans. However, we did not observe a similar protective effect in SIV-infected African monkeys coinfected with pegiviruses, possibly because SIV causes little to no disease in these hosts. C1 [Bailey, Adam L.; Lauck, Michael; Heimbruch, Katelyn; O'Connor, David H.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. [Bailey, Adam L.; Lauck, Michael; Heimbruch, Katelyn; Goldberg, Tony L.; O'Connor, David H.] Wisconsin Natl Primate Res Ctr, Madison, WI USA. [Ghai, Ria R.] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. [Nelson, Chase W.; Hughes, Austin L.] Univ South Carolina, Dept Biol Sci, Columbia, SC 29208 USA. [Goldberg, Tony L.] Univ Wisconsin, Dept Pathobiol Sci, Madison, WI 53706 USA. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [Jasinska, Anna J.; Freimer, Nelson B.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Apetrei, Cristian] Univ Pittsburgh, Ctr Vaccine Res, Pittsburgh, PA USA. [Apetrei, Cristian] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA USA. RP O'Connor, DH (reprint author), Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA.; O'Connor, DH (reprint author), Wisconsin Natl Primate Res Ctr, Madison, WI USA. EM doconnor@primate.wisc.edu OI Ghai, Ria/0000-0001-9775-4826; Kuhn, Jens H./0000-0002-7800-6045 FU National Institutes of Health (NIH) [R01AI077376-01, R01AI084787, R01RR025781, P01AI088564, R01AI116382-01]; National Science Foundation (NSF) [NSF1029302, NSF1029323, NSF1029451, DGE0929297]; NIH-NSF Ecology of Infectious Diseases program [TW009237]; United Kingdom Economic and Social Research Council [TW009237]; Wisconsin Partnership Program through the Wisconsin Center for Infectious Diseases; National Institutes of Health National Center for Research Resources [P51RR000167, R01OD010980]; Office of Research Infrastructure Programs (ORIP) [OD011104]; Research Facilities Improvement Program [RR15459-01, RR020141-01]; University of Wisconsin Medical Scientist Training Program (MSTP) [T32 GM008692]; National Research Service Award (NRSA) through the Microbes in Health and Disease (MHD) training program at the University of Wisconsin [T32 AI55397]; NSF [DGE-0929297]; University of South Carolina (USC); USC Department of Biological Sciences Kathryn Hinnant-Johnson, M.D., Memorial Fellowship; Battelle Memorial Institute's prime contract; U.S. National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I] FX This work was funded by the National Institutes of Health (NIH) (grants R01AI077376-01, R01AI084787, R01RR025781, P01AI088564, and R01AI116382-01), the National Science Foundation (NSF) (grants NSF1029302, NSF1029323, NSF1029451, and DGE0929297), the joint NIH-NSF Ecology of Infectious Diseases program and the United Kingdom Economic and Social Research Council (grant TW009237), and the Wisconsin Partnership Program through the Wisconsin Center for Infectious Diseases. This publication was made possible in part by grants from the National Institutes of Health National Center for Research Resources (grant P51RR000167 to the WNPRC, University of Wisconsin-Madison, and grant R01OD010980, formerly R01RR016300, to the University of California, Los Angeles) and grant OD011104 to the Tulane National Primate Research Center from the Office of Research Infrastructure Programs (ORIP). This research was conducted in part at a facility constructed with support from Research Facilities Improvement Program grants RR15459-01 and RR020141-01. A.L.B. performed this work with support from the University of Wisconsin Medical Scientist Training Program (MSTP) (grant T32 GM008692) and a National Research Service Award (NRSA) through the Microbes in Health and Disease (MHD) training program at the University of Wisconsin (grant T32 AI55397). C.W.N. performed this work with support from NSF Graduate Research Fellowship DGE-0929297, the University of South Carolina (USC) Presidential Fellowship, and the USC Department of Biological Sciences Kathryn Hinnant-Johnson, M.D., Memorial Fellowship. This work was also funded in part through Battelle Memorial Institute's prime contract with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) under contract no. HHSN272200700016I. A subcontractor to Battelle Memorial Institute who performed this work is J.H.K., an employee of Tunnell Government Services, Inc. NR 67 TC 1 Z9 2 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2016 VL 90 IS 15 BP 6724 EP 6737 DI 10.1128/JVI.00573-16 PG 14 WC Virology SC Virology GA DU6EF UT WOS:000382306100009 PM 27170760 ER PT J AU Hogg, JR AF Hogg, J. Robert TI Viral Evasion and Manipulation of Host RNA Quality Control Pathways SO JOURNAL OF VIROLOGY LA English DT Review ID SARCOMA-ASSOCIATED HERPESVIRUS; PRE-MESSENGER-RNA; POLYADENYLATED NUCLEAR-RNA; EXON JUNCTION COMPLEX; CIS-ACTING ELEMENTS; REV GENE-PRODUCT; NONSENSE CODONS; TRIPLE-HELIX; NUCLEOCYTOPLASMIC EXPORT; ENDONUCLEOLYTIC CLEAVAGE AB Viruses have evolved diverse strategies to maximize the functional and coding capacities of their genetic material. Individual viral RNAs are often used as substrates for both replication and translation and can contain multiple, sometimes overlapping open reading frames. Further, viral RNAs engage in a wide variety of interactions with both host and viral proteins to modify the activities of important cellular factors and direct their own trafficking, packaging, localization, stability, and translation. However, adaptations increasing the information density of small viral genomes can have unintended consequences. In particular, viral RNAs have developed features that mark them as potential targets of host RNA quality control pathways. This minireview focuses on ways in which viral RNAs run afoul of the cellular mRNA quality control and decay machinery, as well as on strategies developed by viruses to circumvent or exploit cellular mRNA surveillance. C1 [Hogg, J. Robert] NHLBI, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Hogg, JR (reprint author), NHLBI, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM j.hogg@nih.gov OI Hogg, J. Robert/0000-0001-5729-5135 FU HHS \ NIH \ National Heart, Lung, and Blood Institute (NHLBI); HHS \ NIH \ National Heart, Lung, and Blood Institute (NHLBI) \ Intramural Research Program FX This work, including the efforts of J. Robert Hogg, was funded by HHS vertical bar NIH vertical bar National Heart, Lung, and Blood Institute (NHLBI).; This work was supported by HHS vertical bar NIH vertical bar National Heart, Lung, and Blood Institute (NHLBI) vertical bar Intramural Research Program. NR 122 TC 2 Z9 2 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2016 VL 90 IS 16 BP 7010 EP 7018 DI 10.1128/JVI.00607-16 PG 9 WC Virology SC Virology GA DU6EJ UT WOS:000382306500001 PM 27226372 ER PT J AU Nelson, EV Schmidt, KM Deflube, LR Doganay, S Banadyga, L Olejnik, J Hume, AJ Ryabchikova, E Ebihara, H Kedersha, N Ha, T Muhlberger, E AF Nelson, Emily V. Schmidt, Kristina M. Deflube, Laure R. Doganay, Sultan Banadyga, Logan Olejnik, Judith Hume, Adam J. Ryabchikova, Elena Ebihara, Hideki Kedersha, Nancy Ha, Taekjip Muehlberger, Elke TI Ebola Virus Does Not Induce Stress Granule Formation during Infection and Sequesters Stress Granule Proteins within Viral Inclusions SO JOURNAL OF VIROLOGY LA English DT Article ID MESSENGER-RNA; MARBURG-VIRUS; KINASE PKR; INTERFERON ANTAGONISM; PROCESSING BODIES; VP35 PROTEIN; P-BODIES; REPLICATION; CELLS; NUCLEOPROTEIN AB A hallmark of Ebola virus (EBOV) infection is the formation of viral inclusions in the cytoplasm of infected cells. These viral inclusions contain the EBOV nucleocapsids and are sites of viral replication and nucleocapsid maturation. Although there is growing evidence that viral inclusions create a protected environment that fosters EBOV replication, little is known about their role in the host response to infection. The cellular stress response is an effective antiviral strategy that leads to stress granule (SG) formation and translational arrest mediated by the phosphorylation of a translation initiation factor, the alpha subunit of eukaryotic initiation factor 2 (eIF2 alpha). Here, we show that selected SG proteins are sequestered within EBOV inclusions, where they form distinct granules that colocalize with viral RNA. These inclusion-bound (IB) granules are functionally and structurally different from canonical SGs. Formation of IB granules does not indicate translational arrest in the infected cells. We further show that EBOV does not induce formation of canonical SGs or eIF2 alpha phosphorylation at any time postinfection but is unable to fully inhibit SG formation induced by different exogenous stressors, including sodium arsenite, heat, and hippuristanol. Despite the sequestration of SG marker proteins into IB granules, canonical SGs are unable to form within inclusions, which we propose might be mediated by a novel function of VP35, which disrupts SG formation. This function is independent of VP35's RNA binding activity. Further studies aim to reveal the mechanism for SG protein sequestration and precise function within inclusions. IMPORTANCE Although progress has been made developing antiviral therapeutics and vaccines against the highly pathogenic Ebola virus (EBOV), the cellular mechanisms involved in EBOV infection are still largely unknown. To better understand these intracellular events, we investigated the cellular stress response, an antiviral pathway manipulated by many viruses. We show that EBOV does not induce formation of stress granules (SGs) in infected cells and is therefore unrestricted by their concomitant translational arrest. We identified SG proteins sequestered within viral inclusions, which did not impair protein translation. We further show that EBOV is unable to block SG formation triggered by exogenous stress early in infection. These findings provide insight into potential targets of therapeutic intervention. Additionally, we identified a novel function of the interferon antagonist VP35, which is able to disrupt SG formation. C1 [Nelson, Emily V.; Schmidt, Kristina M.; Deflube, Laure R.; Olejnik, Judith; Hume, Adam J.; Muehlberger, Elke] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Nelson, Emily V.; Schmidt, Kristina M.; Deflube, Laure R.; Olejnik, Judith; Hume, Adam J.; Muehlberger, Elke] Boston Univ, Natl Emerging Infect Dis Labs, Boston, MA 02215 USA. [Doganay, Sultan; Ha, Taekjip] Univ Illinois, Dept Phys, Urbana, IL USA. [Banadyga, Logan; Ebihara, Hideki] NIAID, Virol Lab, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT USA. [Ryabchikova, Elena] Russian Acad Sci, Siberian Branch, Inst Chem Biol & Fundamental Med, Novosibirsk, Russia. [Kedersha, Nancy] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA. [Schmidt, Kristina M.] Inst Novel & Emerging Infect Dis, Fed Res Inst Anim Hlth, Friedrich Loeffler Inst, Greifswald, Germany. RP Muhlberger, E (reprint author), Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA.; Muhlberger, E (reprint author), Boston Univ, Natl Emerging Infect Dis Labs, Boston, MA 02215 USA. EM muehlber@bu.edu RI Ryabchikova, Elena /G-3089-2013 OI Ryabchikova, Elena /0000-0003-4714-1524 FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [U01-AI082954, R03-AI114293, UC6AI058618, AI0655858, CA168872, U19-AI083025]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) FX This work, including the efforts of Elke Muhlberger, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (U01-AI082954). This work, including the efforts of Elke Muhlberger, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R03-AI114293). This work, including the efforts of Elke Muhlberger, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (UC6AI058618). This work, including the efforts of Nancy Kedersha, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI0655858). This work, including the efforts of Nancy Kedersha, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (CA168872). This work, including the efforts of Taekjip Ha, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (U19-AI083025). This work, including the efforts of Hideki Ebihara, was funded by Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID). NR 83 TC 0 Z9 0 U1 2 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2016 VL 90 IS 16 BP 7268 EP 7284 DI 10.1128/JVI.00459-16 PG 17 WC Virology SC Virology GA DU6EJ UT WOS:000382306500021 PM 27252530 ER PT J AU Rostad, CA Stobart, CC Gilbert, BE Pickles, RJ Hotard, AL Meng, J Blanco, JCG Moin, SM Graham, BS Piedra, PA Moore, ML AF Rostad, Christina A. Stobart, Christopher C. Gilbert, Brian E. Pickles, Ray J. Hotard, Anne L. Meng, Jia Blanco, Jorge C. G. Moin, Syed M. Graham, Barney S. Piedra, Pedro A. Moore, Martin L. TI A Recombinant Respiratory Syncytial Virus Vaccine Candidate Attenuated by a Low-Fusion F Protein Is Immunogenic and Protective against Challenge in Cotton Rats SO JOURNAL OF VIROLOGY LA English DT Article ID ENHANCED PULMONARY PATHOLOGY; NEUTRALIZING ANTIBODY; IN-VITRO; SH GENE; INFECTION; DISEASE; GLYCOPROTEIN; DEOPTIMIZATION; IMMUNIZATION; PATHOGENESIS AB Although respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants, a safe and effective vaccine is not yet available. Live-attenuated vaccines (LAVs) are the most advanced vaccine candidates in RSV-naive infants. However, designing an LAV with appropriate attenuation yet sufficient immunogenicity has proven challenging. In this study, we implemented reverse genetics to address these obstacles with a multifaceted LAV design that combined the codon deoptimization of genes for nonstructural proteins NS1 and NS2 (dNS), deletion of the small hydrophobic protein (Delta SH) gene, and replacement of the wild-type fusion (F) protein gene with a low-fusion RSV subgroup B F consensus sequence of the Buenos Aires clade (BAF). This vaccine candidate, RSV-A2-dNS-Delta SH-BAF (DB1), was attenuated in two models of primary human airway epithelial cells and in the upper and lower airways of cotton rats. DB1 was also highly immunogenic in cotton rats and elicited broadly neutralizing antibodies against a diverse panel of recombinant RSV strains. When vaccinated cotton rats were challenged with wild-type RSV A, DB1 reduced viral titers in the upper and lower airways by 3.8 log(10) total PFU and 2.7 log(10) PFU/g of tissue, respectively, compared to those in unvaccinated animals (P < 0.0001). DB1 was thus attenuated, highly immunogenic, and protective against RSV challenge in cotton rats. DB1 is the first RSV LAV to incorporate a low-fusion F protein as a strategy to attenuate viral replication and preserve immunogenicity. IMPORTANCE RSV is a leading cause of infant hospitalizations and deaths. The development of an effective vaccine for this high-risk population is therefore a public health priority. Although live-attenuated vaccines have been safely administered to RSV-naive infants, strategies to balance vaccine attenuation with immunogenicity have been elusive. In this study, we introduced a novel strategy to attenuate a recombinant RSV vaccine by incorporating a low-fusion, subgroup B F protein in the genetic background of codon-deoptimized nonstructural protein genes and a deleted small hydrophobic protein gene. The resultant vaccine candidate, DB1, was attenuated, highly immunogenic, and protective against RSV challenge in cotton rats. C1 [Rostad, Christina A.; Stobart, Christopher C.; Hotard, Anne L.; Meng, Jia; Moore, Martin L.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. [Rostad, Christina A.; Stobart, Christopher C.; Hotard, Anne L.; Meng, Jia; Moore, Martin L.] Childrens Healthcare Atlanta, Atlanta, GA 30342 USA. [Gilbert, Brian E.; Piedra, Pedro A.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Pickles, Ray J.] Univ North Carolina Chapel Hill, Marsico Lung Inst, Chapel Hill, NC USA. [Pickles, Ray J.] Univ North Carolina Chapel Hill, Dept Microbiol & Immunol, Chapel Hill, NC USA. [Blanco, Jorge C. G.] Sigmovir Biosyst Inc, Rockville, MD USA. [Moin, Syed M.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Piedra, Pedro A.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. RP Moore, ML (reprint author), Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA.; Moore, ML (reprint author), Childrens Healthcare Atlanta, Atlanta, GA 30342 USA. EM martin.moore@emory.edu FU HHS\ NIH\ National Institute of Allergy and Infectious Diseases (NIAID) [1R01AI087798, 1U19AI095227, T32AI074492, HHSN272201000004I]; HHS \ NIH \ National Institute of Child Health and Human Development (NICHD) [5K12HD072245] FX This work, including the efforts of Martin L. Moore, Christina Rostad, Christopher C. Stobart, Anne L. Hotard, and Jia Meng, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (1R01AI087798 and 1U19AI095227). This work, including the efforts of Christopher C. Stobart, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (T32AI074492). This work, including the efforts of Brian Edward Gilbert and Pedro A. Piedra, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (HHSN272201000004I). This work, including the efforts of Christina Rostad, was funded by HHS vertical bar NIH vertical bar National Institute of Child Health and Human Development (NICHD) (5K12HD072245). NR 35 TC 3 Z9 3 U1 5 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2016 VL 90 IS 16 BP 7508 EP 7518 DI 10.1128/JVI.00012-16 PG 11 WC Virology SC Virology GA DU6EJ UT WOS:000382306500038 PM 27279612 ER PT J AU Calascibetta, F Micci, L Carnathan, D Lawson, B Vanderford, TH Bosinger, SE Easley, K Chahroudi, A Mackel, J Keele, BF Long, S Lifson, J Paiardini, M Silvestri, G AF Calascibetta, Francesca Micci, Luca Carnathan, Diane Lawson, Benton Vanderford, Thomas H. Bosinger, Steven E. Easley, Kirk Chahroudi, Ann Mackel, Joseph Keele, Brandon F. Long, Samuel Lifson, Jeffrey Paiardini, Mirko Silvestri, Guido TI Antiretroviral Therapy in Simian Immunodeficiency Virus-Infected Sooty Mangabeys: Implications for AIDS Pathogenesis SO JOURNAL OF VIROLOGY LA English DT Article ID CD4(+) T-CELLS; CHRONIC HIV-INFECTION; SIV INFECTION; RHESUS MACAQUES; HOMEOSTATIC PROLIFERATION; LENTIVIRAL INFECTIONS; IMMUNE ACTIVATION; VIRAL RESERVOIR; SUPPRESSION; DEPLETION AB Simian immunodeficiency virus (SIV)-infected sooty mangabeys (SMs) do not develop AIDS despite high levels of viremia. Key factors involved in the benign course of SIV infection in SMs are the absence of chronic immune activation and low levels of infection of CD4(+) central memory (T-CM) and stem cell memory (T-SCM) T cells. To better understand the role of virus replication in determining the main features of SIV infection in SMs, we treated 12 SMs with a potent antiretroviral therapy (ART) regimen for 2 to 12 months. We observed that ART suppressed viremia to <60 copies/ml of plasma in 10 of 12 animals and induced a variable decrease in the level of cell-associated SIV DNA in peripheral blood (average changes of 0.9-, 1.1-, 1.5-, and 3.7-fold for CD4(+) transitional memory [TTM], TCM, effector memory [TEM], and TSCM cells, respectively). ART-treated SIV-infected SMs showed (i) increased percentages of circulating CD4(+) TCM cells, (ii) increased levels of CD4(+) T cells in the rectal mucosa, and (iii) significant declines in the frequencies of HLA-DR+ CD8(+) T cells in the blood and rectal mucosa. In addition, we observed that ART interruption resulted in rapid viral rebound in all SIV-infected SMs, indicating that the virus reservoir persists for at least a year under ART despite lower infection levels of CD4(+) TCM and TSCM cells than those seen in pathogenic SIV infections of macaques. Overall, these data indicate that ART induces specific immunological changes in SIV-infected SMs, thus suggesting that virus replication affects immune function even in the context of this clinically benign infection. IMPORTANCE Studies of natural, nonpathogenic simian immunodeficiency virus (SIV) infection of African monkeys have provided important insights into the mechanisms responsible for the progression to AIDS during pathogenic human immunodeficiency virus (HIV) infection of humans and SIV infection of Asian macaques. In this study, for the first time, we treated SIV-infected sooty mangabeys, a natural host for the infection, with a potent antiretroviral therapy (ART) regimen for periods ranging from 2 to 12 months and monitored in detail how suppression of virus replication affected the main virological and immunological features of this nonpathogenic infection. The observed findings provide novel information on both the pathogenesis of residual immunological disease under ART during pathogenic infection and the mechanisms involved in virus persistence during primate lentiviral infections. C1 [Calascibetta, Francesca; Micci, Luca; Carnathan, Diane; Lawson, Benton; Vanderford, Thomas H.; Bosinger, Steven E.; Chahroudi, Ann; Mackel, Joseph; Paiardini, Mirko; Silvestri, Guido] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Calascibetta, Francesca; Micci, Luca; Carnathan, Diane; Lawson, Benton; Vanderford, Thomas H.; Bosinger, Steven E.; Chahroudi, Ann; Mackel, Joseph; Paiardini, Mirko; Silvestri, Guido] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Calascibetta, Francesca] Univ Milan, L Sacco Dept Biomed & Clin Sci, Milan, Italy. [Easley, Kirk] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Chahroudi, Ann] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Keele, Brandon F.; Long, Samuel; Lifson, Jeffrey] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Silvestri, Guido] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. RP Silvestri, G (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA.; Silvestri, G (reprint author), Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA.; Silvestri, G (reprint author), Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. EM gsilves@emory.edu RI Easley, Kirk/K-6910-2015 OI Easley, Kirk/0000-0003-4419-2617 FU HHS \ NIH \ National Cancer Institute (NCI) [HHSN261200800001E]; HHS \ National Institutes of Health (NIH) [R37 AI66998]; R33 NIH grant [AI104278]; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [P51 OD011132]; Merck FX This work, including the efforts of Jeffrey Lifson, was funded by HHS vertical bar NIH vertical bar National Cancer Institute (NCI) (HHSN261200800001E). This work, including the efforts of Guido Silvestri, was funded by HHS vertical bar National Institutes of Health (NIH) (R37 AI66998).; This work was supported by an R33 NIH grant (AI104278) with principal investigators Guido Silvestri and Mirko Paiardini. Research reported in this publication was also supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number P51 OD011132 (to the YNPRC) and also in part by Merck. NR 45 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2016 VL 90 IS 16 BP 7541 EP 7551 DI 10.1128/JVI.00598-16 PG 11 WC Virology SC Virology GA DU6EJ UT WOS:000382306500041 PM 27279614 ER PT J AU Feigin, VL Roth, GA Naghavi, M Parmar, P Krishnamurthi, R Chugh, S Mensah, GA Norrving, B Shiue, I Ng, M Estep, K Cercy, K Murray, CJL Forouzanfar, MH AF Feigin, Valery L. Roth, Gregory A. Naghavi, Mohsen Parmar, Priya Krishnamurthi, Rita Chugh, Sumeet Mensah, George A. Norrving, Bo Shiue, Ivy Ng, Marie Estep, Kara Cercy, Kelly Murray, Christopher J. L. Forouzanfar, Mohammad H. CA Global Burden Dis Injuries Risk Factors Study Stroke Experts TI Global burden of stroke and risk factors in 188 countries, during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 SO LANCET NEUROLOGY LA English DT Article ID CAUSE-SPECIFIC MORTALITY; HEMORRHAGIC STROKE; CARDIOVASCULAR-DISEASE; PREVALENCE; DISABILITY; COHORT; METAANALYSIS; PREVENTION; CALIFORNIA; INJURIES AB Background The contribution of modifiable risk factors to the increasing global and regional burden of stroke is unclear, but knowledge about this contribution is crucial for informing stroke prevention strategies. We used data from the Global Burden of Disease Study 2013 (GBD 2013) to estimate the population-attributable fraction (PAF) of stroke-related disability-adjusted life-years (DALYs) associated with potentially modifiable environmental, occupational, behavioural, physiological, and metabolic risk factors in different age and sex groups worldwide and in high-income countries and low-income and middle-income countries, from 1990 to 2013. Methods We used data on stroke-related DALYs, risk factors, and PAF from the GBD 2013 Study to estimate the burden of stroke by age and sex (with corresponding 95% uncertainty intervals [UI]) in 188 countries, as measured with stroke related DALYs in 1990 and 2013. We evaluated attributable DALYs for 17 risk factors (air pollution and environmental, dietary, physical activity, tobacco smoke, and physiological) and six clusters of risk factors by use of three inputs: risk factor exposure, relative risks, and the theoretical minimum risk exposure level. For most risk factors, we synthesised data for exposure with a Bayesian meta-regression method (DisMod-MR) or spatial-temporal Gaussian process regression. We based relative risks on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks, such as high body-mass index (BMI), through other risks, such as high systolic blood pressure (SBP) and high total cholesterol. Findings Globally, 90.5% (95% UI 88.5-92.2) of the stroke burden (as measured in DALYs) was attributable to the modifiable risk factors analysed, including 74.2% (95% UI 70.7-76.7) due to behavioural factors (smoking, poor diet, and low physical activity). Clusters of metabolic factors (high SBP, high BMI, high fasting plasma glucose, high total cholesterol, and low glomerular filtration rate; 72.4%, 95% UI 70.2-73.5) and environmental factors (air pollution and lead exposure; 33.4%, 95% UI 32.4-34.3) were the second and third largest contributors to DALYs. Globally, 29.2% (95% UI 28.2-29.6) of the burden of stroke was attributed to air pollution. Although globally there were no significant differences between sexes in the proportion of stroke burden due to behavioural, environmental, and metabolic risk clusters, in the low-income and middle-income countries, the PAF of behavioural risk clusters in males was greater than in females. The PAF of all risk factors increased from 1990 to 2013 (except for second-hand smoking and household air pollution from solid fuels) and varied significantly between countries. Interpretation Our results suggest that more than 90% of the stroke burden is attributable to modifiable risk factors, and achieving control of behavioural and metabolic risk factors could avert more than three-quarters of the global stroke burden. Air pollution has emerged as a significant contributor to global stroke burden, especially in low-income and middle-income countries, and therefore reducing exposure to air pollution should be one of the main priorities to reduce stroke burden in these countries. C1 [Feigin, Valery L.; Parmar, Priya; Krishnamurthi, Rita] Auckland Univ Technol, Fac Hlth & Environm Studies, Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Roth, Gregory A.; Naghavi, Mohsen; Chugh, Sumeet; Ng, Marie; Estep, Kara; Cercy, Kelly; Murray, Christopher J. L.; Forouzanfar, Mohammad H.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Mensah, George A.] NHLBI, CTRIS, NIH, Bldg 10, Bethesda, MD 20892 USA. [Norrving, Bo] Lund Univ, Dept Clin Sci, Neurol, Lund, Sweden. [Shiue, Ivy] Northumbria Univ, Fac Hlth & Life Sci, Newcastle Upon Tyne, Tyne & Wear, England. [Shiue, Ivy] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. RP Feigin, VL (reprint author), Auckland Univ Technol, Fac Hlth & Environm Studies, Sch Publ Hlth & Psychosocial Studies, Natl Inst Stroke & Appl Neurosci, North Shore Campus, Auckland 0627, New Zealand. EM valery.feigin@aut.ac.nz FU Bill & Melinda Gates Foundation; American Heart Association Postdoctoral Fellowship; US National Heart, Lung, and Blood Institute award [K08 HL089675-01A1]; Columbia University Irving Scholarship; Health Research Council of New Zealand; Brain Research New Zealand Centre of Research Excellence; "Ageing Well" Programme of the National Science Challenge, Ministry of Business, Innovation and Employment of New Zealand FX This research was supported by the Bill & Melinda Gates Foundation, an American Heart Association Postdoctoral Fellowship to GAR; US National Heart, Lung, and Blood Institute award K08 HL089675-01A1 and a Columbia University Irving Scholarship; and Health Research Council of New Zealand to VLF, RK, and PP. VLF was also partly funded by the Brain Research New Zealand Centre of Research Excellence and the "Ageing Well" Programme of the National Science Challenge, Ministry of Business, Innovation and Employment of New Zealand. The views expressed in this Article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, National Institutes of Health, or the US Department of Health and Human Services. NR 44 TC 27 Z9 27 U1 19 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD AUG PY 2016 VL 15 IS 9 BP 913 EP 924 DI 10.1016/S1474-4422(16)30073-4 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA DT1YY UT WOS:000381279200011 PM 27291521 ER PT J AU Gratzinger, D Jaffe, ES AF Gratzinger, Dita Jaffe, Elaine S. TI Mucocutaneous ulcer: a mimic of EBV plus diffuse large B cell lymphoma in the immunodeficiency setting SO LEUKEMIA & LYMPHOMA LA English DT Letter ID LYMPHOPROLIFERATIVE DISORDERS C1 [Gratzinger, Dita] Stanford Univ, Dept Pathol, Sch Med, 300 Pasteur Dr L235, Stanford, CA 94305 USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Gratzinger, D (reprint author), Stanford Univ, Dept Pathol, Sch Med, 300 Pasteur Dr L235, Stanford, CA 94305 USA. EM ditag@stanford.edu OI Gratzinger, Dita/0000-0002-9182-8123 NR 7 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD AUG PY 2016 VL 57 IS 8 BP 1982 EP 1983 DI 10.3109/10428194.2016.1166492 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA DT2DI UT WOS:000381290600037 PM 27071493 ER PT J AU Wang, F Dai, JC Li, MJ Chan, WC Kwok, CCH Leung, SL Wu, C Li, WT Yu, WC Tsang, KH Law, SH Lee, PMY Wong, CKM Shen, HB Wong, SYS Yang, XHR Tse, LA AF Wang, Feng Dai, Juncheng Li, Mengjie Chan, Wing-cheong Kwok, Carol Chi-hei Leung, Siu-lan Wu, Cherry Li, Wentao Yu, Wai-cho Tsang, Koon-ho Law, Sze-hong Lee, Priscilla Ming-yi Wong, Carmen Ka-man Shen, Hongbing Wong, Samuel Yeung-shan Yang, Xiaohong R. Tse, Lap Ah TI Risk assessment model for invasive breast cancer in Hong Kong women SO MEDICINE LA English DT Article DE breast cancer; estrogen receptor; LASSO model; light at night; menopause; risk assessment ID PROJECTING INDIVIDUALIZED PROBABILITIES; SHIFT-WORK; CIRCADIAN DISRUPTION; ALCOHOL-CONSUMPTION; SLEEP DURATION; CHINESE WOMEN; CARCINOGENICITY; METAANALYSIS; VALIDATION; PREVENTION AB No risk assessment tool is available for identifying high risk population of breast cancer (BCa) in Hong Kong. A case-control study including 918 BCa cases and 923 controls was used to develop the risk assessment model among Hong Kong Chinese women. Each participant received an in-depth interview to obtain their lifestyle and environmental risk factors. Least absolute shrinkage and selection operator (LASSO) selection model was used to select the optimal risk factors (LASSO-model). A risk score system was constructed to evaluate the cumulative effects of selected factors. Bootstrap simulation was used to test the internal validation of the model. Model performance was evaluated by receiver-operator characteristic curves and the area under the curve (AUC). Age, number of parity, number of BCa cases in 1st-degree relatives, exposure to light at night, and sleep quality were the common risk factors for all women. Alcohol drinking was included for premenopausal women; body mass index, age at menarche, age at 1st give birth, breast feeding, using of oral contraceptive, hormone replacement treatment, and history of benign breast diseases were included for postmenopausal women. The AUCs were 0.640 (95% CI, 0.598-0.681) and 0.655 (95% CI, 0.621-0.653) for pre- and postmenopausal women, respectively. Further subgroup evaluation revealed that the model performance was better for women aged 50 to 70 years or ER-positive. This BCa risk assessment tool in Hong Kong Chinese women based on LASSO selection is promising, which shows a slightly higher discriminative accuracy than those developed in other populations. C1 [Wang, Feng; Dai, Juncheng; Li, Mengjie; Li, Wentao; Lee, Priscilla Ming-yi; Wong, Carmen Ka-man; Wong, Samuel Yeung-shan; Tse, Lap Ah] Chinese Univ Hong Kong, JC Sch Publ Hlth & Primary Care, Sha Tin, Hong Kong, Peoples R China. [Dai, Juncheng; Shen, Hongbing] Nanjing Med Univ, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Collaborat Innovat Ctr Canc Personalized Med, Dept Epidemiol & Biostat,Sch Publ Hlth, Nanjing, Jiangsu, Peoples R China. [Chan, Wing-cheong] North Dist Hosp, Dept Surg, Kowloon, Hong Kong, Peoples R China. [Kwok, Carol Chi-hei] Princess Margaret Hosp, Dept Oncol, Kowloon, Hong Kong, Peoples R China. [Leung, Siu-lan] Pamela Youde Nethersole Eastern Hosp, Dept Surg, Kowloon, Hong Kong, Peoples R China. [Wu, Cherry] North Dist Hosp, Dept Pathol, Kowloon, Hong Kong, Peoples R China. [Yu, Wai-cho] Princess Margaret Hosp, Dept Med & Geriatr, Kowloon, Hong Kong, Peoples R China. [Tsang, Koon-ho] Yan Chai Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Law, Sze-hong] Yan Chai Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Yang, Xiaohong R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Tse, LA (reprint author), Chinese Univ Hong Kong, JC Sch Publ Hlth & Primary Care, Sha Tin, Hong Kong, Peoples R China. EM shelly@cuhk.edu.hk FU Research Grants Council of Hong Kong [474811] FX This work was supported by Research Grants Council of Hong Kong (Grant number 474811). NR 42 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7974 EI 1536-5964 J9 MEDICINE JI Medicine (Baltimore) PD AUG PY 2016 VL 95 IS 32 AR e4515 DI 10.1097/MD.0000000000004515 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DU5IX UT WOS:000382246500036 PM 27512870 ER PT J AU Clemons, PA Shamji, A Hon, C Wagner, BK Schreiber, SL Krasnitz, A Sordella, R Sander, C Lowe, SW Powers, S Smith, K Aburi, M Lavarone, A Lasorella, A Silva, J Stockwell, B Califano, A Boehm, JS Vazquez, F Weir, BA Golub, TR Hahn, WC Khuri, FR Moreno, CS Du, YH Cooper, L Ivanov, AA Johns, MA Fu, HA Nikolova, O Mendez, E Gadi, VK Margolin, AA Grandori, C Kemp, CJ Warren, EH Riddell, SR McIntosh, MW Gevaert, O Ji, HP Kuo, CJ Dhruv, H Finlay, D Kiefer, J Kim, S Vuori, K Berens, ME Weissman, J Bivona, T Bandyopadhyay, S Hangauer, M Boettcher, M McManus, M McCormick, F Aksoy, O Simonds, EF Zheng, TN Chen, J An, ZY Balmain, A Weiss, WA Chen, K Liang, H Scott, KL Mills, GB Posner, BA MacMillan, J Minna, J White, MA Roth, MG Jagu, S Mazerik, JN Gerhard, DS AF Clemons, Paul A. Shamji, Alykhan Hon, Cindy Wagner, Bridget K. Schreiber, Stuart L. Krasnitz, Alex Sordella, Raffaella Sander, Chris Lowe, Scott W. Powers, Scott Smith, Kenneth Aburi, Mahalaxmi Lavarone, Antonio Lasorella, Anna Silva, Jose Stockwell, Brent Califano, Andrea Boehm, Jesse S. Vazquez, Francisca Weir, Barbara A. Golub, Todd R. Hahn, William C. Khuri, Fadlo R. Moreno, Carlos S. Du, Yuhong Cooper, Lee Ivanov, Andrey A. Johns, Margaret A. Fu, Haian Nikolova, Olga Mendez, Eduardo Gadi, Vijayakrishna K. Margolin, Adam A. Grandori, Carla Kemp, Christopher J. Warren, Edus H. Riddell, Stanley R. McIntosh, Martin W. Gevaert, Olivier Ji, Hanlee P. Kuo, Calvin J. Dhruv, Harshil Finlay, Darren Kiefer, Jeffrey Kim, Seungchan Vuori, Kristiina Berens, Michael E. Weissman, Jonathan Bivona, Trever Bandyopadhyay, Sourav Hangauer, Matt Boettcher, Michael McManus, Michael McCormick, Frank Aksoy, Ozlem Simonds, Erin F. Zheng, Tina Chen, Justin An, Zhenyi Balmain, Allan Weiss, William A. Chen, Ken Liang, Han Scott, Kenneth L. Mills, Gordon B. Posner, Bruce A. MacMillan, John Minna, John White, Michael A. Roth, Michael G. Jagu, Subhashini Mazerik, Jessica N. Gerhard, Daniela S. CA Canc Target Discovery Dev Network TI Transforming Big Data into Cancer-Relevant Insight: An Initial, Multi-Tier Approach to Assess Reproducibility and Relevance The Cancer Target Discovery and Development Network SO MOLECULAR CANCER RESEARCH LA English DT Article ID DRUG-SENSITIVITY; INHIBITION; LANDSCAPE; TBK1 AB The Cancer Target Discovery and Development (CTD2) Network was established to accelerate the transformation of "Big Data" into novel pharmacologic targets, lead compounds, and biomarkers for rapid translation into improved patient outcomes. It rapidly became clear in this collaborative network that a key central issue was to define what constitutes sufficient computational or experimental evidence to support a biologically or clinically relevant finding. This article represents a first attempt to delineate the challenges of supporting and confirming discoveries arising from the systematic analysis of large-scale data resources in a collaborative work environment and to provide a framework that would begin a community discussion to resolve these challenges. The Network implemented a multi-tier framework designed to substantiate the biological and biomedical relevance as well as the reproducibility of data and insights resulting from its collaborative activities. The same approach can be used by the broad scientific community to drive development of novel therapeutic and biomarker strategies for cancer. (C) 2016 AACR. C1 [Jagu, Subhashini; Mazerik, Jessica N.; Gerhard, Daniela S.] NCI, 31 Ctr Dr, Bethesda, MD 20892 USA. [Clemons, Paul A.; Shamji, Alykhan; Hon, Cindy; Wagner, Bridget K.; Schreiber, Stuart L.] Broad Inst, Cambridge, MA USA. [Krasnitz, Alex; Sordella, Raffaella; Sander, Chris; Lowe, Scott W.; Powers, Scott] Cold Springs Harbor Lab, Cold Springs Harbor, NY USA. [Smith, Kenneth; Aburi, Mahalaxmi; Lavarone, Antonio; Lasorella, Anna; Silva, Jose; Stockwell, Brent; Califano, Andrea] Columbia Univ, New York, NY USA. [Boehm, Jesse S.; Vazquez, Francisca; Weir, Barbara A.; Golub, Todd R.; Hahn, William C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Khuri, Fadlo R.; Moreno, Carlos S.; Du, Yuhong; Cooper, Lee; Ivanov, Andrey A.; Johns, Margaret A.; Fu, Haian] Emory Univ, Atlanta, GA 30322 USA. [Nikolova, Olga; Mendez, Eduardo; Gadi, Vijayakrishna K.; Margolin, Adam A.; Grandori, Carla; Kemp, Christopher J.; Warren, Edus H.; Riddell, Stanley R.; McIntosh, Martin W.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Nikolova, Olga; Mendez, Eduardo; Gadi, Vijayakrishna K.; Margolin, Adam A.; Grandori, Carla; Kemp, Christopher J.] Cure First, Seattle, WA USA. [Nikolova, Olga; Mendez, Eduardo; Gadi, Vijayakrishna K.; Margolin, Adam A.; Grandori, Carla; Kemp, Christopher J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Nikolova, Olga; Mendez, Eduardo; Gadi, Vijayakrishna K.; Margolin, Adam A.; Grandori, Carla; Kemp, Christopher J.] Univ Washington, Seattle, WA 98195 USA. [Gevaert, Olivier; Ji, Hanlee P.; Kuo, Calvin J.] Stanford Univ, Stanford, CA 94305 USA. [Dhruv, Harshil; Finlay, Darren; Kiefer, Jeffrey; Kim, Seungchan; Vuori, Kristiina; Berens, Michael E.] Translat Genom Res Inst, Phoenix, AZ USA. [Weissman, Jonathan; Bivona, Trever; Bandyopadhyay, Sourav; Hangauer, Matt; Boettcher, Michael; McManus, Michael; McCormick, Frank; Aksoy, Ozlem; Simonds, Erin F.; Zheng, Tina; Chen, Justin; An, Zhenyi; Balmain, Allan; Weiss, William A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Chen, Ken; Liang, Han; Scott, Kenneth L.; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Posner, Bruce A.; MacMillan, John; Minna, John; White, Michael A.; Roth, Michael G.] Univ Texas Southwestern, Dallas, TX USA. RP Gerhard, DS (reprint author), NCI, 31 Ctr Dr, Bethesda, MD 20892 USA. EM gerhardd@mail.nih.gov RI Moreno, Carlos/B-3863-2009 OI Moreno, Carlos/0000-0002-5582-0028 FU NIH [CA176152, CA168409, CA168426, CA176058, CA168449, CA176303, CA176270, CA176299, CA168397, CA168370, CA176287, CA168394, CA176284] FX S.L. Schreiber was supported by NIH CA176152, S. Powers was supported by NIH CA168409, A. Califano was supported by NIH CA168426, W.C. Hahn was supported by NIH CA176058, H. Fu was supported by NIH CA168449, C.J. Kemp was supported by NIH CA176303, M. Mcintosh was supported by NIH CA176270, C.J. Kuo was supported by NIH CA176299, M. E. Berens was supported by NIH CA168397, M.T. Mcmanus was supported by NIH CA168370, W.A. Weiss was supported by NIH CA176287, G.B. Mills was supported by NIH CA168394, and M.G. Roth was supported by NIH CA176284. NR 20 TC 0 Z9 0 U1 12 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD AUG PY 2016 VL 14 IS 8 BP 675 EP 682 DI 10.1158/1541-7786.MCR-16-0090 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DU5WJ UT WOS:000382283900001 ER PT J AU Shah, N Guo, YJ Wendelsdorf, KV Lu, Y Sparks, R Tsang, JS AF Shah, Naisha Guo, Yongjian Wendelsdorf, Katherine V. Lu, Yong Sparks, Rachel Tsang, John S. TI A crowdsourcing approach for reusing and meta analyzing gene expression data SO NATURE BIOTECHNOLOGY LA English DT Letter ID ENRICHMENT ANALYSIS; SIGNATURES; PROFILES; DISEASE; UPDATE C1 [Shah, Naisha; Wendelsdorf, Katherine V.; Lu, Yong; Sparks, Rachel; Tsang, John S.] NIAID, Syst Genom & Bioinformat Unit, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Guo, Yongjian] NIAID, Off Chief Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Tsang, JS (reprint author), NIAID, Syst Genom & Bioinformat Unit, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM john.tsang@nih.gov NR 22 TC 3 Z9 3 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2016 VL 34 IS 8 BP 803 EP 806 DI 10.1038/nbt.3603 PG 4 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DT2VJ UT WOS:000381339600010 PM 27323300 ER PT J AU Wang, MX Carver, JJ Phelan, VV Sanchez, LM Garg, N Peng, Y Nguyen, DD Watrous, J Kapono, CA Luzzatto-Knaan, T Porto, C Bouslimani, A Melnik, AV Meehan, MJ Liu, WT Criisemann, M Boudreau, PD Esquenazi, E Sandoval-Calderon, M Kersten, RD Pace, LA Quinn, RA Duncan, KR Hsu, CC Floros, DJ Gavilan, RG Kleigrewe, K Northen, T Dutton, RJ Parrot, D Carlson, EE Aigle, B Michelsen, CF Jelsbak, L Sohlenkamp, C Pevzner, P Edlund, A McLean, J Piel, J Murphy, BT Gerwick, L Liaw, CC Yang, YL Humpf, HU Maansson, M Keyzers, RA Sims, AC Johnson, AR Sidebottom, AM Sedio, BE Klitgaard, A Larson, CB Boya, CA Torres-Mendoza, D Gonzalez, DJ Silva, DB Marques, LM Demarque, DP Pociute, E O'Neill, EC Briand, E Helfrich, EJN Granatosky, EA Glukhov, E Ryffel, F Houson, H Mohimani, H Kharbush, JJ Zeng, Y Vorholt, JA Kurita, KL Charusanti, P McPhail, KL Nielsen, KF Vuong, L Elfeki, M Traxler, MF Engene, N Koyama, N Vining, OB Baric, R Silva, RR Mascuch, SJ Tomasi, S Jenkins, S Macherla, V Hoffman, T Agarwal, V Williams, PG Dai, JQ Neupane, R Gurr, J Rodriguez, AMC Lamsa, A Zhang, C Dorrestein, K Duggan, BM Almaliti, J Allard, PM Phapale, P Nothias, LF Alexandrovr, T Litaudon, M Wolfender, JL Kyle, JE Metz, TO Peryea, T Nguyen, DT VanLeer, D Shinn, P Jadhav, A Muller, R Waters, KM Shi, WY Liu, XT Zhang, LX Knight, R Jensen, PR Palsson, BO Pogliano, K Linington, RG Gutierrez, M Lopes, NP Gerwick, WH Moore, BS Dorrestein, PC Bandeira, N AF Wang, Mingxun Carver, Jeremy J. Phelan, Vanessa V. Sanchez, Laura M. Garg, Neha Peng, Yao Don Duy Nguyen Watrous, Jeramie Kapono, Clifford A. Luzzatto-Knaan, Tal Porto, Carla Bouslimani, Amina Melnik, Alexey V. Meehan, Michael J. Liu, Wei -Ting Criisemann, Max Boudreau, Paul D. Esquenazi, Eduardo Sandoval-Calderon, Mario Kersten, Roland D. Pace, Laura A. Quinn, Robert A. Duncan, Katherine R. Hsu, Cheng-Chih Floros, Dimitrios J. Gavilan, Ronnie G. Kleigrewe, Karin Northen, Trent Dutton, Rachel J. Parrot, Delphine Carlson, Erin E. Aigle, Bertrand Michelsen, Charlotte F. Jelsbak, Lars Sohlenkamp, Christian Pevzner, Pavel Edlund, Anna McLean, Jeffrey Piel, Jorn Murphy, Brian T. Gerwick, Lena Liaw, Chih-Chuang Yang, Yu-Liang Humpf, Hans-Ulrich Maansson, Maria Keyzers, Robert A. Sims, Amy C. Johnson, Andrew R. Sidebottom, Ashley M. Sedio, Brian E. Klitgaard, Andreas Larson, Charles B. Boya P, Cristopher A. Torres-Mendoza, Daniel Gonzalez, David J. Silva, Denise B. Marques, Lucas M. Demarque, Daniel P. Pociute, Egle O'Neill, Ellis C. Briand, Enora Helfrich, Eric J. N. Granatosky, Eve A. Glukhov, Evgenia Ryffel, Florian Houson, Hailey Mohimani, Hosein Kharbush, Jenan J. Zeng, Yi Vorholt, Julia A. Kurita, Kenji L. Charusanti, Pep McPhail, Kerry L. Nielsen, Kristian Fog Vuong, Lisa Elfeki, Maryam Traxler, Matthew F. Engene, Niclas Koyama, Nobuhiro Vining, Oliver B. Baric, Ralph Silva, Ricardo R. Mascuch, Samantha J. Tomasi, Sophie Jenkins, Stefan Macherla, Venkat Hoffman, Thomas Agarwal, Vinayak Williams, Philip G. Dai, Jingqui Neupane, Ram Gurr, Joshua Rodriguez, Andres M. C. Lamsa, Anne Zhang, Chen Dorrestein, Kathleen Duggan, Brendan M. Almaliti, Jehad Allard, Pierre-Marie Phapale, Prasad Nothias, Louis-Felix Alexandrovr, Theodore Litaudon, Marc Wolfender, Jean-Luc Kyle, Jennifer E. Metz, Thomas O. Peryea, Tyler Dac-Trung Nguyen VanLeer, Danielle Shinn, Paul Jadhav, Ajit Muller, Rolf Waters, Katrina M. Shi, Wenyuan Liu, Xueting Zhang, Lixin Knight, Rob Jensen, Paul R. Palsson, Bernhard O. Pogliano, Kit Linington, Roger G. Gutierrez, Marcelino Lopes, Norberto P. Gerwick, William H. Moore, Bradley S. Dorrestein, Pieter C. Bandeira, Nuno TI Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking SO NATURE BIOTECHNOLOGY LA English DT Article ID SPECTRAL DATABASE; GENE-CLUSTER; GENOME; DEREPLICATION; METABOLOMICS; IDENTIFICATION; TECHNOLOGIES; REPOSITORY; DISCOVERY; RESOURCE AB The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry (MS) techniques are well-suited to high-throughput characterization of NP, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social Molecular Networking (GNPS; http://gnps.ucsd.edu), an open-access knowledge base for community-wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS, crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of 'living data' through continuous reanalysis of deposited data. C1 [Wang, Mingxun; Carver, Jeremy J.; Pevzner, Pavel] Univ Calif San Diego, Comp Sci & Engn, La Jolla, CA 92093 USA. [Wang, Mingxun; Carver, Jeremy J.; Pevzner, Pavel; Mohimani, Hosein; Bandeira, Nuno] Univ Calif San Diego, Ctr Computat Mass Spectrometry, La Jolla, CA USA. [Phelan, Vanessa V.; Sanchez, Laura M.; Garg, Neha; Watrous, Jeramie; Luzzatto-Knaan, Tal; Porto, Carla; Bouslimani, Amina; Melnik, Alexey V.; Meehan, Michael J.; Pace, Laura A.; Gonzalez, David J.; Koyama, Nobuhiro; Dorrestein, Kathleen; Duggan, Brendan M.; Almaliti, Jehad; Gerwick, William H.; Moore, Bradley S.; Dorrestein, Pieter C.; Bandeira, Nuno] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Collaborat Mass Spectrometry Innovat Ctr, La Jolla, CA USA. [Peng, Yao; Don Duy Nguyen; Kapono, Clifford A.; Hsu, Cheng-Chih; Floros, Dimitrios J.; Zeng, Yi] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA USA. [Liu, Wei -Ting] Stanford Univ, Dept Microbiol & Immunol, Palo Alto, CA 94304 USA. [Criisemann, Max; Boudreau, Paul D.; Duncan, Katherine R.; Kleigrewe, Karin; Gerwick, Lena; Larson, Charles B.; O'Neill, Ellis C.; Briand, Enora; Glukhov, Evgenia; Kharbush, Jenan J.; Mascuch, Samantha J.; Jensen, Paul R.; Gerwick, William H.; Moore, Bradley S.; Dorrestein, Pieter C.] Univ Calif San Diego, Scripps Inst Oceanog, Ctr Marine Biotechnol & Biomed, La Jolla, CA USA. [Esquenazi, Eduardo; Pociute, Egle; Houson, Hailey; Vuong, Lisa; Macherla, Venkat] Sirenas Marine Discovery, San Diego, CA USA. [Sandoval-Calderon, Mario; Sohlenkamp, Christian] Univ Nacl Autonoma Mexico, Ctr Ciencias Genom, Cuernavaca, Morelos, Mexico. [Kersten, Roland D.] Salk Inst Biol Studies, La Jolla, CA USA. [Quinn, Robert A.] San Diego State Univ, Dept Biol, San Diego, CA 92182 USA. [Duncan, Katherine R.] Scottish Marine Inst, Scottish Assoc Marine Sci, Oban, Argyll, Scotland. [Gavilan, Ronnie G.; Sedio, Brian E.; Boya P, Cristopher A.; Torres-Mendoza, Daniel; Gutierrez, Marcelino] INDICASAT, Ctr Drug Discovery & Biodivers, City Of Knowledge, Panama. [Northen, Trent; Jenkins, Stefan] Lawrence Berkeley Natl Lab, Genome Dynam, Berkeley, CA USA. [Dutton, Rachel J.] Harvard, FAS Ctr Syst Biol, Cambridge, MA USA. [Parrot, Delphine; Tomasi, Sophie] Univ Rennes 1, Prod Nat Synth Chim Med, Rennes, France. [Carlson, Erin E.] Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA. [Aigle, Bertrand] Univ Lorraine, Dynam Genomes & Adaptat Microbienne, Vandoeuvre Les Nancy, France. [Michelsen, Charlotte F.; Jelsbak, Lars; Maansson, Maria; Klitgaard, Andreas; Nielsen, Kristian Fog] Tech Univ Denmark, Dept Syst Biol, Lyngby, Denmark. [Edlund, Anna] J Craig Venter Inst, Microbial & Environm Genom, La Jolla, CA USA. [Edlund, Anna; McLean, Jeffrey; Shi, Wenyuan] UC Los Angeles, Sch Dent, Los Angeles, CA USA. [McLean, Jeffrey] Univ Washington, Dept Periodont, Seattle, WA 98195 USA. [Piel, Jorn; Helfrich, Eric J. N.; Ryffel, Florian; Vorholt, Julia A.] Swiss Fed Inst Technol, Inst Microbiol, Zurich, Switzerland. [Murphy, Brian T.; Elfeki, Maryam] Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL USA. [Liaw, Chih-Chuang] Natl Sun Yat Sen Univ, Dept Marine Biotechnol & Resources, Kaohsiung, Taiwan. [Yang, Yu-Liang] Acad Sinica, Agr Biotechnol Res Ctr, Taipei, Taiwan. [Humpf, Hans-Ulrich] Univ Munster, Inst Food Chem, Munster, Germany. [Keyzers, Robert A.] Victoria Univ Wellington, Sch Chem & Phys Sci, Wellington, New Zealand. [Keyzers, Robert A.] Victoria Univ Wellington, Ctr Biodiscovery, Wellington, New Zealand. [Sims, Amy C.; Baric, Ralph] Univ North Carolina Chapel Hill, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Johnson, Andrew R.; Sidebottom, Ashley M.] Indiana Univ, Dept Chem, Bloomington, IN USA. [Sedio, Brian E.] Smithsonian Trop Res Inst, Ancon, Panama. [Larson, Charles B.; Gonzalez, David J.; Dorrestein, Pieter C.; Bandeira, Nuno] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA USA. [Silva, Denise B.; Marques, Lucas M.; Demarque, Daniel P.; Silva, Ricardo R.; Rodriguez, Andres M. C.; Lopes, Norberto P.] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Sao Paulo, Brazil. [Silva, Denise B.] Univ Fed Mato Grosso do Sul, Ctr Ciencias Biol & Saude, Campo Grande, Brazil. [Briand, Enora] Univ Rennes 1, CNRS, UMR 6553, ECOBIO, Rennes, France. [Granatosky, Eve A.] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. [Kurita, Kenji L.; Linington, Roger G.] UC Santa Cruz, PBSci Chem & Biochem Dept, Santa Cruz, CA USA. [Charusanti, Pep; Palsson, Bernhard O.] Univ Calif San Diego, Dept Bioengn, La Jolla, CA USA. [McPhail, Kerry L.; Vining, Oliver B.] Oregon State Univ, Coll Pharm, Dept Pharmaceut Sci, Corvallis, OR 97331 USA. [Traxler, Matthew F.] Univ Calif Berkeley, Dept Plant & Microbial Biol, Berkeley, CA USA. [Engene, Niclas] Florida Int Univ, Dept Biol Sci, Miami, FL 33199 USA. [Hoffman, Thomas; Muller, Rolf] Helmholtz Inst Pharmaceut Res Saarland, Dept Pharmaceut Biotechnol, Saarbrucken, Germany. [Agarwal, Vinayak; Moore, Bradley S.] Univ Calif San Diego, Scripps Inst Oceanog, Ctr Oceans & Human Hlth, La Jolla, CA USA. [Williams, Philip G.; Dai, Jingqui; Neupane, Ram; Gurr, Joshua] Univ Hawaii Manoa, Dept Chem, Honolulu, HI 96822 USA. [Lamsa, Anne; Pogliano, Kit] Univ Calif San Diego, Div Biol Sci, La Jolla, CA USA. [Zhang, Chen] Univ Calif San Diego, Dept Nanoengn, La Jolla, CA USA. [Allard, Pierre-Marie; Wolfender, Jean-Luc] Univ Geneva, Sch Pharmaceut Sci, Geneva, Switzerland. [Phapale, Prasad; Alexandrovr, Theodore] European Mol Biol Lab, Struct & Computat Biol, Heidelberg, Germany. [Nothias, Louis-Felix; Litaudon, Marc] Univ Paris Saclay, Labex CEBA, ICSN, CNRS,UPR 2301, Gif Sur Yvette, France. [Kyle, Jennifer E.; Metz, Thomas O.; Waters, Katrina M.] Pacific NW Natl Lab, Biol Sci, Richland, WA 99352 USA. [Peryea, Tyler; Dac-Trung Nguyen; VanLeer, Danielle; Shinn, Paul; Jadhav, Ajit] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Liu, Xueting] Chinese Acad Sci, Inst Microbiol, Beijing, Peoples R China. [Knight, Rob] Univ Calif San Diego, Dept Pediat, La Jolla, CA USA. RP Bandeira, N (reprint author), Univ Calif San Diego, Ctr Computat Mass Spectrometry, La Jolla, CA USA.; Dorrestein, PC; Bandeira, N (reprint author), Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Collaborat Mass Spectrometry Innovat Ctr, La Jolla, CA USA.; Dorrestein, PC (reprint author), Univ Calif San Diego, Scripps Inst Oceanog, Ctr Marine Biotechnol & Biomed, La Jolla, CA USA.; Dorrestein, PC; Bandeira, N (reprint author), Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA USA. EM pdorrestein@ucsd.edu; bandeira@ucsd.edu RI Nielsen, Kristian/C-7233-2011; Vorholt, Julia/K-3514-2016; Porto, Carla/D-6888-2013; Demarque, Daniel/K-7325-2014; Briand, Enora/P-6074-2016; almaliti, jehad/R-7507-2016; Muller, Rolf/B-1559-2008; O'Neill, Ellis/N-3805-2014; OI Nielsen, Kristian/0000-0002-5848-0911; Porto, Carla/0000-0001-8331-2760; Demarque, Daniel/0000-0002-3576-5148; Briand, Enora/0000-0001-8996-0072; almaliti, jehad/0000-0002-3562-0846; Muller, Rolf/0000-0002-1042-5665; O'Neill, Ellis/0000-0002-5941-2806; Torres-Mendoza, Daniel/0000-0002-3540-4238; Duncan, Katherine R./0000-0002-3670-4849; Klitgaard, Andreas/0000-0002-2533-570X; Phelan, Vanessa/0000-0001-7156-9294; Northen, Trent/0000-0001-8404-3259; PHAPALE, PRASAD/0000-0002-9487-597X; Keyzers, Rob/0000-0002-7658-7421 FU US National Institutes of Health (NIH) [5P41GM103484-07, GM094802, AI095125, GM097509, S10RR029121, UL1RR031980, GM085770, U01TW0007401, U01AI12316-01]; National Institute of Allergy and Infectious Diseases (NIAID), NIH; Department of Health and Human Services [HHSN272200800060C]; NIH [K01 GM103809, T32 GM075762, K99DE024543, 1F32GM089044, 5R21AI085540, U01TW006634-06]; NIH IRACDA [K12 GM068524]; United States-Israel Binational Agricultural Research and Development Fund Vaadia-BARD [FI-494-13]; Science without Borders Program from CNPq; Sao Paulo Research Foundation (FAPESP) [2014/01651-8, 2012/18031-7]; German Academic Exchange Service (DAAD); Deutsche Forschungsgemeinschaft (D.F.G.); Marie Curie IOF Fellowship within the 7th European Community Framework Program (FP7-PEOPLE-IOF) [301244-CYANOMIC]; Ministry of Science and Technology of Taiwan [MOST103-2628-B-110-001-MY3]; Novo Nordisk Foundation; National Program on Key Basic Research Project [2013BC734000]; National Natural Science Foundation of China [81102369, 31125002]; INSA grant, Rennes; FAPESP [2012/18031-7, 2014/01884-2, 2014/18052-0, 2013/16496-5, 2014/50265-3]; CAPES/PNPD; CNPq-INCT_if; Notre Dame Chemistry-Biochemistry-Biology Interface (CBBI) program; National Institutes of Health [1R01DE023810-01, 1R01GM095373]; Villum Foundation [VKR023113]; Augustinus Foundation [13-4656]; Aase & Ejnar Danielsens Foundation [10-001120]; UC MEXUS-CONACYT Collaborative Grant [CN-12-552]; NSF [DEB 1010816]; Smithsonian Institution Grand Challenges Award; DFG (Forschergruppe 854); SNF [IZLSZ3_149025]; Danish Council for Independent Research, Technology, and Production Sciences [09-064967]; Agilent Thought Leader Program; NIH/NIAID [U19-AI106772]; Department of Defense [W81XWH-13-1-0171]; Oregon Sea Grant [NA10OAR4170059/R/BT-48]; NSF; Research Corporation for Science Advancement (Cottrell Scholar Award); Indiana University Quantitative Chemical Biology trainee fellowship; Danish Research Council for Technology and Production Science; Sapere Aude [116262]; FNS [200020_146200]; [CNPq-PQ 480 306385/2011-2] FX This work was partially supported by US National Institutes of Health (NIH) grants 5P41GM103484-07, GM094802, AI095125, GM097509, S10RR029121, UL1RR031980, GM085770, U01TW0007401, and U01AI12316-01; N.B. was also partially supported as an Alfred P. Sloan Fellow. In addition, this work was supported by the National Institute of Allergy and Infectious Diseases (NIAID), NIH, and the Department of Health and Human Services, under Contract Number HHSN272200800060C. V.V.P. is supported by the NIH grant K01 GM103809. L.M.S. is supported by NIH IRACDA K12 GM068524 award. T.L.-K. is supported by the United States-Israel Binational Agricultural Research and Development Fund Vaadia-BARD No. FI-494-13. C.P. is supported by Science without Borders Program from CNPq. A.M.C.R. is supported by Sao Paulo Research Foundation (FAPESP) grant#2014/01651-8, 2012/18031-7. K.K. was supported by a fellowship within the Postdoc-Programme of the German Academic Exchange Service (DAAD). M.C. was supported by a Deutsche Forschungsgemeinschaft (D.F.G.) postdoctoral fellowship. E.B. is supported by a Marie Curie IOF Fellowship within the 7th European Community Framework Program (FP7-PEOPLE-2011-IOF, grant number 301244-CYANOMIC). C.-C.L. was supported by a grant from the Ministry of Science and Technology of Taiwan (MOST103-2628-B-110-001-MY3). P.C. and B.O.P. were supported by the Novo Nordisk Foundation. Lixin Zhang and Xueting Liu are supported by the National Program on Key Basic Research Project (2013BC734000) and the National Natural Science Foundation of China (81102369 and 31125002). D.P. is supported by an INSA grant, Rennes. R.R.S. is supported by FAPESP grant#2014/01884-2. D.P.D. is supported by FAPESP grant#2014/18052-0. L.M.M. is supported by FAPESP grant#2013/16496-5. D.B.S. is supported by FAPESP grant#2012/18031-7. N.P.L. is supported by FAPESP(2014/50265-3), CAPES/PNPD, CNPq-PQ 480 306385/2011-2, and CNPq-INCT_if. E.A.G. is supported by the Notre Dame Chemistry-Biochemistry-Biology Interface (CBBI) program and NIH T32 GM075762. W.S. and J.S.M. are supported by grants from the National Institutes of Health 1R01DE023810-01 and 1R01GM095373. A.E. is supported by a grant from the NIH K99DE024543. C.F.M. and L.J. are supported by the Villum Foundation VKR023113, the Augustinus Foundation 13-4656, and the Aase & Ejnar Danielsens Foundation 10-001120. M.S.-C. was supported by UC MEXUS-CONACYT Collaborative Grant CN-12-552. M.F.T. was supported by NIH grant 1F32GM089044. Contributions by B.E.S. were supported by NSF grant DEB 1010816 and a Smithsonian Institution Grand Challenges Award. E.J.N.H. and J.P. are supported by the DFG (Forschergruppe 854) and by SNF grant IZLSZ3_149025. K.F.N. and A.K. are supported by the Danish Council for Independent Research, Technology, and Production Sciences (09-064967) and the Agilent Thought Leader Program. A.C.S. and R.S.B. were supported by NIH/NIAID U19-AI106772. B.T.M. and M.E. were supported under Department of Defense grant #W81XWH-13-1-0171. Contributions by O.B.V. and K.L.M. were supported by Oregon Sea Grant NA10OAR4170059/R/BT-48, NIH 5R21AI085540, and U01TW006634-06. E.E.C., A.M.S., and A.R.J. were supported by an NSF CAREER Award, a Pew Biomedical Scholar Award (E.E.C.), a Sloan Research Fellow Award (E.E.C.), the Research Corporation for Science Advancement (Cottrell Scholar Award; E.E.C.) and an Indiana University Quantitative Chemical Biology trainee fellowship (A.R.J.). M.M. was supported by the Danish Research Council for Technology and Production Science with Sapere Aude (116262). P.-M. A.; was supported by FNS for fellowship on Subside (200020_146200). We thank V. Paul, R. Taylor, L. Aluwihare, F. Rohwer, B. Pullman, J. Fang, M. Overgaard, M. Katze, R.D. Smith, S.K. Mazmanian, W. Fenical, E. Macagno, X. He, and C. Neubauer for feedback and support for their laboratory personnel to contribute to the work. We thank B. Gust and co-workers at the University of Tuebingen for assisting us to obtain Streptomyces sp. DSM5940. NR 54 TC 26 Z9 26 U1 37 U2 50 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2016 VL 34 IS 8 BP 828 EP 837 DI 10.1038/nbt.3597 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DT2VJ UT WOS:000381339600019 PM 27504778 ER PT J AU Bhattacharya, P Dey, R Dagur, PK Joshi, AB Ismail, N Gannavaram, S Debrabant, A Akue, AD KuKuruga, MA Selvapandiyan, A McCoy, JP Nakhasi, HL AF Bhattacharya, Parna Dey, Ranadhir Dagur, Pradeep K. Joshi, Amritanshu B. Ismail, Nevien Gannavaram, Sreenivas Debrabant, Alain Akue, Adovi D. KuKuruga, Mark A. Selvapandiyan, Angamuthu McCoy, John Philip, Jr. Nakhasi, Hira L. TI Live Attenuated Leishmania donovani Centrin Knock Out Parasites Generate Non-inferior Protective Immune Response in Aged Mice against Visceral Leishmaniasis SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID CD8(+) T-CELLS; DENDRITIC CELLS; NITRIC-OXIDE; ELDERLY INDIVIDUALS; DELETED PARASITES; VARICELLA VACCINE; PERIPHERAL-BLOOD; INNATE IMMUNITY; TH1 RESPONSE; IN-VIVO AB Background Visceral leishmaniasis (VL) caused by the protozoan parasite Leishmania donovani causes severe disease. Age appears to be critical in determining the clinical outcome of VL and at present there is no effective vaccine available against VL for any age group. Previously, we showed that genetically modified live attenuated L. donovani parasites (LdCen-/-) induced a strong protective innate and adaptive immune response in young mice. In this study we analyzed LdCen-/- parasite mediated modulation of innate and adaptive immune response in aged mice (18 months) and compared to young (2 months) mice. Methodology Analysis of innate immune response in bone marrow derived dendritic cells (BMDCs) from both young and aged mice upon infection with LdCen-/- parasites, showed significant enhancement of innate effector responses, which consequently augmented CD4(+) Th1 cell effector function compared to LdWT infected BMDCs in vitro. Similarly, parasitized splenic dendritic cells from LdCen-/- infected young and aged mice also revealed induction of proinflammatory cytokines (IL-12, IL-6, IFN-gamma and TNF) and subsequent down regulation of anti- inflammatory cytokine (IL-10) genes compared to LdWT infected mice. We also evaluated in vivo protection of the LdCen-/- immunized young and aged mice against virulent L. donovani challenge. Immunization with LdCen-/- induced higher IgG2a antibodies, lympho-proliferative response, pro- and anti-inflammatory cytokine responses and stimulated splenocytes for heightened leishmanicidal activity associated with nitric oxide production in young and aged mice. Furthermore, upon virulent L. donovani challenge, LdCen-/- immunized mice from both age groups displayed multifunctional Th1-type CD4 and cytotoxic CD8 T cells correlating to a significantly reduced parasite burden in the spleen and liver compared to naive mice. It is interesting to note that even though there was no difference in the LdCen-/-induced innate response in dendritic cells between aged and young mice; the adaptive response specifically in terms of T cell and B cell activation in aged animals was reduced compared to young mice which correlated with less protection in old mice compared to young mice. Conclusions Taken together, LdCen-/-immunization induced a significant but diminished host protective response in aged mice after challenge with virulent L. donovani parasites compared to young mice. C1 [Bhattacharya, Parna; Dey, Ranadhir; Joshi, Amritanshu B.; Ismail, Nevien; Gannavaram, Sreenivas; Debrabant, Alain; Nakhasi, Hira L.] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Dagur, Pradeep K.; McCoy, John Philip, Jr.] NHLBI, Flow Cytometry Core, NIH, Bldg 10, Bethesda, MD 20892 USA. [Akue, Adovi D.; KuKuruga, Mark A.] Ctr Biol Evaluat & Res, Off Vaccines Res & Review, Silver Spring, MD USA. [Selvapandiyan, Angamuthu] Inst Mol Med, New Delhi, India. RP Bhattacharya, P; Nakhasi, HL (reprint author), US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Parna.Bhattacharya@fda.hhs.gov; Hira.Nakhasi@fda.hhs.gov FU Intramural Research Program at the Center for Biologics Evaluation and Research, FDA FX This research was supported in part by the Intramural Research Program at the Center for Biologics Evaluation and Research, FDA (PB, RD, NI, ABJ, SG, AD, HLN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 82 TC 0 Z9 0 U1 5 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 AUG PY 2016 VL 10 IS 8 AR e0004963 DI 10.1371/journal.pntd.0004963 PG 28 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DU7JR UT WOS:000382390800079 PM 27580076 ER PT J AU Denis, ACS Leitner, WW Wali, T James, S AF Denis, Adriana Costero-Saint Leitner, Wolfgang W. Wali, Tonu James, Stephanie TI Meeting Report: Translational Considerations of Novel Vector Management Approaches SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID FIELD TRIALS; MOSQUITOS; WORKING C1 [Denis, Adriana Costero-Saint; Wali, Tonu] NIAID, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Leitner, Wolfgang W.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD USA. [James, Stephanie] Fdn Natl Inst Hlth, Bethesda, MD 20892 USA. RP James, S (reprint author), Fdn Natl Inst Hlth, Bethesda, MD 20892 USA. EM sjames@fnih.org RI Leitner, Wolfgang/F-5741-2011 OI Leitner, Wolfgang/0000-0003-3125-5922 NR 12 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2016 VL 10 IS 8 AR e0004800 DI 10.1371/journal.pntd.0004800 PG 5 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DU7JR UT WOS:000382390800006 ER PT J AU Ellis, EM Sharp, TM Perez-Padilla, J Gonzalez, L Poole-Smith, BK Lebo, E Baker, C Delorey, MJ Torres-Velasquez, B Ochoa, E Rivera-Garcia, B Diaz-Pinto, H Clavell, L Puig-Ramos, A Janka, GE Tomashek, KM AF Ellis, Esther M. Sharp, Tyler M. Perez-Padilla, Janice Gonzalez, Liza Poole-Smith, B. Katherine Lebo, Emmaculate Baker, Charlotte Delorey, Mark J. Torres-Velasquez, Brenda Ochoa, Eduardo Rivera-Garcia, Brenda Diaz-Pinto, Hector Clavell, Luis Puig-Ramos, Anabel Janka, Gritta E. Tomashek, Kay M. TI Incidence and Risk Factors for Developing Dengue-Associated Hemophagocytic Lymphohistiocytosis in Puerto Rico, 2008-2013 SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID RARE CASE-REPORT; HEMORRHAGIC-FEVER; VIRUS-INFECTION AB Background Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal disorder characterized by fever, pancytopenia, hepatosplenomegaly, and increased serum ferritin. HLH is being increasingly reported as a complication of dengue, a common tropical acute febrile illness. Methodology/Principal Findings After a cluster of pediatric dengue-associated HLH patients was identified during the 20122013 dengue epidemic in Puerto Rico, active surveillance and a case-control investigation was conducted at four referral hospitals to determine the incidence of HLH in children and identify risk factors for HLH following dengue. Patients with dengue-associated HLH (cases) were matched by month of illness onset and admission hospital to dengue patients that did not develop HLH (controls). During 2008-2013, a total of 33 HLH patients were identified, of which 22 (67%) were associated with dengue and 1 died (dengue-associated HLH casefatality rate: 4.5%). Two patients with dengue-associated HLH had illness onset in 2009, none had illness onset during the 2010 dengue epidemic, and 20 had illness onset during the 2012-2013 epidemic. Frequency of infection with either dengue virus (DENV)-1 or DENV-4 did not differ between cases and controls. Cases were younger than controls (median age: 1 vs. 13 years, p < 0.01), were hospitalized longer (18 vs. 5 days, p < 0.01), and were admitted more frequently to pediatric intensive care units (100% vs. 16%, p < 0.01). Cases had co-infection (18.2% vs. 4.5%, p = 0.04), recent influenza-like illness (54.5% vs. 25.0%, p = 0.01), and longer duration of fever (7 vs. 5 days; p < 0.01). Cases were more likely to have lymphadenopathy, hepatomegaly, splenomegaly, anemia, and elevated liver transaminases (p <= 0.02). Conclusions/Significance During this cluster of dengue-associated HLH cases that was temporally associated with the 2012-2013 epidemic, most patients with dengue-associated HLH were infants and had higher morbidity than dengue inpatients. Physicians throughout the tropics should be aware of HLH as a potential complication of dengue, particularly in patients with anemia and severe liver injury. C1 [Ellis, Esther M.; Sharp, Tyler M.; Perez-Padilla, Janice; Poole-Smith, B. Katherine; Torres-Velasquez, Brenda; Tomashek, Kay M.] Ctr Dis Control & Prevent, Dengue Branch, San Juan, PR 00920 USA. [Ellis, Esther M.; Lebo, Emmaculate; Baker, Charlotte] Ctr Dis Control & Prevent, Div Sci Educ & Profess Dev, Atlanta, GA USA. [Gonzalez, Liza] Ponce Hlth Sci Univ, Ponce, PR USA. [Delorey, Mark J.] Ctr Dis Control & Prevent, Div Vector Borne Dis, Ft Collins, CO USA. [Ochoa, Eduardo; Diaz-Pinto, Hector] Puerto Rico Childrens Hosp, Bayamon, PR USA. [Rivera-Garcia, Brenda] Puerto Rico Dept Hlth, San Juan, PR USA. [Clavell, Luis] San Jorge Childrens Hosp, San Juan, PR USA. [Puig-Ramos, Anabel] Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA. [Janka, Gritta E.] Univ Med Ctr, Hamburg, Germany. [Tomashek, Kay M.] NIH, Off Clin Res Resources, Div Microbiol & Infect Dis, Bldg 10, Bethesda, MD 20892 USA. RP Sharp, TM (reprint author), Ctr Dis Control & Prevent, Dengue Branch, San Juan, PR 00920 USA. EM tsharp@cdc.gov NR 45 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2016 VL 10 IS 8 AR e0004939 DI 10.1371/journal.pntd.0004939 PG 14 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DU7JR UT WOS:000382390800073 PM 27556807 ER PT J AU Zheng, YL Zhang, X Fu, HX Guo, M Shukla, V Amin, ND Jing, E Bao, L Luo, HY Li, B Lu, XH Gao, YC AF Zheng, Ya-Li Zhang, Xia Fu, Hai-Xia Guo, Mei Shukla, Varsha Amin, Niranjana D. Jing, E. Bao, Li Luo, Hong-Yan Li, Bo Lu, Xiao-Hua Gao, Yong-Cai TI Knockdown of Expression of Cdk5 or p35 (a Cdk5 Activator) Results in Podocyte Apoptosis SO PLOS ONE LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; GLOMERULOSCLEROSIS; DIFFERENTIATION; CELLS; NEURODEGENERATION; GLOMERULI; REGULATOR; DEPLETION; PEPTIDE; NEURONS AB Podocytes are terminally differentiated glomerular epithelial cells. Podocyte loss has been found in many renal diseases. Cdk5 is a cyclin-dependent protein kinase which is predominantly regulated by p35. To study the role of Cdk5/p35 in podocyte survival, we first applied western blotting (WB) analysis to confirm the time-course expression of Cdk5 and p35 during kidney development and in cultured immortalized mouse podocytes. We also demonstrated that p35 plays an important role in promoting podocyte differentiation by overexpression of p35 in podocytes. To deregulate the expression of Cdk5 or p35 in mouse podocytes, we used RNAi and analyzed cell function and apoptosis assaying for podocyte specific marker Wilms Tumor 1 (WT1) and cleaved caspase 3, respectively. We also counted viable cells using cell counting kit-8. We found that depletion of Cdk5 causes decreased expression of WT1 and apoptosis. It is noteworthy, however, that downregulation of p35 reduced Cdk5 activity, but had no effect on cleaved caspase 3 expression. It did, however, reduce expression of WT1, a transcription factor, and produced podocyte dysmorphism. On the other hand increased apoptosis could be detected in p35-deregulated podocytes using the TUNEL analysis and immunofluorescent staining with cleaved caspase3 antibody. Viability of podocytes was decreased in both Cdk5 and p35 knockdown cells. Knocking down Cdk5 or p35 gene by RNAi does not affect the cycline I expression, another Cdk5 activator in podocyes. We conclude that Cdk5 and p35 play a crucial role in maintaining podocyte differentiation and survival, and suggest these proteins as targets for therapeutic intervention in podocyte-damaged kidney diseases. C1 [Zheng, Ya-Li; Zhang, Xia; Jing, E.; Bao, Li; Luo, Hong-Yan; Li, Bo; Lu, Xiao-Hua; Gao, Yong-Cai] Northwest Univ Nationalities, Coll Med, Affiliated Hosp 1, Dept Nephrol,Ningxia Peoples Hosp, Yinchuan 750002, Ningxia, Peoples R China. [Fu, Hai-Xia] Cent Hosp Rizhao City, Ctr Blood Purificat, Rizhao 276800, Shangdong, Peoples R China. [Shukla, Varsha; Amin, Niranjana D.] NINDS, Lab Neurochem, Bethesda, MD 20814 USA. [Guo, Mei] Fudan Univ, Zhongshan Xuhui Hosp, Shanghai 200031, Peoples R China. RP Zheng, YL (reprint author), Northwest Univ Nationalities, Coll Med, Affiliated Hosp 1, Dept Nephrol,Ningxia Peoples Hosp, Yinchuan 750002, Ningxia, Peoples R China. EM yalinew@yahoo.com FU National Natural Science Foundation of China [81160093, 81460161]; Natural Science Foundation of Ningxia Province [NZ14160]; Department of Science and Technology of Ningxia Province [2011ZYH169, 2013ZYS103] FX This work was supported by the following grant sponsors: National Natural Science Foundation of China, grant no. 81160093 and 81460161; Natural Science Foundation of Ningxia Province, grant no. NZ14160; and Department of Science and Technology of Ningxia Province, grant no. 2013ZYS103 and 2011ZYH169 (international collaboration with the intramural funds of NIH/NINDS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 1 PY 2016 VL 11 IS 8 AR e0160252 DI 10.1371/journal.pone.0160252 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS9NO UT WOS:000381110300035 PM 27479491 ER PT J AU Carvalho, AF Kohler, CA Fernandes, BS Quevedo, J Miskowiak, KW Brunoni, AR Machado-Vieira, R Maes, M Vieta, E Berk, M AF Carvalho, A. F. Kohler, C. A. Fernandes, B. S. Quevedo, J. Miskowiak, K. W. Brunoni, A. R. Machado-Vieira, R. Maes, M. Vieta, E. Berk, M. TI Bias in emerging biomarkers for bipolar disorder SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Bias; biomarkers; bipolar disorder; meta-analysis; psychiatry; review ID NEUROTROPHIC FACTOR; OXIDATIVE STRESS; METAANALYSIS; HETEROGENEITY; PSYCHIATRY; EXCESS; RDOC; PSYCHOPATHOLOGY; SCHIZOPHRENIA; ASSOCIATIONS AB Background To date no comprehensive evaluation has appraised the likelihood of bias or the strength of the evidence of peripheral biomarkers for bipolar disorder (BD). Here we performed an umbrella review of meta-analyses of peripheral non-genetic biomarkers for BD. Method The Pubmed/Medline, EMBASE and PsycInfo electronic databases were searched up to May 2015. Two independent authors conducted searches, examined references for eligibility, and extracted data. Meta-analyses in any language examining peripheral non-genetic biomarkers in participants with BD (across different mood states) compared to unaffected controls were included. Results Six references, which examined 13 biomarkers across 20 meta-analyses (5474 BD cases and 4823 healthy controls) met inclusion criteria. Evidence for excess of significance bias (i.e. bias favoring publication of positive' nominally significant results) was observed in 11 meta-analyses. Heterogeneity was high for (I-2 50%) 16 meta-analyses. Only two biomarkers met criteria for suggestive evidence namely the soluble IL-2 receptor and morning cortisol. The median power of included studies, using the effect size of the largest dataset as the plausible true effect size of each meta-analysis, was 15.3%. Conclusions Our findings suggest that there is an excess of statistically significant results in the literature of peripheral biomarkers for BD. Selective publication of positive' results and selective reporting of outcomes are possible mechanisms. C1 [Carvalho, A. F.; Kohler, C. A.] Univ Fed Ceara, Dept Psychiat, Fac Med, Fortaleza, Ceara, Brazil. [Carvalho, A. F.; Kohler, C. A.] Univ Fed Ceara, Translat Psychiat Res Grp, Fac Med, Fortaleza, Ceara, Brazil. [Fernandes, B. S.; Maes, M.; Berk, M.] Deakin Univ, IMPACT Strateg Res Ctr, Sch Med, Geelong, Vic, Australia. [Fernandes, B. S.; Maes, M.; Berk, M.] Barwon Hlth, Geelong, Vic, Australia. [Fernandes, B. S.] Univ Fed Rio Grande do Sul, Dept Biochem, Lab Calcium Binding Prot Cent Nervous Syst, Porto Alegre, RS, Brazil. [Quevedo, J.] Univ Texas Med Sch Houston, Dept Psychiat & Behav Sci, Ctr Expt Models Psychiat, Houston, TX USA. [Quevedo, J.] Univ Southern Santa Catarina, Lab Neurosci, Grad Program Hlth Sci, Hlth Sci Unit, Criciuma, SC, Brazil. [Miskowiak, K. W.] Rigshosp, Psychiat Ctr Copenhagen, Copenhagen Univ Hosp, Copenhagen, Denmark. [Brunoni, A. R.] Univ Sao Paulo, Interdisciplinary Ctr Appl Neuromodulat CINA, Univ Hosp, Sao Paulo, Brazil. [Brunoni, A. R.] Univ Sao Paulo, Dept & Inst Psychiat, SIN, Lab Neurosci LIM 27, Sao Paulo, Brazil. [Machado-Vieira, R.] Univ Sao Paulo, Lab Neurosci, LIM 27, Inst & Dept Psychiat, Sao Paulo, Brazil. [Machado-Vieira, R.] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo, Brazil. [Machado-Vieira, R.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Vieta, E.] Univ Barcelona, Bipolar Disorders Unit, Inst Neurosci, Hosp Clin,IDIBAPS,CIBERSAM, Barcelona, Catalonia, Spain. [Berk, M.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Dept Psychiat, Natl Ctr Excellence Youth Mental Hlth, Parkville, Vic, Australia. [Berk, M.] Univ Melbourne, Orygen Youth Hlth Res Ctr, Parkville, Vic, Australia. RP Carvalho, AF (reprint author), Univ Fed Ceara, Dept Clin Med, Fac Med, Rua Prof Costa Mendes 1608,4 Andar, BR-60430040 Fortaleza, Ceara, Brazil. EM andrefc7@terra.com.br RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Vieta, Eduard/0000-0002-0548-0053; Russowsky Brunoni, Andre/0000-0002-6310-3571 FU CNPq (Brazil); CAPES (Brazil); CNPq, Brazil [MCTI/CNPQ/Universal 14/2014461833/2014-0]; NARSAD Young Investigator from the Brain & Behavior Research Foundation [20493]; FAPESP Young Researcher from the Sao Paulo State Foundation [20911-5]; National Council for Scientific and Technological Development (CNPq) [470904]; NHMRC Senior Principal Research Fellowship [1059660] FX A.F.C. and J.Q. are supported by research fellowship awards from CNPq (Brazil). C.A.K. is supported by a postdoctoral fellowship from CAPES (Brazil). B.S.F. is supported by a scholarship and by a research grant MCTI/CNPQ/Universal 14/2014461833/2014-0, both from CNPq, Brazil. A.R.B. is supported by the following grants: 2013 NARSAD Young Investigator from the Brain & Behavior Research Foundation (grant no. 20493), 2012 FAPESP Young Researcher from the Sao Paulo State Foundation (grant no. 20911-5) and National Council for Scientific and Technological Development (CNPq, grant no. 470904). M.B. is supported by a NHMRC Senior Principal Research Fellowship (1059660). NR 56 TC 1 Z9 1 U1 7 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD AUG PY 2016 VL 46 IS 11 BP 2287 EP 2297 DI 10.1017/S0033291716000957 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DT1FZ UT WOS:000381228400005 PM 27193198 ER PT J AU Shaw, P Weingart, D Bonner, T Watson, B Park, MTM Sharp, W Lerch, JP Chakravarty, MM AF Shaw, P. Weingart, D. Bonner, T. Watson, B. Park, M. T. M. Sharp, W. Lerch, J. P. Chakravarty, M. M. TI Defining the neuroanatomic basis of motor coordination in children and its relationship with symptoms of attention-deficit/hyperactivity disorder SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Attention-deficit; hyperactivity disorder; brain imaging; cerebellum; cortex; motor coordination ID OF-THE-LITERATURE; HUMAN BRAIN; SEX-DIFFERENCES; ADHD; CORTEX; PERFORMANCE; CEREBELLUM; ACTIVATION; VOLUME; SKILLS AB Background When children have marked problems with motor coordination, they often have problems with attention and impulse control. Here, we map the neuroanatomic substrate of motor coordination in childhood and ask whether this substrate differs in the presence of concurrent symptoms of attention-deficit/hyperactivity disorder (ADHD). Method Participants were 226 children. All completed Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)-based assessment of ADHD symptoms and standardized tests of motor coordination skills assessing aiming/catching, manual dexterity and balance. Symptoms of developmental coordination disorder (DCD) were determined using parental questionnaires. Using 3 Tesla magnetic resonance data, four latent neuroanatomic variables (for the cerebral cortex, cerebellum, basal ganglia and thalamus) were extracted and mapped onto each motor coordination skill using partial least squares pathway modeling. Results The motor coordination skill of aiming/catching was significantly linked to latent variables for both the cerebral cortex (t = 4.31, p < 0.0001) and the cerebellum (t = 2.31, p = 0.02). This effect was driven by the premotor/motor cortical regions and the superior cerebellar lobules. These links were not moderated by the severity of symptoms of inattention, hyperactivity and impulsivity. In categorical analyses, the DCD group showed atypical reduction in the volumes of these regions. However, the group with DCD alone did not differ significantly from those with DCD and co-morbid ADHD. Conclusions The superior cerebellar lobules and the premotor/motor cortex emerged as pivotal neural substrates of motor coordination in children. The dimensions of these motor coordination regions did not differ significantly between those who had DCD, with or without co-morbid ADHD. C1 [Shaw, P.; Weingart, D.; Bonner, T.; Watson, B.; Sharp, W.] NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bldg 31,B1 B37, Bethesda, MD 20892 USA. [Park, M. T. M.] Western Univ, Schulich Sch Med & Dent, London, ON, Canada. [Park, M. T. M.; Chakravarty, M. M.] Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Montreal, PQ, Canada. [Lerch, J. P.] Univ Toronto, Program Neurosci & Mental Hlth, Hosp Sick Children, Toronto, ON, Canada. [Lerch, J. P.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Chakravarty, M. M.] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. [Chakravarty, M. M.] McGill Univ, Dept Biol & Biomed Engn, Montreal, PQ, Canada. RP Shaw, P (reprint author), NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bldg 31,B1 B37, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov FU National Human Genome Research Institute; National Institute of Mental Health; Canadian Institutes of Health Research; National Sciences and Engineering Research Council of Canada; Weston Brian Institute; Michael J. Fox Foundation for Parkinson's Research; Alzheimer's Society; Fond de Recherches Sante Quebec FX P.S. is funded by the intramural programs of the National Human Genome Research Institute and National Institute of Mental Health. M.M.C. is funded by the Canadian Institutes of Health Research, National Sciences and Engineering Research Council of Canada, Weston Brian Institute, Michael J. Fox Foundation for Parkinson's Research, and Alzheimer's Society. M.M.C. also receives salary and research support from the Fond de Recherches Sante Quebec. NR 62 TC 0 Z9 0 U1 9 U2 9 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD AUG PY 2016 VL 46 IS 11 BP 2363 EP 2373 DI 10.1017/S0033291716000660 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DT1FZ UT WOS:000381228400011 PM 27282929 ER PT J AU Goldstein, RB Smith, SM Chou, SP Saha, TD Jung, J Zhang, HT Pickering, RP Ruan, WJ Huang, BJ Grant, BF AF Goldstein, Rise B. Smith, Sharon M. Chou, S. Patricia Saha, Tulshi D. Jung, Jeesun Zhang, Haitao Pickering, Roger P. Ruan, W. June Huang, Boji Grant, Bridget F. TI The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions-III SO SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY LA English DT Article DE Posttraumatic stress disorder; Epidemiology; Comorbidity ID COMORBIDITY SURVEY-REPLICATION; GENERAL-POPULATION SAMPLE; MENTAL-HEALTH; LIFETIME PREVALENCE; HOUSEHOLD DYSFUNCTION; PERSONALITY-DISORDERS; PROCEDURAL VALIDITY; ANXIETY DISORDERS; SUBSTANCE USE; IV DISORDERS AB To present current, nationally representative US findings on the past-year and lifetime prevalences, sociodemographic correlates, psychiatric comorbidity, associated disability, and treatment of DSM-5 posttraumatic stress disorder (PTSD). Face-to-face interviews with 36,309 adults in the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III. PTSD, alcohol and drug use disorders, and selected mood, anxiety, and personality disorders were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-5. Past-year and lifetime prevalences were 4.7 and 6.1 %, higher for female, white, Native American, younger, and previously married respondents, those with < high school education and lower incomes, and rural residents. PTSD was significantly associated with a broad range of substance use, mood, anxiety, and personality disorders, and past-month disability. Among respondents with lifetime PTSD, 59.4 % sought treatment; an average of 4.5 years elapsed from disorder onset to first treatment. DSM-5 PTSD is prevalent, highly comorbid, disabling, and associated with delayed help seeking. Additional research is needed to elucidate relationships identified herein, estimate PTSD-related costs, investigate hypotheses regarding etiology, course, and treatment, and support decisions about resource allocation to service delivery and research. Initiatives are needed to destigmatize PTSD, educate the public about its treatment, and encourage affected individuals to seek help. C1 [Goldstein, Rise B.; Smith, Sharon M.; Chou, S. Patricia; Saha, Tulshi D.; Jung, Jeesun; Zhang, Haitao; Pickering, Roger P.; Ruan, W. June; Huang, Boji; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Ln,MS 9304, Bethesda, MD 20892 USA. [Goldstein, Rise B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B13C, Bethesda, MD 20892 USA. [Smith, Sharon M.] NHLBI, Translat Blood Sci & Resources Branch, Div Blood Dis & Resources, NIH, 6701 Rockledge Dr, Bethesda, MD 20892 USA. RP Goldstein, RB (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Ln,MS 9304, Bethesda, MD 20892 USA.; Goldstein, RB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B13C, Bethesda, MD 20892 USA. EM goldster@mail.nih.gov; smithsh1@mail.nih.gov; pchou@mail.nih.gov; sahatd@mail.nih.gov; jungj3@mail.nih.gov; zhangh13@mail.nih.gov; rpickeri@mail.nih.gov; ruanj@mail.nih.gov; huangbo@mail.nih.gov; bgrant@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Drug Abuse; Intramural Program of the National Institutes of Health, NIAAA FX The National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III) is funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) with supplemental support from the National Institute on Drug Abuse. This research was supported in part by the Intramural Program of the National Institutes of Health, NIAAA. All authors are employees of the National Institutes of Health. NR 72 TC 6 Z9 6 U1 18 U2 19 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0933-7954 EI 1433-9285 J9 SOC PSYCH PSYCH EPID JI Soc. Psychiatry Psychiatr. Epidemiol. PD AUG PY 2016 VL 51 IS 8 BP 1137 EP 1148 DI 10.1007/s00127-016-1208-5 PG 12 WC Psychiatry SC Psychiatry GA DT3UU UT WOS:000381407500008 PM 27106853 ER PT J AU Halpern, WG Ameri, M Bowman, CJ Elwell, MR Mirsky, ML Oliver, J Regan, KS Remick, AK Sutherland, VL Thompson, KE Tremblay, C Yoshida, M Tomlinson, L AF Halpern, Wendy G. Ameri, Mehrdad Bowman, Christopher J. Elwell, Michael R. Mirsky, Michael L. Oliver, Julian Regan, Karen S. Remick, Amera K. Sutherland, Vicki L. Thompson, Kary E. Tremblay, Claudine Yoshida, Midori Tomlinson, Lindsay TI Scientific and Regulatory Policy Committee Points to Consider Review: Inclusion of Reproductive and Pathology End Points for Assessment of Reproductive and Developmental Toxicity in Pharmaceutical Drug Development SO TOXICOLOGIC PATHOLOGY LA English DT Article DE preclinical research and development; reproductive system; safety assessment; toxicologic pathology; teratology; clinical pathology; developmental pathology ID SPRAGUE-DAWLEY RATS; PRECLINICAL JUVENILE TOXICITY; MONKEYS MACACA-FASCICULARIS; REPEAT-DOSE TOXICITY; CYNOMOLGUS MONKEYS; MAMMARY-GLAND; MONOCLONAL-ANTIBODY; CIRCULATING HORMONES; METABOLIZING-ENZYMES; POSITION PAPER AB Standard components of nonclinical toxicity testing for novel pharmaceuticals include clinical and anatomic pathology, as well as separate evaluation of effects on reproduction and development to inform clinical development and labeling. General study designs in regulatory guidances do not specifically mandate use of pathology or reproductive end points across all study types; thus, inclusion and use of these end points are variable. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology (STP) formed a Working Group to assess the current guidelines and practices on the use of reproductive, anatomic pathology, and clinical pathology end points in general, reproductive, and developmental toxicology studies. The Working Group constructed a survey sent to pathologists and reproductive toxicologists, and responses from participating organizations were collected through the STP for evaluation by the Working Group. The regulatory context, relevant survey results, and collective experience of the Working Group are discussed and provide the basis of each assessment by study type. Overall, the current practice of including specific end points on a case-by-case basis is considered appropriate. Points to consider are summarized for inclusion of reproductive end points in general toxicity studies and for the informed use of pathology end points in reproductive and developmental toxicity studies. C1 [Halpern, Wendy G.] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA. [Ameri, Mehrdad] GlaxoSmithKline, King Of Prussia, PA USA. [Bowman, Christopher J.; Mirsky, Michael L.] Pfizer, Groton, CT USA. [Elwell, Michael R.] Covance, Chantilly, VA USA. [Oliver, Julian] Incyte, Wilmington, DE USA. [Regan, Karen S.] Regan Path Tox Serv, Ashland, OH USA. [Remick, Amera K.] WIL Res, Hillsborough, NC USA. [Sutherland, Vicki L.] NIEHS NTP, Res Triangle Pk, NC USA. [Thompson, Kary E.] Bristol Myers Squibb, New Brunswick, NJ USA. [Tremblay, Claudine] Charles River Labs, Senneville, PQ, Canada. [Yoshida, Midori] Food Safety Commiss Japan, Minato Ku, Tokyo, Japan. [Tomlinson, Lindsay] Pfizer, Cambridge, MA USA. RP Halpern, WG (reprint author), Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA. EM halpern.wendy@gene.com FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported [in part] by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 104 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD AUG PY 2016 VL 44 IS 6 BP 789 EP 809 DI 10.1177/0192623316650052 PG 21 WC Pathology; Toxicology SC Pathology; Toxicology GA DS7ZE UT WOS:000381001300001 PM 27235322 ER PT J AU Dunnick, JK Merrick, BA Brix, A Morgan, DL Gerrish, K Wang, Y Flake, G Foley, J Shockley, KR AF Dunnick, June K. Merrick, B. Alex Brix, Amy Morgan, Daniel L. Gerrish, Kevin Wang, Yu Flake, Gordon Foley, Julie Shockley, Keith R. TI Molecular Changes in the Nasal Cavity after N, N-dimethyl-p-toluidine Exposure SO TOXICOLOGIC PATHOLOGY LA English DT Article DE N, N-dimethyl-p-toluidine; nasal cavity toxicity; molecular markers ID STEM-CELL ANTIGEN; OXIDATIVE-STRESS; SIGNALING PATHWAY; GROWTH-FACTOR; SKIN-LESIONS; PROBE LEVEL; F344 RATS; GENE; EXPRESSION; CANCER AB N, N-dimethyl-p-toluidine (DMPT; Cas No. 99-97-8), an accelerant for methyl methacrylate monomers in medical devices, is a nasal cavity carcinogen according to a 2-yr cancer study of male and female F344/N rats, with the nasal tumors arising from the transitional cell epithelium. In this study, we exposed male F344/N rats for 5 days to DMPT (0, 1, 6, 20, 60, or 120 mg/kg [oral gavage]) to explore the early changes in the nasal cavity after short-term exposure. Lesions occurred in the nasal cavity including hyperplasia of transitional cell epithelium (60 and 120 mg/kg). Nasal tissue was rapidly removed and preserved for subsequent laser capture microdissection and isolation of the transitional cell epithelium (0 and 120 mg/kg) for transcriptomic studies. DMPT transitional cell epithelium gene transcript patterns were characteristic of an antioxidative damage response (e.g., Akr7a3, Maff, and Mgst3), cell proliferation, and decrease in signals for apoptosis. The transcripts of amino acid transporters were upregulated (e.g., Slc7a11). The DMPT nasal transcript expression pattern was similar to that found in the rat nasal cavity after formaldehyde exposure, with over 1,000 transcripts in common. Molecular changes in the nasal cavity after DMPT exposure suggest that oxidative damage is a mechanism of the DMPT toxic and/or carcinogenic effects. C1 [Dunnick, June K.] NIEHS, Toxicol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Merrick, B. Alex] NIEHS, Biomol Screening Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Brix, Amy] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Morgan, Daniel L.] NIEHS, NTP Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Gerrish, Kevin] NIEHS, Mol Genom Core, POB 12233, Res Triangle Pk, NC 27709 USA. [Wang, Yu; Flake, Gordon; Foley, Julie] NIEHS, Cellular & Mol Pathol, POB 12233, Res Triangle Pk, NC 27709 USA. [Shockley, Keith R.] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. RP Dunnick, JK (reprint author), NIEHS, Toxicol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM dunnickj@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The intramural program of the National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, supported this work. NR 75 TC 0 Z9 0 U1 3 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD AUG PY 2016 VL 44 IS 6 BP 835 EP 847 DI 10.1177/0192623316637708 PG 13 WC Pathology; Toxicology SC Pathology; Toxicology GA DS7ZE UT WOS:000381001300004 PM 27099258 ER PT J AU Yamashita, H Hoenerhoff, MJ Peddada, SD Sills, RC Pandiri, AR AF Yamashita, Haruhiro Hoenerhoff, Mark J. Peddada, Shyamal D. Sills, Robert C. Pandiri, Arun R. TI Chemical Exacerbation of Light-induced Retinal Degeneration in F344/N Rats in National Toxicology Program Rodent Bioassays SO TOXICOLOGIC PATHOLOGY LA English DT Article DE F344/N rat; ocular phototoxicity; retinal degeneration; light-induced exacerbation; carcinogenicity bioassay; NTP database survey; retinal atrophy ID ORDER-RESTRICTED INFERENCE; HUMAN INFANT FORMULA; ALBINO RATS; TAURINE DEFICIENCY; VISUAL DYSFUNCTION; FISCHER-344 RATS; GANGLION-CELLS; VISIBLE-LIGHT; LONG-TERM; DAMAGE AB Retinal degeneration due to chronic ambient light exposure is a common spontaneous age-related finding in albino rats, but it can also be related to exposures associated with environmental chemicals and drugs. Typically, light-induced retinal degeneration has a central/hemispherical localization whereas chemical-induced retinal degeneration has a diffuse localization. This study was conducted to identify and characterize treatment-related retinal degeneration in National Toxicology Program rodent bioassays. A total of 3 chronic bioassays in F344/N rats (but not in B6C3F1/N mice) were identified that had treatment-related increases in retinal degeneration (kava kava extract, acrylamide, and leucomalachite green). A retrospective light microscopic evaluation of the retinas from rats in these 3 studies showed a dose-related increase in the frequencies of retinal degeneration, beginning with the loss of photoreceptor cells, followed by the inner nuclear layer cells. These dose-related increased frequencies of degenerative retinal lesions localized within the central/hemispherical region are suggestive of exacerbation of light-induced retinal degeneration. C1 [Yamashita, Haruhiro; Hoenerhoff, Mark J.; Sills, Robert C.; Pandiri, Arun R.] NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, 111 TW Alexander Dr MD B306, Res Triangle Pk, NC 27709 USA. [Yamashita, Haruhiro] Taisho Pharmaceut Co Ltd, Saitama, Japan. [Hoenerhoff, Mark J.] Univ Michigan, Sch Med, Unit Lab Anim Med, In Vivo Anim Core, Ann Arbor, MI USA. [Peddada, Shyamal D.] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. RP Pandiri, AR (reprint author), NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, 111 TW Alexander Dr MD B306, Res Triangle Pk, NC 27709 USA. EM pandiriak@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 67 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD AUG PY 2016 VL 44 IS 6 BP 892 EP 903 DI 10.1177/0192623316650050 PG 12 WC Pathology; Toxicology SC Pathology; Toxicology GA DS7ZE UT WOS:000381001300009 PM 27230502 ER PT J AU Hussain, S Ji, ZX Taylor, AJ DeGraff, LM George, M Tucker, CJ Chang, CH Li, RB Bonner, JC Garantziotis, S AF Hussain, Salik Ji, Zhaoxia Taylor, Alexia J. DeGraff, Laura M. George, Margaret Tucker, Charles J. Chang, Chong Hyun Li, Ruibin Bonner, James C. Garantziotis, Stavros TI Multiwalled Carbon Nanotube Functionalization with High Molecular Weight Hyaluronan Significantly Reduces Pulmonary Injury SO ACS NANO LA English DT Article DE multiwalled carbon nanotubes; hyaluronan; lung; inflammation; fibrosis; mucous metaplasia; differentiated human bronchial epithelia ID PREDICTIVE TOXICOLOGICAL APPROACH; ALLERGIC AIRWAY INFLAMMATION; LUNG FIBROGENIC ACTIVITY; EPITHELIAL-CELLS; CANCER-CELLS; FIBROTIC RESPONSE; TARGETED DELIVERY; FIBROSIS; EXPOSURE; NANOPARTICLES AB Commercialization of multiwalled carbon nanotubes (MWCNT)-based applications has been hampered by concerns regarding their lung toxicity potential. Hyaluronic acid (HA) is a ubiquitously found polysaccharide, which is anti-inflammatory in its native high molecular weight form. HA-functionalized smart MWCNTs have shown promise as tumor-targeting drug delivery agents and can enhance bone repair and regeneration. However, it is unclear whether HA functionalization could reduce the pulmonary toxicity potential of MWCNTs. Using in vivo and in vitro approaches, we investigated the effectiveness of MWCNT functionalization with HA in increasing nanotube biocompatibility and reducing lung inflammatory and fibrotic effects. We utilized three-dimensional cultures of differentiated primary human bronchial epithelia to translate findings from rodent assays to humans. We found that HA functionalization increased stability and dispersion of MWCNTs and reduced postexposure lung inflammation, fibrosis, and mucus cell metaplasia compared with nonfunctionalized MWCNTs. Cocultures of fully differentiated bronchial epithelial cells (cultivated at air-liquid interface) and human lung fibroblasts (submerged) displayed significant reduction in injury, oxidative stress, as well as pro-inflammatory gene and protein expression after exposure to HA-functionalized MWCNTs compared with MWCNTs alone. In contrast, neither type of nanotubes stimulated cytokine production in primary human alveolar macrophages. In aggregate, our results demonstrate the effectiveness of HA functionalization as a safer design approach to eliminate MWCNT-induced lung injury and suggest that HA functionalization works by reducing MWCNT-induced epithelial injury. C1 [Hussain, Salik; George, Margaret; Garantziotis, Stavros] NIEHS, Clin Res Unit, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Ji, Zhaoxia; Chang, Chong Hyun; Li, Ruibin] Univ Calif Los Angeles, UC Ctr Environm Implicat Nanotechnol, Los Angeles, CA 90095 USA. [Li, Ruibin] Soochow Univ, Sch Radiol & Interdisciplinary Sci RAD X, Collaborat Innovat Ctr Radiat Med Jiangsu Higher, Suzhou 215123, Peoples R China. [DeGraff, Laura M.] NIEHS, Immun Inflammat & Dis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Tucker, Charles J.] NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. [Taylor, Alexia J.; Bonner, James C.] North Carolina State Univ, Toxicol Program, Dept Biol Sci, Raleigh, NC 27695 USA. RP Hussain, S (reprint author), NIEHS, Clin Res Unit, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM salik.hussain@nih.gov RI Hussain, Salik/O-1687-2016; Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU NIH, National institute of Environmental Health Sciences (NIEHS); NIEHS [R01-ES020897]; National Science Foundation; Environmental Protection Agency [DBI-1266377]; U.S. Public Health Service [R01 ES016746, U19 ES019528] FX We want to thank Schantel Bouknight for scoring of lung sections. We also wish to gratefully acknowledge the excellent technical assistance provided by Dave Brar, Natasha Clayton, Eli Ney, Connie Cummings, Deloris Sutton, Annette Rice, Jamie Marshburn, and the NIEHS Core facilities for flow cytometry and florescent imaging. This work was supported by the Intramural Research Program of the NIH, National institute of Environmental Health Sciences (NIEHS) and NIEHS grant R01-ES020897 awarded to J.C.B. Partial support was also provided by the National Science Foundation and the Environmental Protection Agency to University of California at Los Angeles under cooperative agreement number DBI-1266377 and U.S. Public Health Service Grants (R01 ES016746 and U19 ES019528). Any opinions, findings, conclusions, or recommendations expressed herein are those of the author(s) and do not necessarily reflect the views of the National Science Foundation or the Environmental Protection Agency. NR 79 TC 1 Z9 1 U1 21 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 EI 1936-086X J9 ACS NANO JI ACS Nano PD AUG PY 2016 VL 10 IS 8 BP 7675 EP 7688 DI 10.1021/acsnano.6b03013 PG 14 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA DU1HP UT WOS:000381959100051 PM 27459049 ER PT J AU Rutten, LJF Hesse, BW St Sauver, JL Wilson, P Chawla, N Hartigan, DB Moser, RP Taplin, S Glasgow, R Arora, NK AF Rutten, Lila J. Finney Hesse, Bradford W. St Sauver, Jennifer L. Wilson, Patrick Chawla, Neetu Hartigan, Danielle B. Moser, Richard P. Taplin, Stephen Glasgow, Russell Arora, Neeraj K. TI Health Self-Efficacy Among Populations with Multiple Chronic Conditions: the Value of Patient-Centered Communication SO ADVANCES IN THERAPY LA English DT Article DE Multi-morbidity; Multiple chronic conditions; Patient-centered communication; Self-efficacy; Survey ID CHRONIC DISEASE; MANAGEMENT PROGRAM; PRIMARY-CARE; MENTAL-ILLNESS; DEPRESSION; OUTCOMES; SYSTEM; RISK; MULTIMORBIDITY; PERSPECTIVES AB Introduction: Using cross-sectional survey data, we assessed the association between chronic illness burden and health-related self-efficacy, evaluating whether patient-centered communication is associated with self-efficacy and if that relationship varies by chronic illness burden. Methods: Data were from the Health Information National Trends Survey, a cross-sectional survey of the US adult population collected in 2012-2013 (n = 3630). Health-related self-efficacy was measured with the item: "Overall, how confident are you about your ability to take good care of your health?" and the prevalence of six chronic conditions and depression/anxiety was assessed. Patient-centered communication was measured as the frequency with which respondents perceived their healthcare providers allowed them to ask questions, gave attention to their emotions, involved them in decisions, made sure they understood how to take care of their health, helped them to deal with uncertainty, and if they felt they could rely on their healthcare providers to take care of their healthcare needs. Results: Health-related self-efficacy was significantly lower among individuals with greater illness burden. In adjusted analysis, individuals who experienced more positive patient-centered communication reported higher levels of self-efficacy (beta = 0.26, P < 0.0001); this association was strongest among those with greater illness burden. Conclusion: Higher levels of self-efficacy were observed among patients reporting more positive patient-centered communication; the observed association was stronger among those with greater chronic illness burden. C1 [Rutten, Lila J. Finney; St Sauver, Jennifer L.; Wilson, Patrick] Mayo Clin, Dept Hlth Sci, Rochester, MN 55905 USA. [Hesse, Bradford W.; Moser, Richard P.; Taplin, Stephen] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Chawla, Neetu] Kaiser Permanente, Div Res, Oakland, CA USA. [Hartigan, Danielle B.] Bentley Univ, Dept Nat & Appl Sci, Waltham, MA USA. [Glasgow, Russell] Univ Colorado, Dept Family Med, Denver, CO 80202 USA. [Glasgow, Russell] Univ Colorado, Adult & Child Consortium Hlth Outcomes Res & Deli, Denver, CO 80202 USA. [Arora, Neeraj K.] Patient Centered Outcomes Res Inst, Washington, DC USA. RP Rutten, LJF (reprint author), Mayo Clin, Dept Hlth Sci, Rochester, MN 55905 USA. EM rutten.lila@mayo.edu FU National Cancer Institute [HHSN261201000064C]; Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery FX HINTS was funded by contract # HHSN261201000064C from the National Cancer Institute. This study was funded, in part, by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. This work was completed, while Dr. Arora was employed at the National Cancer Institute and does not reflect the policy or position of the Patient-Centered Outcomes Research Institute. The article processing charges for this publication were funded by the authors. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. NR 43 TC 0 Z9 0 U1 5 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0741-238X EI 1865-8652 J9 ADV THER JI Adv. Ther. PD AUG PY 2016 VL 33 IS 8 BP 1440 EP 1451 DI 10.1007/s12325-016-0369-7 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DS9AG UT WOS:000381073600012 ER PT J AU Kirkpatrick, AR Patel, EU Celum, CL Moore, RD Blankson, JN Mehta, SH Kirk, GD Margolick, JB Quinn, TC Eshleman, SH Laeyendecker, O AF Kirkpatrick, Allison R. Patel, Eshan U. Celum, Connie L. Moore, Richard D. Blankson, Joel N. Mehta, Shruti H. Kirk, Gregory D. Margolick, Joseph B. Quinn, Thomas C. Eshleman, Susan H. Laeyendecker, Oliver TI Development and Evaluation of a Modified Fourth-Generation Human Immunodeficiency Virus Enzyme Immunoassay for Cross-Sectional Incidence Estimation in Clade B Populations SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID RECENT HIV-INFECTIONS; ANTIRETROVIRAL THERAPY; AVIDITY INDEX; TYPE-1; COHORT; ASSAY; SPECIFICITY; LOAD AB Background: Accurate methods for cross-sectional incidence estimation are needed for HIV surveillance and prevention research. We developed an avidity assay based on the fourth-generation Genetic Systems HIV Combo Ag/Ab EIA (Bio-Rad Combo assay) and evaluated its performance. Materials and Methods: The Bio-Rad Combo assay was modified incubating samples with and without 0.025M diethylamine (DEA). The avidity index (AI) was calculated as the ratio of the DEA-treated to untreated result for a specific sample. We analyzed 2,140 samples from 808 individuals from the United States with known duration of HIV infection. The mean duration of recent infection (MDRI) and the false-recent rate (FRR, fraction of samples from individuals known to be infected >2 years misclassified as recent) were calculated for AI cutoffs of 20%-90% for the avidity assay alone and in combination with a viral load assay (VL, limit of detection 400 copies/ml). Factors associated with misclassification of samples collected >= 2 years after infections were also evaluated. Results: The MDRI for the Bio-Rad Combo Avidity assay ranged from 50 days using an AI cutoff of 20% to 276 days using an AI cutoff of 90%; the FRR ranged from 0% to 9%. When samples with a VL <400 copies/ml were classified as nonrecent, the FRRs were reduced approximately twofold and the MDRI estimates were reduced by similar to 20%. An AI cutoff of 50% provided an MDRI of 135 days with an FRR of 2.1%. All samples from elite suppressors had an AI >80%. In adjusted analysis, viral suppression and low CD4 cell count were significantly associated with misclassification among individuals infected >2 years. Conclusions: This modified Bio-Rad Combo Avidity assay may be a useful tool for cross-sectional HIV incidence estimation. Further research is needed to evaluate use of this assay in combination with other assays to accurately estimate population-level HIV incidence. C1 [Kirkpatrick, Allison R.; Patel, Eshan U.; Quinn, Thomas C.; Laeyendecker, Oliver] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, 855 North Wolfe St,Rangos Bldg,Room 538A, Baltimore, MD 21205 USA. [Celum, Connie L.] Univ Washington, Dept Med, Seattle, WA USA. [Moore, Richard D.; Blankson, Joel N.; Quinn, Thomas C.; Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Mehta, Shruti H.; Kirk, Gregory D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Margolick, Joseph B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Laeyendecker, O (reprint author), NIAID, Immunoregulat Lab, Div Intramural Res, NIH, 855 North Wolfe St,Rangos Bldg,Room 538A, Baltimore, MD 21205 USA. EM olaeyen1@jhmi.edu OI Patel, Eshan/0000-0003-2174-5004 FU HIV Prevention Trials Network (HPTN) - National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Office of AIDS Research of the National Institutes of Health (NIH), Department of Health and Human Services (DHHS) [UM1AI068613]; NIAID [R01 AI095068]; Division of Intramural Research, NIAID, NIH FX This work was supported by the HIV Prevention Trials Network (HPTN) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the Office of AIDS Research, of the National Institutes of Health (NIH), Department of Health and Human Services (DHHS) (UM1AI068613), and by R01 AI095068 (NIAID). Additional funding was provided by the Division of Intramural Research, NIAID, NIH. NR 35 TC 1 Z9 1 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD AUG PY 2016 VL 32 IS 8 BP 756 EP 762 DI 10.1089/aid.2015.0198 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DS1ZS UT WOS:000380504800004 PM 26988426 ER PT J AU Hall, KD Chen, KY Guo, J Lam, YY Leibel, RL Mayer, LES Reitman, ML Rosenbaum, M Smith, SR Walsh, BT Ravussin, E AF Hall, Kevin D. Chen, Kong Y. Guo, Juen Lam, Yan Y. Leibel, Rudolph L. Mayer, Laurel E. S. Reitman, Marc L. Rosenbaum, Michael Smith, Steven R. Walsh, B. Timothy Ravussin, Eric TI Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE body composition; energy expenditure; ketogenic diet; insulin; carbohydrate; fat; macronutrients ID HIGH-FAT DIET; RANDOMIZED CONTROLLED-TRIAL; METABOLIC ADAPTATION; CALORIC RESTRICTION; ADIPOSE-TISSUE; HIGH-PROTEIN; WEIGHT-GAIN; CARBOHYDRATE; BALANCE; HUMANS AB Background: The carbohydrate-insulin model of obesity posits that habitual consumption of a high-carbohydrate diet sequesters fat within adipose tissue because of hyperinsulinemia and results in adaptive suppression of energy expenditure (EE). Therefore, isocaloric exchange of dietary carbohydrate for fat is predicted to result in increased EE, increased fat oxidation, and loss of body fat. In contrast, a more conventional view that "a calorie is a calorie" predicts that isocaloric variations in dietary carbohydrate and fat will have no physiologically important effects on EE or body fat. Objective: We investigated whether an isocaloric low-carbohydrate ketogenic diet (KD) is associated with changes in EE, respiratory quotient (RQ), and body composition. Design: Seventeen overweight or obese men were admitted to metabolic wards, where they consumed a high-carbohydrate baseline diet (BD) for 4 wk followed by 4 wk of an isocaloric KD with clamped protein. Subjects spent 2 consecutive days each week residing in metabolic chambers to measure changes in EE (EEchamber), sleeping EE (SEE), and RQ. Body composition changes were measured by dual-energy X-ray absorptiometry. Average EE during the final 2 wk of the BD and KD periods was measured by doubly labeled water (EEDLW). Results: Subjects lost weight and body fat throughout the study corresponding to an overall negative energy balance of similar to 300 kcal/d. Compared with BD, the KD coincided with increased EEchamber (57 +/- 13 kcal/d, P = 0.0004) and SEE (89 +/- 14 kcal/d, P < 0.0001) and decreased RQ (-0.111 +/- 0.003, P < 0.0001). EEDLW increased by 151 +/- 63 kcal/d (P = 0.03). Body fat loss slowed during the KD and coincided with increased protein utilization and loss of fat-free mass. Conclusion: The isocaloric KD was not accompanied by increased body fat loss but was associated with relatively small increases in EE that were near the limits of detection with the use of state-of-the-art technology. C1 [Hall, Kevin D.; Chen, Kong Y.; Guo, Juen; Reitman, Marc L.] NIDDK, Bethesda, MD 20892 USA. [Lam, Yan Y.; Ravussin, Eric] Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. [Leibel, Rudolph L.; Mayer, Laurel E. S.; Rosenbaum, Michael; Walsh, B. Timothy] Columbia Univ, New York, NY USA. [Smith, Steven R.] Translat Res Inst Metab & Diabet, Orlando, FL USA. RP Hall, KD (reprint author), NIDDK, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov OI Chen, Kong/0000-0002-0306-1904; Reitman, Marc/0000-0002-0426-9475 FU Nutrition Sciences Initiative; Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases; NIH [UL1 TR00040]; Nutrition Obesity Research Center Grant [P30DK072476] FX Supported by the Nutrition Sciences Initiative. This work was also supported in part by the Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (KDH, KYC, and MLR), NIH grant UL1 TR00040 (Columbia Clinical and Translational Science Award; MR and RL), and Nutrition Obesity Research Center Grant P30DK072476 (ER). NR 46 TC 10 Z9 10 U1 23 U2 35 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG 1 PY 2016 VL 104 IS 2 BP 324 EP 333 DI 10.3945/ajcn.116.133561 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU0CZ UT WOS:000381870200012 PM 27385608 ER PT J AU Schleicher, RL Sternberg, MR Lacher, DA Sempos, CT Looker, AC Durazo-Arvizu, RA Yetley, EA Chaudhary-Webb, M Maw, KL Pfeiffer, CM Johnson, CL AF Schleicher, Rosemary L. Sternberg, Maya R. Lacher, David A. Sempos, Christopher T. Looker, Anne C. Durazo-Arvizu, Ramon A. Yetley, Elizabeth A. Chaudhary-Webb, Madhulika Maw, Khin L. Pfeiffer, Christine M. Johnson, Clifford L. TI The vitamin D status of the US population from 1988 to 2010 using standardized serum concentrations of 25-hydroxyvitamin D shows recent modest increases SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE standardization; survey; vitamin D; trend; NHANES; supplements ID TANDEM MASS-SPECTROMETRY; D DEFICIENCY; CLINICAL-PRACTICE; HYPOVITAMINOSIS-D; HEALTH; PREVALENCE; TRENDS; ADULTS; PREVENTION; OBESITY AB Background: Temporal trends in the US population's vitamin D status have been uncertain because of nonstandardized serum 25-hydroxyvitamin D [25(OH)D] measurements. Objective: To accurately assess vitamin D status trends among those aged >= 12 y, we used data from the cross-sectional NHANESs. Design: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measuring 25(OH)D (sum of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D-3), calibrated to standard reference materials, was used to predict LC-MS/MS-equivalent concentrations from radioimmunoassay data (1988-2006 surveys; n = 38,700) and to measure LC-MS/MS concentrations (2007-2010 surveys; n = 12,446). Weighted arithmetic means and the prevalence of 25(OH)D above or below cutoff concentrations were calculated to evaluate long-term trends. Results: Overall, mean predicted 25(OH)D showed no time trend from 1988 to 2006, but during 2007-2010 the mean measured 25(OH)D was 5-6 nmol/L higher. Those groups who showed the largest 25(OH)D increases (7-11 nmol/L) were older, female, non-Hispanic white, and vitamin D supplement users. During 19882010, the proportions of persons with 25(OH)D,40 nmol/L were 14-18% (overall), 46-60% (non-Hispanic blacks), 21-28% (Mexican Americans), and 6-10% (non-Hispanic whites). Conclusions: An accurate method for measuring 25(OH)D showed stable mean concentrations in the US population (1988-2006) and recent modest increases (2007-2010). Although it is unclear to what extent supplement usage compared with different laboratory methods explain the increases in 25(OH)D, the use of higher vitamin D supplement dosages coincided with the increase. Marked race-ethnic differences in 25(OH)D concentrations were apparent. These data provide the first standardized information about temporal trends in the vitamin D status of the US population. C1 [Schleicher, Rosemary L.; Sternberg, Maya R.; Chaudhary-Webb, Madhulika; Maw, Khin L.; Pfeiffer, Christine M.] CDC, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Lacher, David A.; Looker, Anne C.; Johnson, Clifford L.] CDC, Natl Ctr Hlth Stat, Atlanta, GA 30333 USA. [Sempos, Christopher T.; Durazo-Arvizu, Ramon A.; Yetley, Elizabeth A.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. RP Pfeiffer, CM (reprint author), CDC, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. EM cfp8@cdc.gov FU CDC; NIH/Office of Dietary Supplements FX Data collection and laboratory analyses of vitamin D were funded by the CDC and the NIH/Office of Dietary Supplements. NR 55 TC 6 Z9 6 U1 5 U2 6 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG 1 PY 2016 VL 104 IS 2 BP 454 EP 461 DI 10.3945/ajcn.115.127985 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU0CZ UT WOS:000381870200026 PM 27385610 ER PT J AU Terry, AL Cogswell, ME Wang, CY Chen, TC Loria, CM Wright, JD Zhang, XL Lacher, DA Merritt, RK Bowman, BA AF Terry, Ana L. Cogswell, Mary E. Wang, Chia-Yih Chen, Te-Ching Loria, Catherine M. Wright, Jacqueline D. Zhang, Xinli Lacher, David A. Merritt, Robert K. Bowman, Barbara A. TI Feasibility of collecting 24-h urine to monitor sodium intake in the National Health and Nutrition Examination Survey SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE 24-hour urine; sodium excretion; NHANES; biomarker; hypertension; sodium intake ID AMINO BENZOIC-ACID; BLOOD-PRESSURE; UNITED-STATES; SALT INTAKE; COMPLETENESS; POTASSIUM; BIOMARKERS; EXCRETION AB Background: Twenty-four-hour urine sodium excretion is recommended for monitoring population sodium intake. Because of concerns about participation and completion, sodium excretion has not been collected previously in US nationally representative surveys. Objective: We assessed the feasibility of implementing 24-h urine collections as part of a nationally representative survey. Design: We selected a random half sample of nonpregnant US adults aged 20-69 y in 3 geographic locations of the 2013 NHANES. Participants received explicit instructions, started and ended the urine collection in a urine study mobile examination center, and answered questions about their collection. Among those with a complete 24-h urine collection, a random one-half were asked to collect a second 24-h urine sample. Sodium, potassium, chloride, and creatinine excretion were analyzed. Results: The final NHANES examination response rate for adults aged 20-69 y in these 3 study locations was 71%. Of those examined (n = 476), 282 (59%) were randomly selected to participate in the 24-h urine collection. Of these, 212 persons [75% of those selected for 24-h urine collection; 53% (equal to 71% x 75% of those selected for the NHANES)] collected a complete initial 24-h specimen and 92 persons (85% of 108 selected) collected a second complete 24-h urine sample. Moremen than women completed an initial collection (P = 0.04); otherwise, completion did not vary by sociodemographic characteristics, body mass index, education, or employment status for either collection. Mean 24-h urine volume and sodium excretion were 1964 +/- 1228 mL and 3657 +/- 2003 mg, respectively, for the first 24-h urine sample, and 2048 +/- 1288 mL and 3773 +/- 1891 mg, respectively, for the second collection. Conclusion: Given the 53% final component response rate and 75% completion rate, 24-h urine collections were deemed feasible and implemented in the NHANES 2014 on a subsample of adults aged 20-69 y to assess population sodium intake. C1 [Terry, Ana L.; Wang, Chia-Yih; Chen, Te-Ching; Zhang, Xinli; Lacher, David A.] CDC, Div Hlth & Nutr Examinat Surveys, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Cogswell, Mary E.; Merritt, Robert K.; Bowman, Barbara A.] CDC, Div Heart Dis & Stroke Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Loria, Catherine M.; Wright, Jacqueline D.] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Zhang, Xinli] Harris IT Serv Corp, Herndon, VA USA. RP Terry, AL (reprint author), CDC, Div Hlth & Nutr Examinat Surveys, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. EM auc5@cdc.gov FU CDC and NIH FX The data collection and laboratory analyses were funded by the CDC and the NIH. NR 27 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG 1 PY 2016 VL 104 IS 2 BP 480 EP 488 DI 10.3945/ajcn.115.121954 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU0CZ UT WOS:000381870200029 PM 27413136 ER PT J AU Fox, AR Gordon, LK Heckenlively, JR Davis, JL Goldstein, DA Lowder, CY Nussenblatt, RB Butler, NJ Dalal, M Jayasundera, T Smith, WM Lee, RW Adamus, G Chan, CC Hooks, JJ Morgans, CW Detrick, B Sen, HN AF Fox, Austin R. Gordon, Lynn K. Heckenlively, John R. Davis, Janet L. Goldstein, Debra A. Lowder, Careen Y. Nussenblatt, Robert B. Butler, Nicholas J. Dalal, Monica Jayasundera, Thiran Smith, Wendy M. Lee, Richard W. Adamus, Grazyna Chan, Chi-Chao Hooks, John J. Morgans, Catherine W. Detrick, Barbara Sen, H. Nida TI Consensus on the Diagnosis and Management of Nonparaneoplastic Autoimmune Retinopathy Using a Modified Delphi Approach SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID ANTIRETINAL ANTIBODY DETECTION; STANDARDIZATION; NEED AB PURPOSE: To develop diagnostic criteria for nonparaneoplastic autoimmune retinopathy (AIR) through expert panel consensus and to examine treatment patterns among clinical experts. DESIGN: Modified Delphi process. METHODS: A survey of uveitis specialists in the American Uveitis Society, a face-to-face meeting (AIR Workshop) held at the National Eye Institute, and 2 iterations of expert panel surveys were used in a modified Delphi process. The expert panel consisted of 17 experts, including uveitis specialists and researchers with expertise in antiretinal antibody detection. Supermajority consensus was used and defined as 75% of experts in agreement. RESULTS: There was unanimous agreement among experts regarding the categorization of autoimmune retinopathies as nonparaneoplastic and paraneoplastic, including cancer-associated retinopathy and melanoma-associated retinopathy. Diagnostic criteria and tests essential to the diagnosis of nonparaneoplastic AIR and multiple supportive criteria reached consensus. For treatment, experts agreed that corticosteroids and conventional immunosuppressives should be used (prescribed) as first- or second-line treatments, though a consensus agreed that biologics and intravenous immunoglobulin were considered appropriate in the treatment of nonparaneoplastic AIR patients regardless of the stage of disease. Experts agreed that more evidence is needed to treat nonparaneoplastic AIR patients with long-term immunomodulatory therapy and that there is enough equipoise to justify randomized, placebo-controlled trials to determine if nonparaneoplastic AIR patients should be treated with long-term immunomodulatory therapy. Regarding antiretinal antibody detection, consensus agreed that a standardized assay system is needed to detect serum antiretinal antibodies. Consensus agreed that an ideal assay should have a 2-tier design and that Western blot and immunohistochemistry should be the methods used to identify antiretinal antibodies. CONCLUSIONS: Consensus was achieved using a modified Delphi process to develop diagnostic criteria for nonparaneoplastic AIR. There is enough equipoise to justify randomized, placebo-controlled trials to determine whether patients with nonparaneoplastic AIR should be treated with long-term immunomodulatory therapy. Efforts to develop a standardized 2-tier assay system for the detection of antiretinal antibodies have been initiated as a result of this study. Published by Elsevier Inc. C1 [Fox, Austin R.; Nussenblatt, Robert B.; Chan, Chi-Chao; Hooks, John J.; Sen, H. Nida] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Gordon, Lynn K.] Univ Calif Los Angeles, David Geffen Sch Med, Stein Eye Inst, Los Angeles, CA 90095 USA. [Heckenlively, John R.; Jayasundera, Thiran] Univ Michigan, Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. [Davis, Janet L.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Goldstein, Debra A.] Northwestern Univ, Dept Ophthalmol, Feinberg Sch Med, Chicago, IL 60611 USA. [Lowder, Careen Y.] Cleveland Clin, Cole Eye Inst, Cleveland, OH 44106 USA. [Butler, Nicholas J.] Harvard Med Sch, Massachusetts Eye & Ear, Boston, MA USA. [Butler, Nicholas J.] Vet Affairs Boston Healthcare Syst, Jamaica Plain, MA USA. [Dalal, Monica] George Washington Univ, Dept Ophthalmol, Washington, DC USA. [Lee, Richard W.] Univ Bristol, Bristol Eye Hosp, Bristol, Avon, England. [Adamus, Grazyna] Casey Eye Inst, Ocular Immunol Lab, Astoria, OR USA. [Morgans, Catherine W.] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. [Detrick, Barbara] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Sen, HN (reprint author), 10 Ctr Dr 10D45, Bethesda, MD 20892 USA. EM senh@nei.nih.gov RI Lee, Richard/A-3116-2017 OI Lee, Richard/0000-0002-9480-6843 FU NEI INTRAMURAL RESEARCH PROGRAM, THE NIH OFFICE OF RARE DISeases Research (ORDR); NIH Medical Research Scholars Program; NIH FX THIS WORK IS SUPPORTED BY THE NEI INTRAMURAL RESEARCH PROGRAM, THE NIH OFFICE OF RARE DISeases Research (ORDR), and the NIH Medical Research Scholars Program. The NIH Medical Research Scholars Program is a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, The Doris Duke Charitable Foundation, The Newport Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. Financial disclosures: Janet L. Davis, Consultant: AbbVie Inc (Chicago, IL); Debra A. Goldstein, Consultant: Bausch & Lomb (Bridgewater, NJ), Xoma (Berkeley, CA), Clearside Biomedical (Alpharetta, GA), Independent Data Monitoring Committee: AbbVie Inc (Chicago, IL); Careen Y. Lowder, Data and safety monitoring committee: Allergan (Dublin, Ireland); Richard W. Lee, Consultant: Roche-Genentech(South San Francisco, CA), EMD Serono (Darmstadt, Germany); Barbara Detrick, Consultant: Siemens Healthcare Diagnostics Inc (Tarrytown, NY), Abbott Laboratories (Chicago, IL). The following authors have no financial disclosures: Austin R. Fox, Lynn K. Gordon, John R. Heckenlively, Robert B. Nussenblatt, Nicholas J. Butler, Monica Dalal, Thiran Jayasundera, Wendy M. Smith, Grazyna Adamus, Chi-Chao Chan, John J. Hooks, Catherine W. Morgans, and H. Nida Sen. All authors attest that they meet the current ICMJE criteria for authorship. NR 15 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD AUG PY 2016 VL 168 BP 183 EP 190 DI 10.1016/j.ajo.2016.05.013 PG 8 WC Ophthalmology SC Ophthalmology GA DT0IG UT WOS:000381166600020 PM 27210277 ER PT J AU Ciencewicki, JM Verhein, KC Gerrish, K Mccaw, ZR Li, JY Bushel, PR Kleeberger, SR AF Ciencewicki, Jonathan M. Verhein, Kirsten C. Gerrish, Kevin Mccaw, Zachary R. Li, Jianying Bushel, Pierre R. Kleeberger, Steven R. TI Effects of mannose-binding lectin on pulmonary gene expression and innate immune inflammatory response to ozone SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE neutrophils; genome-wide transcriptomics; pattern recognition analysis; tumor necrosis factor-alpha; innate immunity ID INDUCED LUNG INFLAMMATION; REPERFUSION INJURY; DENDRITIC CELLS; VIRUS-INFECTION; AIR-POLLUTION; IN-VITRO; RECEPTORS; MICE; SUSCEPTIBILITY; INHIBITION AB Ozone is a common, potent oxidant pollutant in industrialized nations. Ozone exposure causes airway hyperreactivity, lung hyperpermeability, inflammation, and cell damage in humans and laboratory animals, and exposure to ozone has been associated with exacerbation of asthma, altered lung function, and mortality. The mechanisms of ozone-nduced lung injury and differential susceptibility are not fully understood. Ozone-induced lung inflammation is mediated, in part, by the innate immune system. We hypothesized that mannose-binding lectin (MBL), an innate immunity serum protein, contributes to the proin-flammatory events caused by ozone-mediated activation of the innate immune system. Wild-type (Mbl (+/+)) and MBL-deficient (Mbl (-/-)) mice were exposed to ozone (0.3 ppm) for up to 72 h, and bronchoal-veolar lavage fluid was examined for inflammatory markers. Mean numbers of eosinophils and neutrophils and levels of the neutrophil attractants C-X-C motif chemokines 2 [Cxcl2 (major intrinsic protein 2)] and 5 [Cxcl5 (limb expression, LIX)] in the bronchoal-veolar lavage fluid were significantly lower in Mbl (+/+) than Mbl (-/-) mice exposed to ozone. Using genome-wide mRNA microarray analyses, we identified significant differences in transcript response profiles and networks at baseline [e.g., nuclear factor erythroid-related factor 2 (NRF2)-mediated oxidative stress response] and after exposure (e.g., humoral immune response) between Mbl (+/+) and Mbl (-/-) mice. The microarray data were further analyzed to discover several informative differential response patterns and subsequent gene sets, including the antimicrobial response and the inflammatory response. We also used the lists of gene transcripts to search the LINCS L1000CDS(2) data sets to identify agents that are predicted to perturb ozone-induced changes in gene transcripts and inflammation. These novel findings demonstrate that targeted deletion of Mbl caused differential levels of inflammation-related gene sets at baseline and after exposure to ozone and significantly reduced pulmonary inflammation, thus indicating an important innate immunomodulatory role of the gene in this model. C1 [Ciencewicki, Jonathan M.; Verhein, Kirsten C.; Mccaw, Zachary R.; Kleeberger, Steven R.] NIEHS, Immun Inflammat & Dis Lab, 111 TW Alexander Dr,Bldg 101,MD D-201, Res Triangle Pk, NC 27709 USA. [Gerrish, Kevin] NIEHS, Signal Transduct Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Li, Jianying; Bushel, Pierre R.] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. RP Kleeberger, SR (reprint author), NIEHS, Immun Inflammat & Dis Lab, 111 TW Alexander Dr,Bldg 101,MD D-201, Res Triangle Pk, NC 27709 USA. EM kleeber1@niehs.nih.gov FU Intramural Research Program of the National Institute of Environmental Health Sciences; Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences and Department of Health and Human Services. NR 57 TC 0 Z9 0 U1 4 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD AUG 1 PY 2016 VL 311 IS 2 BP L280 EP L291 DI 10.1152/ajplung.00205.2015 PG 12 WC Physiology; Respiratory System SC Physiology; Respiratory System GA DT6XP UT WOS:000381628600009 PM 27106289 ER PT J AU Brown, J AF Brown, Jeremy TI National Institutes of Health Support for Clinical Emergency Care Research, 2011 to 2014 SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID BIG DATA; MEDICINE AB Study objective: I report on the results of a portfolio analysis of National Institutes of Health (NIH) support for clinical emergency care research. Methods: A targeted query was created with data-mining techniques that accessed the NIH database for 2011 to 2014. The search was constructed to have a clinical focus; animal and bench research projects, as well as career development grants, were excluded. The search results were manually reviewed for appropriateness and then analyzed. Results: Six-hundred eighty-eight applications were analyzed. During the study period, the number of new emergency care projects submitted to NIH increased from 62 in 2011 to 153 in 2014. A total of 112 new applications were funded for $100 million, with an overall success rate of 23%. The total amount of support for both new and existing projects during the 4-year study period was $263 million. One third of the funded principal investigators were emergency medicine faculty, and their success rate for R01 funding was twice the NIH average. Conclusion: Emergency care research makes up 0.7% of NIH spending on new research project grants. The success rate is high for emergency medicine principal investigators conducting clinical work. The overall success rate for emergency medicine RO1s is similar to that of other clinical specialties. C1 [Brown, Jeremy] NIGMS, Off Emergency Care Res, NIH, Bethesda, MD 20892 USA. RP Brown, J (reprint author), NIGMS, Off Emergency Care Res, NIH, Bethesda, MD 20892 USA. EM jeremy.brown@nih.gov NR 8 TC 2 Z9 2 U1 4 U2 4 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 AUG PY 2016 VL 68 IS 2 BP 164 EP 171 DI 10.1016/j.annemergmed.2016.01.039 PG 8 WC Emergency Medicine SC Emergency Medicine GA DT0II UT WOS:000381166800006 PM 26973176 ER PT J AU Anantpadma, M Kouznetsova, J Wang, H Huang, RL Kolokoltsov, A Guha, R Lindstrom, AR Shtanko, O Simeonov, A Maloney, DJ Maury, W LaCount, DJ Jadhav, A Davey, RA AF Anantpadma, Manu Kouznetsova, Jennifer Wang, Hang Huang, Ruili Kolokoltsov, Andrey Guha, Rajarshi Lindstrom, Aaron R. Shtanko, Olena Simeonov, Anton Maloney, David J. Maury, Wendy LaCount, Douglas J. Jadhav, Ajit Davey, Robert A. TI Large-Scale Screening and Identification of Novel Ebola Virus and Marburg Virus Entry Inhibitors SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID NIEMANN-PICK C1; HEMORRHAGIC-FEVER; NONHUMAN-PRIMATES; IN-VITRO; GLYCOPROTEIN; INFECTION; CELLS; MACROPINOCYTOSIS; PROTEIN; FILOVIRIDAE AB Filoviruses are highly infectious, and no FDA-approved drug therapy for filovirus infection is available. Most work to find a treatment has involved only a few strains of Ebola virus and testing of relatively small drug libraries or compounds that have shown efficacy against other virus types. Here we report the findings of a high-throughput screening of 319,855 small molecules from the Molecular Libraries Small Molecule Repository library for their activities against Marburg virus and Ebola virus. Nine of the most potent, novel compounds that blocked infection by both viruses were analyzed in detail for their mechanisms of action. The compounds inhibited known key steps in the Ebola virus infection mechanism by blocking either cell surface attachment, macropinocytosis-mediated uptake, or endosomal trafficking. To date, very few specific inhibitors of macropinocytosis have been reported. The 2 novel macropinocytosis inhibitors are more potent inhibitors of Ebola virus infection and less toxic than ethylisopropylamiloride, one commonly accepted macropinocytosis inhibitor. Each compound blocked infection of primary human macrophages, indicating their potential to be developed as new antifiloviral therapies. C1 [Anantpadma, Manu; Shtanko, Olena; Davey, Robert A.] Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX 78227 USA. [Kouznetsova, Jennifer; Wang, Hang; Huang, Ruili; Guha, Rajarshi; Simeonov, Anton; Maloney, David J.; Jadhav, Ajit] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Lindstrom, Aaron R.; LaCount, Douglas J.] Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN USA. [Maury, Wendy] Univ Iowa, Dept Microbiol, Iowa City, IA USA. [Kolokoltsov, Andrey] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX USA. [Kolokoltsov, Andrey] Pharmeco LLC, Moscow, Russia. RP Davey, RA (reprint author), Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX 78227 USA. EM rdavey@txbiomed.org FU Cowles Fellowship Program at Texas Biomedical Research Institute; Southwest Foundation Forum Grant; Ewing Halsell Foundation; HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [5R21AI115082-02, 5R03MH086850-02, AI077519]; DOD \ Defense Threat Reduction Agency (DTRA) [HDTRA1-12-1-0002] FX This work, including the efforts of Manu Anantpadma, was funded by Cowles Fellowship Program at Texas Biomedical Research Institute. This work, including the efforts of Manu Anantpadma, was funded by Southwest Foundation Forum Grant. This work, including the efforts of Robert A. Davey, was funded by Ewing Halsell Foundation. This work, including the efforts of Robert A. Davey, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (5R21AI115082-02 and 5R03MH086850-02). This work, including the efforts of Wendy Maury, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI077519). This work, including the efforts of Robert A. Davey, was funded by DOD vertical bar Defense Threat Reduction Agency (DTRA) (HDTRA1-12-1-0002). NR 54 TC 2 Z9 2 U1 6 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2016 VL 60 IS 8 BP 4471 EP 4481 DI 10.1128/AAC.00543-16 PG 11 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DS5AJ UT WOS:000380792600005 PM 27161622 ER PT J AU Hardiman, CA Weingarten, RA Conlan, S Khil, P Dekker, JP Mathers, AJ Sheppard, AE Segre, JA Frank, KM AF Hardiman, C. A. Weingarten, R. A. Conlan, S. Khil, P. Dekker, J. P. Mathers, A. J. Sheppard, A. E. Segre, J. A. Frank, K. M. TI Horizontal Transfer of Carbapenemase-Encoding Plasmids and Comparison with Hospital Epidemiology Data SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID SEQUENCE TYPE 258; KLEBSIELLA-PNEUMONIAE; ESCHERICHIA-COLI; RESISTANT ENTEROBACTERIACEAE; MOLECULAR EPIDEMIOLOGY; BETA-LACTAMASE; NEW-JERSEY; GENE; DISSEMINATION; CONJUGATION AB Carbapenemase-producing organisms have spread worldwide, and infections with these bacteria cause significant morbidity. Horizontal transfer of plasmids carrying genes that encode carbapenemases plays an important role in the spread of multidrug-resistant Gram-negative bacteria. Here we investigate parameters regulating conjugation using an Escherichia coli laboratory strain that lacks plasmids or restriction enzyme modification systems as a recipient and also using patient isolates as donors and recipients. Because conjugation is tightly regulated, we performed a systematic analysis of the transfer of Klebsiella pneumoniae carbapenemase (bla(KPC))encoding plasmids into multiple strains under different environmental conditions to investigate critical variables. We used four bla(KPC)-carrying plasmids isolated from patient strains obtained from two hospitals: pKpQIL and pKPC-47e from the National Institutes of Health, and pKPC_UVA01 and pKPC_UVA02 from the University of Virginia. Plasmid transfer frequency differed substantially between different donor and recipient pairs, and the frequency was influenced by plasmid content, temperature, and substrate, in addition to donor and recipient strain. pKPC-47e was attenuated in conjugation efficiency across all conditions tested. Despite its presence in multiple clinical species, pKPC_UVA01 had lower conjugation efficiencies than pKpQIL into recipient strains. The conjugation frequency of these plasmids into K. pneumoniae and E. coli patient isolates ranged widely without a clear correlation with clinical epidemiological data. Our results highlight the importance of each variable examined in these controlled experiments. The in vitro models did not reliably predict plasmid mobilization observed in a patient population, indicating that further studies are needed to understand the most important variables affecting horizontal transfer in vivo. C1 [Hardiman, C. A.; Weingarten, R. A.; Khil, P.; Dekker, J. P.; Frank, K. M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Conlan, S.; Segre, J. A.] NHGRI, Bethesda, MD 20892 USA. [Mathers, A. J.] Univ Virginia Hlth Syst, Charlottesville, VA USA. [Sheppard, A. E.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Med, Modernizing Med Microbiol Consortium, Oxford, England. RP Frank, KM (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM karen.frank@nih.gov FU Biotechnology and Biological Sciences Research Council (BBSRC); National Institutes of Health Director's Challenge Innovation Award; NIHR Oxford Biomedical Research Centre; Wellcome Trust [087646/Z/08/Z]; HHS \ NIH \ National Human Genome Research Institute (NHGRI); Medical Research Council (MRC); DH \ National Institute for Health Research (NIHR) [G0800778]; HHS \ NIH \ NIH Clinical Center (Clinical Center) FX This work, including the efforts of A. J. Mathers and A. E. Sheppard, was funded by Biotechnology and Biological Sciences Research Council (BBSRC). This work, including the efforts of C. A. Hardiman, R. A. Weingarten, S. Conlan, J. A. Segre, and K. M. Frank, was funded by National Institutes of Health Director's Challenge Innovation Award. This work, including the efforts of A. J. Mathers and A. E. Sheppard, was funded by NIHR Oxford Biomedical Research Centre. This work, including the efforts of A. J. Mathers and A. E. Sheppard, was funded by Wellcome Trust (087646/Z/08/Z). This work, including the efforts of S. Conlan and J. A. Segre, was funded by HHS vertical bar NIH vertical bar National Human Genome Research Institute (NHGRI). This work, including the efforts of A. J. Mathers and A. E. Sheppard, was funded by Medical Research Council (MRC). This work, including the efforts of A. J. Mathers and A. E. Sheppard, was funded by DH vertical bar National Institute for Health Research (NIHR) (G0800778). This work, including the efforts of C. A. Hardiman, R. A. Weingarten, P. Khil, J. P. Dekker, and K. M. Frank, was funded by HHS vertical bar NIH vertical bar NIH Clinical Center (Clinical Center). NR 56 TC 2 Z9 2 U1 6 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2016 VL 60 IS 8 BP 4910 EP 4919 DI 10.1128/AAC.00014-16 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DS5AJ UT WOS:000380792600056 PM 27270289 ER PT J AU Afonso, CL Amarasinghe, GK Banyai, K Bao, YM Basler, CF Bavari, S Bejerman, N Blasdell, KR Briand, FX Briese, T Bukreyev, A Calisher, CH Chandran, K Cheng, JS Clawson, AN Collins, PL Dietzgen, RG Dolnik, O Domier, LL Durrwald, R Dye, JM Easton, AJ Ebihara, H Farkas, SL Freitas-Astua, J Formenty, P Fouchier, RAM Fu, YP Ghedin, E Goodin, MM Hewson, R Horie, M Hyndman, TH Jiang, DH Kitajima, EW Kobinger, GP Kondo, H Kurath, G Lamb, RA Lenardon, S Leroy, EM Li, CX Lin, XD Liu, LJ Longdon, B Marton, S Maisner, A Muhlberger, E Netesov, SV Nowotny, N Patterson, JL Payne, SL Paweska, JT Randall, RE Rima, BK Rota, P Rubbenstroth, D Schwemmle, M Shi, M Smither, SJ Stenglein, MD Stone, DM Takada, A Terregino, C Tesh, RB Tian, JH Tomonaga, K Tordo, N Towner, JS Vasilakis, N Verbeek, M Volchkov, VE Wahl-Jensen, V Walsh, JA Walker, PJ Wang, D Wang, LF Wetzel, T Whitfield, AE Xie, JT Yuen, KY Zhang, YZ Kuhn, JH AF Afonso, Claudio L. Amarasinghe, Gaya K. Banyai, Krisztian Bao, Yiming Basler, Christopher F. Bavari, Sina Bejerman, Nicolas Blasdell, Kim R. Briand, Francois-Xavier Briese, Thomas Bukreyev, Alexander Calisher, Charles H. Chandran, Kartik Cheng, Jiasen Clawson, Anna N. Collins, Peter L. Dietzgen, Ralf G. Dolnik, Olga Domier, Leslie L. Duerrwald, Ralf Dye, John M. Easton, Andrew J. Ebihara, Hideki Farkas, Szilvia L. Freitas-Astua, Juliana Formenty, Pierre Fouchier, Ron A. M. Fu, Yanping Ghedin, Elodie Goodin, Michael M. Hewson, Roger Horie, Masayuki Hyndman, Timothy H. Jiang, Daohong Kitajima, Elliot W. Kobinger, Gary P. Kondo, Hideki Kurath, Gael Lamb, Robert A. Lenardon, Sergio Leroy, Eric M. Li, Ci-Xiu Lin, Xian-Dan Liu, Lijiang Longdon, Ben Marton, Szilvia Maisner, Andrea Muhlberger, Elke Netesov, Sergey V. Nowotny, Norbert Patterson, Jean L. Payne, Susan L. Paweska, Janusz T. Randall, Rick E. Rima, Bertus K. Rota, Paul Rubbenstroth, Dennis Schwemmle, Martin Shi, Mang Smither, Sophie J. Stenglein, Mark D. Stone, David M. Takada, Ayato Terregino, Calogero Tesh, Robert B. Tian, Jun-Hua Tomonaga, Keizo Tordo, Noel Towner, Jonathan S. Vasilakis, Nikos Verbeek, Martin Volchkov, Viktor E. Wahl-Jensen, Victoria Walsh, John A. Walker, Peter J. Wang, David Wang, Lin-Fa Wetzel, Thierry Whitfield, Anna E. Xie, Jiatao Yuen, Kwok-Yung Zhang, Yong-Zhen Kuhn, Jens H. TI Taxonomy of the order Mononegavirales: update 2016 SO ARCHIVES OF VIROLOGY LA English DT Article ID COMPLETE GENOME SEQUENCE; PARROT BORNAVIRUS 5; AVIAN PARAMYXOVIRUS; INTERNATIONAL COMMITTEE; FELINE MORBILLIVIRUS; RATIFICATION VOTE; DOMESTIC CATS; VIRUS; IDENTIFICATION; PROPOSALS AB In 2016, the order Mononegavirales was emended through the addition of two new families (Mymonaviridae and Sunviridae), the elevation of the paramyxoviral subfamily Pneumovirinae to family status (Pneumoviridae), the addition of five free-floating genera (Anphevirus, Arlivirus, Chengtivirus, Crustavirus, and Wastrivirus), and several other changes at the genus and species levels. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV). C1 [Afonso, Claudio L.] ARS, Southeast Poultry Res Lab, USDA, Athens, GA 30602 USA. [Amarasinghe, Gaya K.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. [Banyai, Krisztian; Farkas, Szilvia L.; Marton, Szilvia] Hungarian Acad Sci, Vet Med Res Inst, Agr Res Ctr, Budapest, Hungary. [Bao, Yiming] NIH, Informat Engn Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Basler, Christopher F.] Georgia State Univ, Ctr Microbial Pathogenesis, Inst Biomed Sci, Atlanta, GA 30303 USA. [Bavari, Sina; Dye, John M.] United States Army Med Res Inst Infect Dis, Frederick, MD USA. [Bejerman, Nicolas; Lenardon, Sergio] Inst Nacl Tecnol Agr, Inst Patol Vegetal, Ctr Invest Agr, Cordoba, Argentina. [Bejerman, Nicolas] Consejo Nacl Invest Cient & Tecn, Buenos Aires, DF, Argentina. [Blasdell, Kim R.; Walker, Peter J.] CSIRO Hlth & Biosecur, Australian Anim Hlth Lab, Geelong, Vic, Australia. [Briand, Francois-Xavier] French Agcy Food Environm & Occupat Hlth & Safety, Avian & Rabbit Virol Immunol & Parasitol Unit, Ploufragan, France. [Briese, Thomas] Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY 10027 USA. [Bukreyev, Alexander; Tesh, Robert B.] Univ Texas Med Branch, Dept Pathol, Galveston Natl Lab, Galveston, TX 77555 USA. [Bukreyev, Alexander; Tesh, Robert B.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston Natl Lab, Galveston, TX 77555 USA. [Calisher, Charles H.] Colorado State Univ, Arthropod Borne & Infect Dis Lab, Coll Vet Med & Biomed Sci, Ft Collins, CO 80523 USA. [Chandran, Kartik] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Cheng, Jiasen; Fu, Yanping; Jiang, Daohong; Liu, Lijiang; Xie, Jiatao] Huazhong Agr Univ, State Key Lab Agr Microbiol, Prov Key Lab Plant Pathol Hubei Prov, Coll Plant Sci & Technol, Wuhan, Peoples R China. [Clawson, Anna N.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, Div Clin Res, NIH, B-8200 Res Plaza, Frederick, MD 21702 USA. [Collins, Peter L.] NIAID, Resp Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 21702 USA. [Dietzgen, Ralf G.] Univ Queensland, Queensland Alliance Agr & Food Innovat, St Lucia, Qld, Australia. [Dolnik, Olga; Maisner, Andrea] Univ Marburg, Inst Virol, Marburg, Germany. [Domier, Leslie L.] Univ Illinois, Dept Crop Sci, Champaign, IL 61820 USA. [Duerrwald, Ralf] IDT Biol, Dessau Rosslau, Germany. [Easton, Andrew J.; Walsh, John A.] Univ Warwick, Sch Life Sci, Coventry, W Midlands, England. [Ebihara, Hideki] NIAID, Rocky Mt Labs, Integrated Res Facil, NIH, Hamilton, MT 59840 USA. [Freitas-Astua, Juliana] Embrapa Cassava & Fruits, Cruz Das Almas, BA, Brazil. [Formenty, Pierre] WHO, Geneva, Switzerland. [Fouchier, Ron A. M.] Erasmus Univ, Med Ctr, Dept Virosci, Postgrad Sch Mol Med, Rotterdam, Netherlands. [Ghedin, Elodie] NYU, Dept Biol, Ctr Genom & Syst Biol, New York, NY 10003 USA. [Goodin, Michael M.] Univ Kentucky, Plant Pathol, Lexington, KY 40506 USA. [Hewson, Roger] Publ Hlth England, Salisbury, Wilts, England. [Horie, Masayuki] Kagoshima Univ, Joint Fac Vet Med, Transboundary Anim Dis Res Ctr, Kagoshima, Japan. [Hyndman, Timothy H.] Murdoch Univ, Sch Vet & Life Sci, Murdoch, WA, Australia. [Kitajima, Elliot W.] Univ Sao Paulo, Nucleo Apoio Pesquisa Microscopia Eletr Aplicada, Escola Super Agr Luiz de Queiroz, Sao Paulo, Brazil. [Kobinger, Gary P.] Publ Hlth Agcy Canada, Special Pathogens Program, Natl Microbiol Lab, Winnipeg, MB, Canada. [Kondo, Hideki] Okayama Univ, Inst Plant Sci & Resources, Kurashiki, Okayama, Japan. [Kurath, Gael] US Geol Survey, Western Fisheries Res Ctr, Seattle, WA 98115 USA. [Lamb, Robert A.] Northwestern Univ, Dept Mol Biosci, Evanston, IL 60208 USA. [Lamb, Robert A.] Northwestern Univ, Howard Hughes Med Inst, Evanston, IL 60208 USA. [Leroy, Eric M.] Ctr Int Rech Med Franceville, Inst Rech Dev, Franceville, Gabon. [Shi, Mang; Zhang, Yong-Zhen] Chinese Ctr Dis Control & Prevent, State Key Lab Infect Dis Prevent & Control, Natl Inst Communicable Dis Control & Prevent, Beijing, Peoples R China. [Li, Ci-Xiu] Collaborat Innovat Ctr Diag & Treatment Infect Di, Hangzhou, Zhejiang, Peoples R China. [Lin, Xian-Dan] Wenzhou Ctr Dis Control & Prevent, Wenzhou, Peoples R China. [Longdon, Ben] Univ Cambridge, Dept Genet, Cambridge, England. [Muhlberger, Elke] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Muhlberger, Elke] Boston Univ, Sch Med, Natl Emerging Infect Dis Lab, Boston, MA 02118 USA. [Netesov, Sergey V.] Novosibirsk State Univ, Novosibirsk, Novosibirsk Obl, Russia. [Nowotny, Norbert] Univ Vet Med, Inst Virol, Vienna, Austria. [Nowotny, Norbert] Mohammed Bin Rashid Univ Med & Hlth Sci, Dept Basic Med Sci, Coll Med, Dubai, U Arab Emirates. [Patterson, Jean L.] Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX 78227 USA. [Payne, Susan L.] Texas A&M Univ, Dept Vet Pathobiol, Coll Vet Med & Biomed Sci, College Stn, TX 77843 USA. [Paweska, Janusz T.] Natl Inst Communicable Dis, Ctr Emerging & Zoonot Dis, Natl Hlth Lab Serv, Sandringham Johannesburg, Gauteng, South Africa. [Randall, Rick E.] Univ St Andrews, Biomed Sci Res Complex, St Andrews, Fife, Scotland. [Rima, Bertus K.] Queens Univ Belfast, Ctr Med Expt, Sch Med Dent & Biomed Sci, Belfast, Antrim, North Ireland. [Rota, Paul] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Rubbenstroth, Dennis; Schwemmle, Martin] Univ Freiburg, Inst Virol, Fac Med, Med Ctr, Freiburg, Germany. [Smither, Sophie J.] CBR Div, Dstl, Salisbury, Wilts, England. [Stenglein, Mark D.] Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Stone, David M.] Ctr Environm Fisheries & Aquaculture Sci, Weymouth, Dorset, England. [Takada, Ayato] Hokkaido Univ, Res Ctr Zoonosis Control, Div Global Epidemiol, Sapporo, Hokkaido, Japan. [Terregino, Calogero] OIE Collaborating Ctr Dis Human Anim Interface, Ist Zooprofilatt Sperimentale Venezie,FAO Referen, Dept Comparat Biomed Sci, Natl OIE Reference Lab Newcastle Dis & Avian Infl, Padua, Italy. [Tian, Jun-Hua] Wuhan Ctr Dis Control & Prevent, Wuhan, Peoples R China. [Tomonaga, Keizo] Kyoto Univ, Inst Virus Res, Kyoto, Japan. [Tordo, Noel] Inst Pasteur, Unite Strategies Antivirales, Paris, France. [Tordo, Noel] Inst Pasteur Guinee, Conakry, Guinea. [Towner, Jonathan S.] Ctr Dis Control & Prevent, Viral Special Pathogens Branch, Div High Consequence Pathogens Pathol, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Vasilakis, Nikos] Univ Texas Med Branch, Ctr Biodefense & Emerging Infect Dis, Dept Pathol, Galveston, TX 77555 USA. [Vasilakis, Nikos] Univ Texas Med Branch, Ctr Trop Dis, Inst Human Infect & Immun, Galveston, TX 77555 USA. [Verbeek, Martin] Wageningen Univ & Res, Wageningen, Netherlands. [Volchkov, Viktor E.] Univ Lyon 1, Mol Basis Viral Pathogen, CIRI, INSERM,U1111,CNRS,UMR5308,Ecole Normal Super Lyon, Lyon, France. [Wahl-Jensen, Victoria] Natl Biodef Anal & Countermeasures Ctr, Frederick, MD 21702 USA. [Wang, David] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Wang, David] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Wang, Lin-Fa] Biosecur Queensland, Dept Agr & Fisheries, Brisbane, Qld, Australia. [Wang, Lin-Fa] Duke NUS Grad Med Sch, Program Emerging Infect Dis, Singapore, Singapore. [Wetzel, Thierry] DLR Rheinpfalz, Inst Plant Protect, Neustadt, Germany. [Whitfield, Anna E.] Kansas State Univ, Plant Pathol, Manhattan, KS 66506 USA. [Yuen, Kwok-Yung] Univ Hong Kong, State Key Lab Emerging Infect Dis, Dept Microbiol, Hong Kong, Hong Kong, Peoples R China. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick IRF Frederick, Div Clin Res, NIH, B-8200 Res Plaza, Frederick, MD 21702 USA. EM kuhnjens@mail.nih.gov RI Netesov, Sergey/A-3751-2013; Fouchier, Ron/A-1911-2014; Verbeek, Martin/D-1445-2017; Stenglein, Mark/E-3541-2017; LEROY, Eric/I-4347-2016; OI Netesov, Sergey/0000-0002-7786-2464; Fouchier, Ron/0000-0001-8095-2869; Verbeek, Martin/0000-0002-8973-3803; Stenglein, Mark/0000-0002-0993-813X; LEROY, Eric/0000-0003-0022-0890; Freitas-Astua, Juliana/0000-0002-0506-6880; Blasdell, Kim/0000-0003-2121-0376; Banyai, Krisztian/0000-0002-6270-1772 FU Battelle Memorial Institute; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I]; DHS ST [HSHQDC-07-C-00020]; National Institutes of Health (NIH) [HHSN272201000040I/HHSN27200004/D04]; NIH, National Library of Medicine FX This work was supported in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016I. A subcontractor to Battelle Memorial Institute who performed this work is: J. H. K., an employee of Tunnell Government Services, Inc. This work was also funded in part under Contract No. HSHQDC-07-C-00020 awarded by DHS S&T for the management and operation of the National Biodefense Analysis and Countermeasures Center (NBACC), a Federally Funded Research and Development Center (V. W.-J.); and National Institutes of Health (NIH) contract HHSN272201000040I/HHSN27200004/D04 (N. V., R. B. T.). Y. B. was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 31 TC 32 Z9 32 U1 7 U2 9 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 AUG PY 2016 VL 161 IS 8 BP 2351 EP 2360 DI 10.1007/s00705-016-2880-1 PG 10 WC Virology SC Virology GA DR8FZ UT WOS:000380135100037 PM 27216929 ER PT J AU Lu, MT Park, J Ghemigian, K Mayrhofer, T Puchner, SB Liu, T Fleg, JL Udelson, JE Truong, QA Ferencik, M Hoffmann, U AF Lu, Michael T. Park, Jakob Ghemigian, Khristine Mayrhofer, Thomas Puchner, Stefan B. Liu, Ting Fleg, Jerome L. Udelson, James E. Truong, Quynh A. Ferencik, Maros Hoffmann, Udo TI Epicardial and paracardial adipose tissue volume and attenuation - Association with high-risk coronary plaque on computed tomographic angiography in the ROMICAT II trial SO ATHEROSCLEROSIS LA English DT Article DE Coronary CT angiography; High-risk coronary plaque; Coronary atherosclerosis; Epicardial adipose tissue; Paracardial adipose tissue ID ACUTE CHEST-PAIN; VISCERAL ABDOMINAL FAT; NAPKIN-RING SIGN; PERICARDIAL FAT; CT ANGIOGRAPHY; CARDIOVASCULAR-DISEASE; INTRATHORACIC FAT; ARTERY-DISEASE; INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC LESIONS AB Background and aims: To determine whether epicardial (EAT) and paracardial adipose tissue (PAT) volume and attenuation are associated with high-risk coronary plaque features. Methods: In subjects with suspected acute coronary syndrome (ACS) enrolled in the ROMICAT II trial, EAT and PAT volumes indexed to body surface area (BSA) and attenuation were measured on non-contrast coronary artery calcium score (CACS) CT. High-risk plaque features (napkin-ring sign, positive remodeling, low density plaque, spotty calcium) and stenosis were assessed on coronary CT angiography (CTA). The association of EAT and PAT volume and attenuation with high-risk plaque and whether this was independent of clinical risk assessment, CACS and significant coronary artery disease (CAD) was determined. Results: Of 467 (mean 54 +/- 8 yrs, 53% male) with CACS and CTA, 167 (36%) had high-risk plaque features. Those with high-risk plaque had significantly higher indexed EAT (median 59 (Q1-Q3: 45-75) cc/m(2) vs. 49 (35-65) cc/m(2), p < 0.001) and PAT volume (median: 51 (36-73) cc/m(2) vs. 33 (22-52) cc/m(2), p < 0.001). Higher indexed EAT volume was associated with high-risk plaque [univariate OR 1.02 (95%-CI: 1.01-1.03) per cc/m(2) of EAT, p < 0.001], which remained significant [univariate OR 1.04 (95%-CI: 1.00 -1.08) per cc/m(2) of EAT, p = 0.040] after adjustment for risk factors, CACS, and stenosis >= 50%. Higher indexed PAT volume was associated with high-risk plaque in univariate analysis [OR 1.02 (1.01-1.03) per cc/m(2) of PAT, p < 0.001], though this was not significant in multivariate analysis. At a threshold of > 62.3 cc/m(2), EAT volume was associated with high-risk plaque [univariate OR 2.50 (95%-CI: 1.69-3.72), p < 0.001)], which remained significant [OR 1.83 (95%-CI: 1.10-3.05), p = 0.020] after adjustment. Subjects with high-risk plaque had lower mean attenuation EAT (-88.1 vs. -86.9 HU, p = 0.008) and PAT (-106 vs. -103 HU, p < 0.001), though this was not significant in multivariable analysis. Conclusions: Greater volumes of EAT are associated with high-risk plaque independent of risk factors, CACS and obstructive CAD. This observation supports possible local influence of EAT on development of high-risk coronary plaque. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Lu, Michael T.; Park, Jakob; Ghemigian, Khristine; Mayrhofer, Thomas; Ferencik, Maros; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Lu, Michael T.; Park, Jakob; Ghemigian, Khristine; Mayrhofer, Thomas; Ferencik, Maros; Hoffmann, Udo] Harvard Med Sch, Boston, MA USA. [Park, Jakob] Heidelberg Univ, Heidelberg, Germany. [Mayrhofer, Thomas] Stralsund Univ Appl Sci, Sch Business Studies, Stralsund, Germany. [Puchner, Stefan B.] Univ Hosp Vienna, Div Cardiovasc & Intervent Radiol, Vienna, Austria. [Liu, Ting] China Med Univ, Affiliated Hosp 1, Shenyang, Peoples R China. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA USA. [Truong, Quynh A.] Weill Cornell Med Coll, New York, NY USA. [Ferencik, Maros] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Lu, MT (reprint author), Div Cardiovasc Imaging, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM mlu@mgh.harvard.edu FU American Roentgen Ray Society FX The authors acknowledge NIH 5T32HL076136, the MGH Executive Committee on Research and the American Roentgen Ray Society Scholarship (MTL), the German Cardiac Society and German National Academic Foundation (JP), the American Heart Association 13FTF16450001 (MF), Siemens Healthcare, NIH/NHLBI 5K24HL113128 and 5U01HL092040-04 (UH). NR 52 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2016 VL 251 BP 47 EP 54 DI 10.1016/j.atherosclerosis.2016.05.033 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DT1SJ UT WOS:000381262100008 PM 27266821 ER PT J AU Aberra, TM Joshi, AA Lerman, JB Rodante, JA Dahiya, AK Teague, HL Ng, Q Silverman, JI Sorokin, AV Salahuddin, T Lockshin, BN Ahlman, MA Playford, MP Chen, MY Gelfand, JM Mehta, NN AF Aberra, Tsion M. Joshi, Aditya A. Lerman, Joseph B. Rodante, Justin A. Dahiya, Asha K. Teague, Heather L. Ng, Qimin Silverman, Joanna I. Sorokin, Alexander V. Salahuddin, Taufiq Lockshin, Benjamin N. Ahlman, Mark A. Playford, Martin P. Chen, Marcus Y. Gelfand, Joel M. Mehta, Nehal N. TI Self-reported depression in psoriasis is associated with subclinical vascular diseases SO ATHEROSCLEROSIS LA English DT Article DE Psoriasis; Subclinical cardiovascular disease; Depression; Anxiety; Inflammation ID CORONARY-ARTERY-DISEASE; MYOCARDIAL-INFARCTION; HEART-DISEASE; FDG PET/CT; RISK; SYMPTOMS; COHORT; ATHEROSCLEROSIS; INFLAMMATION; METAANALYSIS AB Background and aims: Psoriasis is a chronic inflammatory disorder associated with vascular inflammation, measured by 18-fluorodeoxyglucose positron emission tomography/computed tomography (18-FDG PET/CT), and an increased risk of myocardial infarction. Patients with psoriasis are also more likely to suffer from comorbid depression. Whether depression accelerates the development of subclinical atherosclerosis in psoriasis is unknown. Methods: Patients were selected from within a larger psoriasis cohort. Those who reported a history of depression (N = 36) on survey were matched by age and gender to patients who reported no history of psychiatric illness (N = 36). Target-to-background ratio from FDG PET/CT was used to assess aortic vascular inflammation and coronary CT angiography scans were analyzed to determine coronary plaque burden. Multivariable linear regression was performed to understand the effect of self-reported depression on vascular inflammation and coronary plaque burden after adjustment for Framingham risk (standardized beta reported). Results: In unadjusted analyses, vascular inflammation and coronary plaque burden were significantly increased in patients with self-reported depression as compared to patients with psoriasis alone. After adjustment for Framingham Risk Score, vascular inflammation (beta = 0.26, p = 0.02), total plaque burden (beta = 0.17, p = 0.03), and non-calcified burden (beta = 0.17, p = 0.03) were associated with self-reported depression. Conclusions: Self-reported depression in psoriasis is associated with increased vascular inflammation and coronary plaque burden. Depression may play an important role in promoting subclinical atherosclerosis beyond traditional cardiovascular risk factors. Published by Elsevier Ireland Ltd. C1 [Aberra, Tsion M.; Joshi, Aditya A.; Lerman, Joseph B.; Rodante, Justin A.; Dahiya, Asha K.; Teague, Heather L.; Ng, Qimin; Silverman, Joanna I.; Sorokin, Alexander V.; Salahuddin, Taufiq; Playford, Martin P.; Chen, Marcus Y.; Mehta, Nehal N.] NHLBI, NIH, Bethesda, MD 20892 USA. [Lockshin, Benjamin N.] DermAssociates, Silver Spring, MD USA. [Ahlman, Mark A.] NIH, Mol Biomed Imaging Lab, Bethesda, MD 20892 USA. [Gelfand, Joel M.] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. [Gelfand, Joel M.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Mehta, NN (reprint author), NHLBI, Cardiovasc & Pulm Branch, Clin Res Ctr, 10 Ctr Dr,Room 5-5140, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov FU National Heart, Lung and Blood Institute (NHLBI) [HL006193- 02]; National Psoriasis Foundation; NIH; [R01-HL111293]; [K24 AR064310] FX This study was supported by the National Heart, Lung and Blood Institute (NHLBI) Intramural Research Program (HL006193- 02), R01-HL111293, and K24 AR064310 and National Psoriasis Foundation Discovery Grant.; This research was made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. NR 21 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2016 VL 251 BP 219 EP 225 DI 10.1016/j.atherosclerosis.2016.05.043 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DT1SJ UT WOS:000381262100032 PM 27376696 ER PT J AU Albers, JJ Slee, A Fleg, JL O'Brien, KD Marcovina, SM AF Albers, John J. Slee, April Fleg, Jerome L. O'Brien, Kevin D. Marcovina, Santica M. TI Relationship of baseline HDL subclasses, small dense LDL and LDL triglyceride to cardiovascular events in the AIM-HIGH clinical trial SO ATHEROSCLEROSIS LA English DT Article DE Cardiovascular risk; Homogeneous assays; HDL3-cholesterol; HDL2-cholesterol; Small dense LDL; LDL-triglyceride ID CORONARY-HEART-DISEASE; GLOBAL HEALTH OUTCOMES; LIPOPROTEIN-CHOLESTEROL; HOMOGENEOUS ASSAY; ATHEROTHROMBOSIS INTERVENTION; METABOLIC SYNDROME; ARTERY-DISEASE; RISK; COHORT; ATHEROSCLEROSIS AB Background and aims: Previous results of the AIM-HIGH trial showed that baseline levels of the conventional lipid parameters were not predictive of future cardiovascular (CV) outcomes. The aims of this secondary analysis were to examine the levels of cholesterol in high density lipoprotein (HDL) subclasses (HDL2-C and HDL3-C), small dense low density lipoprotein (sdLDL-C), and LDL triglyceride (LDL-TG) at baseline, as well as the relationship between these levels and CV outcomes. Methods: Individuals with CV disease and low baseline HDL-C levels were randomized to simvastatin plus placebo or simvastatin plus extended release niacin (ERN), 1500 to 2000 mg/day, with ezetimibe added as needed in both groups to maintain an on-treatment LDL-C in the range of 40-80 mg/dL. The primary composite endpoint was death from coronary disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebrovascular revascularization. HDL-C, HDL3-C, sdLDL-C and LDL-TG were measured at baseline by detergent-based homogeneous assays. HDL2-C was computed by the difference between HDL-C and HDL3-C. Analyses were performed on 3094 study participants who were already on statin therapy prior to enrollment in the trial. Independent contributions of lipoprotein fractions to CV events were determined by Cox proportional hazards modeling. Results: Baseline HDL3-C was protective against CV events (HR: 0.84, p = 0.043) while HDL-C, HDL2-C, sdLDL-C and LDL-TG were not event-related (HR: 0.96, p = 0.369; HR: 1.07, p = 0.373; HR: 1.05, p = 0.492; HR: 1.03, p = 0.554, respectively). Conclusions: The results of this secondary analysis of the AIM-HIGH Study indicate that levels of HDL3-C, but not other lipoprotein fractions, are predictive of CV events, suggesting that the HDL3 subclass may be primarily responsible for the inverse association of HDL-C and CV disease. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Albers, John J.; Marcovina, Santica M.] Univ Washington, Northwest Lipid Metab & Diabet Res Labs, 401 Queen Anne Ave N, Seattle, WA 98109 USA. [Slee, April] Axio Res, AIM HIGH Coordinating Ctr, 2601 Fourth Ave,Ste 200, Seattle, WA 98121 USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Dis, 6701 Rockledge Dr,Rm 8150, Bethesda, MD 20892 USA. [O'Brien, Kevin D.] Univ Washington, Div Cardiol, Dept Med, 1959 NE Pacific Ave,Box 356422, Seattle, WA 98195 USA. RP Marcovina, SM (reprint author), Univ Washington, Northwest Lipid Metab & Diabet Res Labs, 401 Queen Anne Ave N, Seattle, WA 98109 USA. EM jja@uw.edu; AprilS@axioresearch.com; flegj@nhlbi.nih.gov; cardiac@uw.edu; smm@uw.edu FU National Heart, Lung, and Blood Institute [U01 HL081616, U01 HL081649]; AbbVie, Inc. FX The Atherothrombosis Intervention in Metabolic syndrome with low high-density lipoprotein/high triglycerides: Impact on Global Health (AIM-HIGH) study was supported by the National Heart, Lung, and Blood Institute (U01 HL081616 and U01 HL081649) and by an unrestricted grant from AbbVie, Inc. AbbVie donated the extended-release niacin, the matching placebo, and the ezetimibe; Merck donated the simvastatin. Neither of these companies had any role in the oversight or design of the study or in the analysis or interpretation of the data. NR 27 TC 1 Z9 1 U1 4 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2016 VL 251 BP 454 EP 459 DI 10.1016/j.atherosclerosis.2016.06.019 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DT1SJ UT WOS:000381262100064 PM 27320173 ER PT J AU Ustun, C Gotlib, J Popat, U Artz, A Litzow, M Reiter, A Nakamura, R Kluin-Nelemans, HC Verstovsek, S Gajewskil, J Perales, MA George, T Shore, T Sperr, W Saber, W Kota, V Yavuz, AS Pullarkat, V Rogosheske, J Hogan, W Van Besien, K Hagglund, H Damaj, G Arock, M Horny, HP Metcalfe, DD Deeg, HJ Devine, S Weisdorfl, D Akin, C Valent, P AF Ustun, Celalettin Gotlib, Jason Popat, Uday Artz, Andrew Litzow, Mark Reiter, Andreas Nakamura, Ryotaro Kluin-Nelemans, Hanneke C. Verstovsek, Srdan Gajewskil, James Perales, Miguel-Angel George, Tracy Shore, Tsiporah Sperr, Wolfgang Saber, Wael Kota, Vamsi Yavuz, Akif Selim Pullarkat, Vinod Rogosheske, John Hogan, William Van Besien, Koen Hagglund, Hans Damaj, Gandhi Arock, Michel Horny, Hans-Peter Metcalfe, Dean D. Deeg, H. Joachim Devine, Steven Weisdorfl, Daniel Akin, Cem Valent, Peter TI Consensus Opinion on Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Editorial Material ID ACUTE MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; EUROPEAN COMPETENCE NETWORK; BONE-MARROW-TRANSPLANTATION; CURRENT TREATMENT OPTIONS; NEOPLASTIC MAST-CELLS; MYELOMASTOCYTIC LEUKEMIA; RESPONSE CRITERIA; TRYPTASE LEVELS; VENOOCCLUSIVE DISEASE C1 [Ustun, Celalettin; Rogosheske, John; Weisdorfl, Daniel] Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. [Gotlib, Jason] Stanford Univ, Div Hematol, Stanford, CA USA. [Popat, Uday] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat, Houston, TX USA. [Artz, Andrew] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL USA. [Litzow, Mark; Hogan, William] Mayo Clin, Dept Internal Med, Div Hematol, Minneapolis, MN USA. [Reiter, Andreas] Univ Med Ctr Mannheim, Dept Hematol & Oncol, Mannheim, Germany. [Nakamura, Ryotaro] City Hope Med Ctr, Dept Hematol Hematopoiet Cell Transplantat, Duarte, CA USA. [Kluin-Nelemans, Hanneke C.] Univ Groningen, Univ Med Ctr Groningen, Dept Hematol, Groningen, Netherlands. [Verstovsek, Srdan] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX USA. [Gajewskil, James] Oregon Hlth & Sci Univ, Dept Hematol, Portland, OR USA. [Perales, Miguel-Angel] Mem Sloan Kettering Canc Ctr, Dept Med, Div Hematol Oncol, New York, NY USA. [George, Tracy] Univ New Mexico, Dept Pathol, Albuquerque, NM USA. [Shore, Tsiporah] Weill Cornell Med Coll, Div Hematol & Oncol, New York, NY USA. [Sperr, Wolfgang] Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol & Ludwig Boltzmann Clus, Vienna, Austria. [Saber, Wael] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Dept Med, Milwaukee, WI USA. [Kota, Vamsi] Emory Univ, Winship Canc Inst, Dept Hematol & Oncol, Div Hematol, Atlanta, GA USA. [Yavuz, Akif Selim] Istanbul Univ, Istanbul Med Sch, Div Hematol, Istanbul, Turkey. [Van Besien, Koen] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Hagglund, Hans] Uppsala Univ, Dept Med Sci, Div Hematol, Uppsala, Sweden. [Damaj, Gandhi] Univ Basse Normandie, Univ Hosp, Sch Med, Inst Hematol,Dept Hematol, Caen, France. [Arock, Michel] Ecole Normale Super, CNRS UMR 8113, Cellular & Mol Oncol Unit, Cachan, France. [Arock, Michel] Univ Pitie Salpetriere, Ctr Hosp, Hematol Lab, Paris, France. [Horny, Hans-Peter] LMU, Inst Pathol, Munich, Germany. [Metcalfe, Dean D.] NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, Bethesda, MD USA. [Deeg, H. Joachim] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Deeg, H. Joachim] Univ Washington, Sch Med, Seattle, WA USA. [Devine, Steven] Ohio State Univ, Dept Med, Div Hematol, Columbus, OH 43210 USA. [Devine, Steven] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Akin, Cem] Harvard Med Sch, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA USA. RP Ustun, C (reprint author), Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. EM custun@umn.edu OI Akin, Cem/0000-0001-6301-4520 FU NCI NIH HHS [P30 CA016672] NR 85 TC 4 Z9 4 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2016 VL 22 IS 8 BP 1348 EP 1356 DI 10.1016/j.bbmt.2016.04.018 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DS1XC UT WOS:000380417400003 PM 27131865 ER PT J AU Pirsl, F Curtis, LM Steinberg, SM Tella, SH Katic, M Dobbin, M Hsu, J Hakim, FT Mays, JW Im, AP Pulanic, D Mitchell, SA Baruffaldi, J Masuch, L Halverson, DC Gress, RE Barsony, J Pavletic, SZ AF Pirsl, Filip Curtis, Lauren M. Steinberg, Seth M. Tella, Sri Harsha Katic, Masenjka Dobbin, Marnie Hsu, Jennifer Hakim, Fran T. Mays, Jacqueline W. Im, Annie P. Pulanic, Drazen Mitchell, Sandra A. Baruffaldi, Judy Masuch, Licia Halverson, David C. Gress, Ronald E. Barsony, Julianna Pavletic, Steven Z. TI Characterization and Risk Factor Analysis of Osteoporosis in a Large Cohort of Patients with Chronic Graft-versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; Allogeneic hematopoietic stem cell transplantation; Osteoporosis; Late effects; Supportive care; Platelets ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; LONG-TERM SURVIVORS; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; MEAN PLATELET VOLUME; CLINICAL-TRIALS; CHRONIC GVHD; REPRODUCTIVE HEALTH; MINERAL DENSITY AB The National Institutes of Health Chronic Graft-versus-Host Disease (cGVHD) Consensus Project Ancillary and Supportive Care Guidelines recommend annual assessment of bone mineral density (BMD) to monitor bone health. The study of osteoporosis in patients with cGVHD has been limited to small numbers of patients, and the guidelines are based on experience with other chronic diseases and expert opinion. We hypothesized that the prevalence of osteoporosis is high in a cohort of 258 patients with moderate to severe cGVHD because of prolonged exposure to risk factors for osteoporosis after allogeneic hematopoietic stem cell transplantation. We defined osteoporosis using BMD criteria (T-score <=-2.5) at 3 anatomic sites the femoral neck (FN), lumbar spine (LS), and total hip (TH) and characterized risk factors through univariate and multivariate analyses. We found that low body weight (FN, P <.0001; LS, P =.0002; TH, P <.0001), malnutrition (FN, P =.0002; LS, P =.03; TH, P =.0076), higher platelet count (FN, P =.0065; TH, P =.0025), higher average National Institutes of Health organ score (FN, P =.038), higher prednisone dose (LS, P =.032), lower complement component 3 (LS, P =.0073), and physical inactivity (FN, P =.01) were associated with osteoporosis in at least 1 site. T-scores were significantly lower in the FN compared with the LS or TH (P <.0001 for both). The prevalence of osteoporosis and osteopenia was high (17% and 60%, respectively), supporting current recommendations for frequent monitoring of BMD. The association of higher platelet count in patients with cGVHD and osteoporosis has not been reported previously and represents a new area of interest in the study of osteoporosis after allogeneic hematopoietic stem cell transplantation. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Pirsl, Filip; Curtis, Lauren M.; Katic, Masenjka; Hsu, Jennifer; Hakim, Fran T.; Baruffaldi, Judy; Masuch, Licia; Halverson, David C.; Gress, Ronald E.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bldg 10,Room 3E-3330, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Tella, Sri Harsha] NICHHD, NIH, Bethesda, MD 20892 USA. [Dobbin, Marnie] NIH, Dept Clin Nutr, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Mays, Jacqueline W.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Im, Annie P.] Univ Pittsburgh, Med Ctr, Adult Hematopoiet Stem Cell Transplant Program, Pittsburgh, PA USA. [Pulanic, Drazen] Univ Hosp Ctr Zagreb, Dept Internal Med, Div Hematol, Zagreb, Croatia. [Pulanic, Drazen] Univ Zagreb, Sch Med, Zagreb, Croatia. [Pulanic, Drazen] JJ Strossmayer Univ Osijek, Fac Med Osijek, Osijek, Croatia. [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Barsony, Julianna] Georgetown Univ, Med Ctr, Dept Med, Div Endocrinol & Metab, Washington, DC 20007 USA. RP Curtis, LM (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Bldg 10,Room 3E-3330, Bethesda, MD 20892 USA. EM curtislm@mail.nih.gov OI Katic, Masenjka/0000-0001-7237-697X FU Intramural NIH HHS [Z99 CA999999] NR 52 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2016 VL 22 IS 8 BP 1517 EP 1524 DI 10.1016/j.bbmt.2016.04.012 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DS1XC UT WOS:000380417400026 PM 27118572 ER PT J AU Schoemans, H Goris, K Durm, RV Vanhoof, J Wolff, D Greinix, H Pavletic, S Lee, SJ Maertens, J Geest, SD Dobbels, F Duarte, RF AF Schoemans, H. Goris, K. Durm, R. V. Vanhoof, J. Wolff, D. Greinix, H. Pavletic, S. Lee, S. J. Maertens, J. Geest, S. D. Dobbels, F. Duarte, R. F. CA EBMT Complications Quality Life TI Development, preliminary usability and accuracy testing of the EBMT 'eGVHD App' to support GvHD assessment according to NIH criteria-a proof of concept SO BONE MARROW TRANSPLANTATION LA English DT Article ID VERSUS-HOST-DISEASE; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; CLINICAL-TRIALS; DIAGNOSIS AB The EBMT Complications and Quality of Life Working Party has developed a computer-based algorithm, the 'eGVHD App', using a user-centered design process. Accuracy was tested using a quasi-experimental crossover design with four expert-reviewed case vignettes in a convenience sample of 28 clinical professionals. Perceived usefulness was evaluated by the technology acceptance model (TAM) and User satisfaction by the Post-Study System Usability Questionnaire (PSSUQ). User experience was positive, with a median of 6 TAM points (interquartile range: 1) and beneficial median total, and subscale PSSUQ scores. The initial standard practice assessment of the vignettes yielded 65% correct results for diagnosis and 45% for scoring. The 'eGVHD App' significantly increased diagnostic and scoring accuracy to 93% (+ 28%) and 88% (+ 43%), respectively (both P < 0.05). The same trend was observed in the repeated analysis of case 2: accuracy improved by using the App (+ 31% for diagnosis and + 39% for scoring), whereas performance tended to decrease once the App was taken away. The 'eGVHD App' could dramatically improve the quality of care and research as it increased the performance of the whole user group by about 30% at the first assessment and showed a trend for improvement of individual performance on repeated case evaluation. C1 [Schoemans, H.; Goris, K.; Maertens, J.] Katholieke Univ Leuven, Univ Hosp Leuven, Dept Hematol, 49 Herestr, B-3000 Leuven, Belgium. [Durm, R. V.] Katholieke Univ Leuven, Univ Hosp Leuven, Dept Informat Technol, Leuven, Belgium. [Vanhoof, J.; Geest, S. D.; Dobbels, F.] Univ Leuven, Acad Ctr Nursing & Midwifery, Leuven, Belgium. [Wolff, D.] Univ Med Ctr Regensburg, Dept Internal Med Hematol & Oncol 3, Regensburg, Germany. [Greinix, H.] Med Univ Graz, Div Hematol, Graz, Austria. [Pavletic, S.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, S. J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Geest, S. D.; Dobbels, F.] Univ Basel, Inst Nursing Sci, Basel, Switzerland. [Duarte, R. F.] Hosp Univ Puerta de Hierro Majadahonda, Calle Joaquin Rodrigo 2, Madrid, Spain. RP Schoemans, H (reprint author), Katholieke Univ Leuven, Univ Hosp Leuven, Dept Hematol, 49 Herestr, B-3000 Leuven, Belgium. EM helene.schoemans@uzleuven.be FU Sofhea (Sociaal Fonds voor Hematologische Aandoeningen of Bloedziekten) FX We would like to acknowledge and thank the whole Department of Hematology of UZ Leuven for participating in this study. We also deeply thank Sofhea (Sociaal Fonds voor Hematologische Aandoeningen of Bloedziekten) for funding this research project. NR 8 TC 1 Z9 1 U1 3 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD AUG PY 2016 VL 51 IS 8 BP 1062 EP 1065 DI 10.1038/bmt.2016.26 PG 4 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA DS4WB UT WOS:000380781200005 PM 27042834 ER PT J AU Anandi, P Jain, NA Tian, X Wu, CO Pophali, PA Koklanaris, E Ito, S Savani, BN Barrett, J Battiwalla, M AF Anandi, P. Jain, N. A. Tian, X. Wu, C. O. Pophali, P. A. Koklanaris, E. Ito, S. Savani, B. N. Barrett, J. Battiwalla, M. TI Factors influencing the late phase of recovery after bone mineral density loss in allogeneic stem cell transplantation survivors SO BONE MARROW TRANSPLANTATION LA English DT Article ID LONG-TERM SURVIVORS; ZOLEDRONIC ACID; AVASCULAR NECROSIS; FRACTURE RISK; FOLLOW-UP; OSTEOPOROSIS; RECIPIENTS; PAMIDRONATE; MECHANISMS; PREVENTION AB Accelerated bone mineral density loss (BMDL) occurs early after allogeneic stem cell transplantation (SCT) and is related to factors such as steroids and chronic GvHD. In order to understand the natural history of BMDL of SCT in the longer term, we evaluated a longitudinal cohort of 148 survivors with a median follow-up of 12 years (range 3-22 years). All women received hormone replacement therapy, and routine calcium/vitamin D supplementation was recommended but similar to 50% of patients still had suboptimal vitamin D levels and bisphosphonates were rarely utilized. BMD significantly improved from 5 to 20+ years but the femoral neck and forearm remained vulnerable sites. Younger age, higher pretransplant body mass index (BMI) and increment in BMI post transplant were significantly associated with increased BMD and protected against osteopenia/osteoporosis. These findings support consideration of BMD loss in SCT survivors in two phases, an early phase of BMD loss (3-5 years) followed by a later phase of BMD recovery, with different protective and aggravating factors. Treatment-and transplant-related factors (such as steroids, immunosuppressives, chronic GvHD, vitamin D) are known to impact the early phase of BMD loss but age and BMI are more influential in the late phase of BMD recovery. C1 [Anandi, P.; Jain, N. A.; Pophali, P. A.; Koklanaris, E.; Ito, S.; Barrett, J.; Battiwalla, M.] NHLBI, Hematol Branch, NIH, Bldg 10 CRC,Room 5-3581,10 Ctr Dr MSC 1202, Bethesda, MD 20892 USA. [Tian, X.; Wu, C. O.] NHLBI, Off Biostat Res, NIH, Bldg 10 CRC,Room 5-3581,10 Ctr Dr MSC 1202, Bethesda, MD 20892 USA. [Savani, B. N.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. RP Battiwalla, M (reprint author), NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bldg 10 CRC,Room 5-3581,10 Ctr Dr MSC 1202, Bethesda, MD 20892 USA. EM minoo.battiwalla@nih.gov RI Pophali, Priyanka/P-8646-2016 FU NHLBI, NIH FX This work was supported by the Intramural Research Program of the NHLBI, NIH. NR 34 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD AUG PY 2016 VL 51 IS 8 BP 1101 EP 1106 DI 10.1038/bmt.2016.85 PG 6 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA DS4WB UT WOS:000380781200014 PM 27042843 ER PT J AU Srour, SA Devesa, SS Morton, LM Check, DP Curtis, RE Linet, MS Dores, GM AF Srour, Samer A. Devesa, Susan S. Morton, Lindsay M. Check, David P. Curtis, Rochelle E. Linet, Martha S. Dores, Graca M. TI Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001-12 SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE myeloproliferative neoplasm; epidemiology; incidence; survival ID CHRONIC MYELOID-LEUKEMIA; JUVENILE MYELOMONOCYTIC LEUKEMIA; ESSENTIAL THROMBOCYTHEMIA; POLYCYTHEMIA-VERA; HEMATOLOGICAL MALIGNANCY; PRIMARY MYELOFIBROSIS; PROGNOSTIC-FACTORS; LIFE EXPECTANCY; MYELODYSPLASTIC SYNDROMES; DIAGNOSTIC-CRITERIA AB Descriptive epidemiological information on myeloproliferative neoplasms (MPNs) and myelodysplastic (MDS)/MPNs is largely derived from single institution and European population-based studies. Data obtained following adoption of the World Health Organization classification of haematopoietic neoplasms and JAK2 V617F mutation testing are sparse. Using population-based data, we comprehensively assessed subtype-specific MPN and MDS/MPN incidence rates (IRs), IR ratios (IRRs) and relative survival (RS) in the United States (2001-12). IRs were highest for polycythaemia vera (PV) (IR=109) and essential thrombocythaemia (ET) (IR=96). Except for ET and mastocytosis, overall IRs were significantly higher among males (IRRs=14-23). All evaluable MPNs were associated with lower IRs among Hispanic whites than non-Hispanic whites (NHWs), with the exception of BCR-ABL1-positive chronic myeloid leukaemia (CML), chronic eosinophilic leukaemia (CEL) and juvenile myelomonocytic leukaemia. Except for CEL, Asians/Pacific Islanders had significantly lower MPN IRs than NHWs. ET, MPN-unclassifiable and CEL IRs were 18%, 19% and 60% higher, respectively, among blacks than NHWs. Five-year RS was more favourable for younger (< 60years) than older individuals and for women compared with men, except for PV at older ages. RS was highest (> 90%) for younger PV and ET patients and lowest (< 20%) for older chronic myelomonocytic leukaemia and atypical BCR-ABL1-negative CML patients. Varying MPN and MDS/MPN incidence patterns by subtype support distinct aetiologies and/or susceptible populations. Decreased survival rates as compared to that expected in the general population were associated with every MPN subtype, highlighting the need for new treatments, particularly among older individuals. C1 [Srour, Samer A.; Dores, Graca M.] Oklahoma City VA Hlth Care Syst, 921 NE 13th St, Oklahoma City, OK 73104 USA. [Srour, Samer A.] Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Med, Oklahoma City, OK 73190 USA. [Devesa, Susan S.; Morton, Lindsay M.; Check, David P.; Curtis, Rochelle E.; Linet, Martha S.; Dores, Graca M.] NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Srour, SA (reprint author), Oklahoma City VA Hlth Care Syst, 921 NE 13th St, Oklahoma City, OK 73104 USA. EM samer-srour@ouhsc.edu FU Oklahoma City Veterans Affairs Health Care System in Oklahoma City; Intramural Research Program, National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX This work was supported by the Oklahoma City Veterans Affairs Health Care System in Oklahoma City; and the Intramural Research Program, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 64 TC 4 Z9 4 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD AUG PY 2016 VL 174 IS 3 BP 382 EP 396 DI 10.1111/bjh.14061 PG 15 WC Hematology SC Hematology GA DS4CO UT WOS:000380729200005 PM 27061824 ER PT J AU Shiels, MS Pfeiffer, RM Besson, C Clarke, CA Morton, LM Nogueira, L Pawlish, K Yanik, EL Suneja, G Engels, EA AF Shiels, Meredith S. Pfeiffer, Ruth M. Besson, Caroline Clarke, Christina A. Morton, Lindsay M. Nogueira, Leticia Pawlish, Karen Yanik, Elizabeth L. Suneja, Gita Engels, Eric A. TI Trends in primary central nervous system lymphoma incidence and survival in the US SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE Lymphoma; central nervous system; incidence; survival; human immunodeficiency virus; transplant ID PRIMARY CNS LYMPHOMA; NON-HODGKINS-LYMPHOMA; UNITED-STATES; CANCER-RISK; IMMUNOCOMPETENT PATIENTS; HIV; SURVEILLANCE; PEOPLE; AIDS AB It is suspected that primary central nervous system lymphoma (PCNSL) rates are increasing among immunocompetent people. We estimated PCNSL trends in incidence and survival among immunocompetent persons by excluding cases among human immunodeficiency virus (HIV)-infected persons and transplant recipients. PCNSL data were derived from 10 Surveillance, Epidemiology and End Results (SEER) cancer registries (1992-2011). HIV-infected cases had reported HIV infection or death due to HIV. Transplant recipient cases were estimated from the Transplant Cancer Match Study. We estimated PCNSL trends overall and among immunocompetent individuals, and survival by HIV status. A total of 4158 PCNSLs were diagnosed (36% HIV-infected; 09% transplant recipients). HIV prevalence in PCNSL cases declined from 641% (1992-1996) to 127% (2007-2011), while the prevalence of transplant recipients remained low. General population PCNSL rates were strongly influenced by immunosuppressed cases, particularly in 20-39 year-old men. Among immunocompetent people, PCNSL rates in men and women aged 65+ years increased significantly (17% and 16%/year), but remained stable in other age groups. Five-year survival was poor, particularly among HIV-infected cases (90%). Among HIV-uninfected cases, 5-year survival increased from 191% (1992-1994) to 301% (2004-2006). In summary, PCNSL rates have increased among immunocompetent elderly adults, but not in younger individuals. Survival remains poor for both HIV-infected and HIV-uninfected PCNSL patients. C1 [Shiels, Meredith S.; Pfeiffer, Ruth M.; Morton, Lindsay M.; Yanik, Elizabeth L.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Besson, Caroline] Bicetre Univ Hosp, Le Kremlin Bicetre, France. [Clarke, Christina A.] Canc Prevent Inst Calif, Fremont, CA USA. [Nogueira, Leticia] Texas Dept State Hlth Serv, Austin, TX USA. [Pawlish, Karen] New Jersey Dept Hlth, Trenton, NJ USA. [Suneja, Gita] Univ Utah, Dept Radiat Oncol, Salt Lake City, UT USA. RP Shiels, MS (reprint author), NCI, NIH, 9609 Med Ctr Dr,Room 6E-218 MSC 9767, Bethesda, MD 20892 USA. EM shielsms@mail.nih.gov OI Besson, Caroline/0000-0003-4364-7173; Yanik, Elizabeth/0000-0002-5835-0201 FU Intramural Research Program of the National Cancer Institute; Minneapolis Medical Research Foundation, Minneapolis, MN [HHSH250201000018C]; Arbor Research Collaborative for Health in Ann Arbor, MI [HHSH234200537009C]; SEER Program of the National Cancer Institute: California [HHSN261201000036C, HHSN261201000035C, HHSN261201000034C]; SEER Program of the National Cancer Institute: Connecticut [HHSN261201000024C]; SEER Program of the National Cancer Institute: Hawaii [HHSN261201 000037C, N01-PC-35137, N01-PC-35139]; SEER Program of the National Cancer Institute: Iowa [HSN 261201000032C, N01-PC-35143]; SEER Program of the National Cancer Institute: New Jersey [HHSN261201300021I, N01-PC-2013-00021]; SEER Program of the National Cancer Institute: Seattle-Puget Sound [N01-PC-35142]; SEER Program of the National Cancer Institute: Utah [HHSN2612013000171]; National Program of Cancer Registries of the Centers for Disease Control and Prevention [1U58 DP000807-01, U58 DP000848-04, 5U58DP003875-01, 5U58DP003883-03, U58DP12-1205 3919-03, 5U58DP003921-03, 5U58/DP003931-02, U58DP 003879, U58DP000832, 5U58DP000824-04]; Massachusetts Cancer Prevention and Control Cooperative Agreement [5458DP003920]; New Jersey (Memorandum of Agreement) [5-100-046-4220-496-6140]; University of Utah; Fred Hutchinson Cancer Research Center in Seattle, WA FX This work was supported by the Intramural Research Program of the National Cancer Institute.; The SRTR is currently operated under contract number HHSH250201000018C (Health Resources and Services Administration) by the Minneapolis Medical Research Foundation, Minneapolis, MN. During the initial period when registry linkages were performed, the SRTR was managed by Arbor Research Collaborative for Health in Ann Arbor, MI (contract HHSH234200537009C). The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C, and HHSN261201000034C), Connecticut (HHSN261201000024C), Hawaii (HHSN261201 000037C, N01-PC-35137, and N01-PC-35139), Iowa (HSN 261201000032C and N01-PC-35143), New Jersey (HHSN261201300021I, N01-PC-2013-00021), Seattle-Puget Sound (N01-PC-35142), and Utah (HHSN2612013000171). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP003875-01), Illinois (5U58DP003883-03), Maryland (U58DP12-1205 3919-03), Michigan (5U58DP003921-03), New Jersey (5U58/ DP003931-02), New York (U58DP 003879), North Carolina (U58DP000832) and Texas (5U58DP000824-04). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, Massachusetts (Massachusetts Cancer Prevention and Control Cooperative Agreement 5458DP003920), New Jersey (Memorandum of Agreement 5-100-046-4220-496-6140), New York (including the Cancer Surveillance Initiative), Texas, Utah, and Washington, as well as the University of Utah and Fred Hutchinson Cancer Research Center in Seattle, WA. NR 30 TC 0 Z9 0 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD AUG PY 2016 VL 174 IS 3 BP 417 EP 424 DI 10.1111/bjh.14073 PG 8 WC Hematology SC Hematology GA DS4CO UT WOS:000380729200008 PM 27018254 ER PT J AU Reusing, SB Manser, AR Enczmann, J Mulder, A Claas, FH Carrington, M Fischer, JC Borkhardt, A Babor, F Uhrberg, M AF Reusing, Sarah B. Manser, Angela R. Enczmann, Juergen Mulder, Arend Claas, Frans H. Carrington, Mary Fischer, Johannes C. Borkhardt, Arndt Babor, Florian Uhrberg, Markus TI Selective downregulation of HLA-C and HLA-E in childhood acute lymphoblastic leukaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Letter DE NK cells; HLA class I; KIR; childhood leukaemia; ALL ID E SURFACE EXPRESSION; CELLS C1 [Reusing, Sarah B.; Manser, Angela R.; Enczmann, Juergen; Fischer, Johannes C.; Uhrberg, Markus] Univ Dusseldorf, Inst Transplantat Diagnost & Cell Therapeut, Dusseldorf, Germany. [Mulder, Arend; Claas, Frans H.] Leiden Univ, Dept Immunohaematol & Bloodtransfus, Med Ctr, Leiden, Netherlands. [Carrington, Mary] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD USA. [Carrington, Mary] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Borkhardt, Arndt; Babor, Florian] Univ Dusseldorf, Dept Pediat Oncol Hematol & Clin Immunol, Ctr Child & Adolescent Hlth, Dusseldorf, Germany. RP Uhrberg, M (reprint author), Univ Dusseldorf, Inst Transplantat Diagnost & Cell Therapeut, Dusseldorf, Germany. EM markus.uhrberg@med.uni-duesseldorf.de OI Fischer, Johannes/0000-0002-2079-1845 FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E] NR 9 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD AUG PY 2016 VL 174 IS 3 BP 477 EP 480 DI 10.1111/bjh.13777 PG 4 WC Hematology SC Hematology GA DS4CO UT WOS:000380729200016 PM 26527563 ER PT J AU Gonzales, FA Taplin, SH Yu, MD Breen, N Cronin, KA AF Gonzales, Felisa A. Taplin, Stephen H. Yu, Mandi Breen, Nancy Cronin, Kathy A. TI Receipt of mammography recommendations among White and non-White women before and after the 2009 United States Preventive Services Task Force recommendation change SO CANCER CAUSES & CONTROL LA English DT Article DE Mammography; Breast cancer screening; Disparities; United States Preventive Services Task Force; Practice guidelines ID BREAST-CANCER-TREATMENT; SHARED DECISION-MAKING; OF-THE-LITERATURE; SCREENING MAMMOGRAPHY; RACIAL/ETHNIC DISPARITIES; MULTIPLE-IMPUTATION; TRENDS; IMPACT; RATES; AGE AB Receipt of a mammography recommendation from a physician is a strong predictor of obtaining a mammogram. In 2009, the United States Preventive Services Task Force (USPSTF) recommended routine biennial mammography for women aged 50-74 but not for women aged 40-49. We examined changes in reports of clinician recommendations for mammography among White and non-White women after these age-specific recommendations were issued. Data from women aged 40-49 and 50-74 were drawn from the 2008 and 2013 National Health Interview Surveys. We used linear probability models to determine whether the proportions of women reporting a mammography recommendation changed after the USPSTF recommendation was issued and whether any changes observed differed across White and non-White women. All analyses were stratified by age groups and mammography history. Among women without a recent mammogram, reported clinician recommendations did not change for White women, but they decreased by 13-percentage points (95 % CI -0.22, -0.03) among non-White women aged 40-49 (p = 0.01) and increased by 9-percentage points (95 % CI 0.01, 0.17) among non-White women aged 50-74 (p = 0.04). Among women with a mammogram in the past 2 years, reported mammography recommendation from a clinician did not change for White or non-White women. Recommendations to reduce screening may be differentially implemented across racial/ethnic groups. Changes in reports of mammography recommendation from a clinician after the USPSTF breast cancer screening recommendation change were observed only among non-White women without a recent history of mammography. It is unclear whether these differences are due to the clinician, the women, or both. C1 [Gonzales, Felisa A.] NCI, Div Canc Control & Populat Sci, BG 9609 RM 3E502 MSC 9712,9609 Med Ctr Dr, Rockville, MD 20850 USA. [Taplin, Stephen H.] NCI, Div Canc Control & Populat Sci, BG 9609 RM 3E342 MSC 9761,9609 Med Ctr Dr, Rockville, MD 20850 USA. [Yu, Mandi] NCI, Div Canc Control & Populat Sci, BG 9609 RM 4E544 MSC 9765,9609 Med Ctr Dr, Rockville, MD 20850 USA. [Breen, Nancy] NCI, Div Canc Control & Populat Sci, BG 2DEM RM 800 MSC 5465,6707 Democracy Blvd, Bethesda, MD 20892 USA. [Cronin, Kathy A.] NCI, Div Canc Control & Populat Sci, BG 9609 RM 4E454 MSC 9765,9609 Med Ctr Dr, Rockville, MD 20850 USA. RP Gonzales, FA (reprint author), NCI, Div Canc Control & Populat Sci, BG 9609 RM 3E502 MSC 9712,9609 Med Ctr Dr, Rockville, MD 20850 USA. EM Felisa.gonzales@nih.gov; taplins@mail.nih.gov; Yum3@mail.nih.gov; breenn@mail.nih.gov; cronink@mail.nih.gov NR 66 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2016 VL 27 IS 8 BP 977 EP 987 DI 10.1007/s10552-016-0775-9 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DS9RK UT WOS:000381120800003 PM 27351918 ER PT J AU Falk, RT Staff, AC Bradwin, G Karumanchi, SA Troisi, R AF Falk, Roni T. Staff, Annetine Cathrine Bradwin, Gary Karumanchi, S. Ananth Troisi, Rebecca TI A prospective study of angiogenic markers and postmenopausal breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial SO CANCER CAUSES & CONTROL LA English DT Article DE Breast cancer risk; Angiogenesis; VEGF sFlt-1; PlGF ID ENDOTHELIAL GROWTH-FACTOR; CLINICAL-USEFULNESS; PROGNOSTIC VALUE; MENSTRUAL-CYCLE; PLASMA-LEVELS; VEGF LEVELS; SERUM; PREGNANCY; PREECLAMPSIA; RECEPTORS AB Pro-angiogenic factors are positively associated with breast tumor staging and poorer prognosis, but their role in the etiology of breast cancer has not been assessed. We measured serum levels of the pro-angiogenic vascular endothelial growth factor A (VEGF), and placental growth factor (PlGF) and anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) in 352 incident breast cancer cases [mean age at diagnosis 67 (range 55-83)] and 352 non-cases in the prostate, lung, colorectal, and ovarian screening trial (women enrolled 1993-2001, followed through 2005) matched on age and date of enrollment. Cases were followed on average 4.2 years from blood draw to diagnosis, range 3.9-12.8 years; 53 % were estrogen receptor positive/progesterone receptor positive (ER+/PR+), and 13 % were ER-/PR-. Quartile-specific hazard ratios (HR) and 95 % confidence intervals (CI) were estimated using weighted Cox proportional hazards regression models adjusted for known breast cancer risk factors. An ordinal variable for the angiogenic markers was used to test for trend in the HR. Comparing the highest to lowest quartile, multivariable HR were 0.90 for VEGF (95 % CI 0.33-2.43, p trend = 0.88), 1.38 for sFlt-1 (95 % CI 0.63-3.04, p trend = 0.63), and 0.62 for PlGF (95 % CI 0.19-2.00, p trend = 0.73). Risk patterns were not altered when all angiogenic markers were included in the model simultaneously, or by restricting analyses to invasive breast cancers, to cases diagnosed two or more years after blood collection or to ER+ tumors. There was no evidence of an increased breast cancer risk associated with circulating levels of pro-angiogenic markers VEGF and PlGF or a reduced risk with circulating levels of anti-angiogenic marker sFlt-1. C1 [Falk, Roni T.] NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20852 USA. [Staff, Annetine Cathrine] Oslo Univ Hosp, Women & Childrens Div, Dept Gynecol & Obstet, N-0424 Oslo, Norway. [Bradwin, Gary] Boston Childrens Hosp, Dept Lab Med, Clin & Epidemiol Res Lab, Boston, MA USA. [Karumanchi, S. Ananth] Harvard Med Sch, Ctr Vasc Biol, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. [Karumanchi, S. Ananth] Harvard Med Sch, Ctr Vasc Biol, Beth Israel Deaconess Med Ctr, Dept Obstet, Boston, MA USA. [Karumanchi, S. Ananth] Harvard Med Sch, Ctr Vasc Biol, Beth Israel Deaconess Med Ctr, Dept Gynecol, Boston, MA USA. [Troisi, Rebecca] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20852 USA. RP Falk, RT (reprint author), NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20852 USA. EM falkr@mail.nih.gov; UXNNAF@ous-hf.no; Gary.Bradwin@childrens.harvard.edu; sananth@bidmc.harvard.edu; troisir@mail.nih.gov FU National Cancer Institute, NIH, U.S. Department of Health and Human Services [HHSN261201200327P] FX This study was supported by the National Cancer Institute, NIH, U.S. Department of Health and Human Services through contract # HHSN261201200327P. NR 43 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2016 VL 27 IS 8 BP 1009 EP 1017 DI 10.1007/s10552-016-0779-5 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DS9RK UT WOS:000381120800006 PM 27357932 ER PT J AU Yang, BY Petrick, JL Chen, J Hagberg, KW Sahasrabuddhe, VV Graubard, BI Jick, S McGlynn, KA AF Yang, Baiyu Petrick, Jessica L. Chen, Jie Hagberg, Katrina Wilcox Sahasrabuddhe, Vikrant V. Graubard, Barry I. Jick, Susan McGlynn, Katherine A. TI Associations of NSAID and paracetamol use with risk of primary liver cancer in the Clinical Practice Research Datalink SO CANCER EPIDEMIOLOGY LA English DT Article DE Analgesics; Liver cancer; Case-control study; Medical records database ID PRACTICE RESEARCH DATABASE; HEPATOCELLULAR-CARCINOMA; DATA RESOURCE; CELL-GROWTH; MORTALITY; ACETAMINOPHEN; INHIBITION; INDUCTION; APOPTOSIS; DISEASE AB Liver cancer incidence has been rising rapidly in Western countries. Nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol are widely-used analgesics that may modulate the risk of liver cancer, but population-based evidence is limited. We conducted a case-control study (1195 primary liver cancer cases and 4640 matched controls) within the United Kingdom's Clinical Practice Research Datalink to examine the association between the use of prescription NSAIDs and paracetamol and development of liver cancer. Multivariable-adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. Overall, ever-use of NSAIDs was not associated with risk of liver cancer (aOR = 1.05, 95% CI = 0.88-1.24), regardless of recency and intensity of use. Use of paracetamol was associated with a slightly increased risk of liver cancer (aOR = 1.18, 95% CI = 1.00-1.39), particularly among individuals with body mass index < 25 kg/m(2) (aOR = 1.56, 95% CI = 1.17-2.09). Our results suggest that NSAID use was not associated with liver cancer risk in this population. Ever-use of paracetamol may be associated with slightly higher liver cancer risk, but results should be interpreted cautiously due to methodological limitations. Given that paracetamol is a widely-used analgesic, further examination of its relationship with liver cancer is warranted. Published by Elsevier Ltd. C1 [Yang, Baiyu; Petrick, Jessica L.; Chen, Jie; Sahasrabuddhe, Vikrant V.; Graubard, Barry I.; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hagberg, Katrina Wilcox; Jick, Susan] Boston Collaborat Drug Surveillance Program, Lexington, MA 02421 USA. [Hagberg, Katrina Wilcox; Jick, Susan] Boston Univ, Sch Publ Hlth, Lexington, MA 02421 USA. [Sahasrabuddhe, Vikrant V.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Yang, BY (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM baiyu.yang@nih.gov RI CPRD, CPRD/B-9594-2017 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This research was supported, in part, by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The authors thank Dr. Marie Bradley for her insightful comments, and Ms. Megan Braunlin for her help with the analyses. NR 28 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD AUG PY 2016 VL 43 BP 105 EP 111 DI 10.1016/j.canep.2016.06.009 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DT8KS UT WOS:000381739700016 PM 27420633 ER PT J AU Mutlu, E Gao, L Collins, LB Walker, NJ Hartwell, HJ Olson, JR Sun, W Gold, A Ball, LM Swenberg, JA AF Mutlu, Esra Gao, Lina Collins, Leonard B. Walker, Nigel J. Hartwell, Hadley J. Olson, James R. Sun, Wei Gold, Avram Ball, Louise M. Swenberg, James A. TI Polychlorinated Biphenyls Induce Oxidative DNA Adducts in Female Sprague-Dawley Rats SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID HEPATIC LIPID-PEROXIDATION; OXYGEN SPECIES PRODUCTION; TOXIC EQUIVALENCY FACTORS; CEREBELLAR GRANULE CELLS; MEMBRANE-BOUND ATPASES; PROTECTIVE ROLE; IN-VIVO; CHEMICAL CARCINOGENESIS; SUBCHRONIC EXPOSURE; CYTOCHROME-P450 1A AB Polychlorinated biphenyls (PCBs) are organic chemicals that were traditionally produced and widely used in industry as mixtures and are presently formed as byproducts of pigment and dye manufacturing. They are known to persist and bioaccumulate in the environment. Some have been shown to induce liver cancer in rodents. Although the mechanism of the toxicity of PCBs is unknown, it has been shown that they increase oxidative stress, including lipid peroxidation. We hypothesized that oxidative stress-induced DNA damage could be a contributor for PCB carcinogenesis and analyzed several DNA adducts in female Sprague Dawley rats exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB 126), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), and a binary mixture (PCB 126 + 153) for 14, 31, and 53 wks. Eight adducts were measured to profile oxidative DNA lesions, including 8-oxo-deoxyguanosine (8-oxo-dG), 1,N-6-ethenodeoxyadenosine (1,N-6-epsilon dA), N-2,3-ethenoguanine (N-2,3-epsilon G), 1,N-2-ethenodeoxyguanosine (1,N-2-epsilon dG), as well as malondialdehyde (M(1)dG), acrolein (AcrdG), crotonaldehyde (CrdG), and 4-nydroxynonenal-derived dG adducts (HNEdG) by LC-MS/MS analysis. Statistically significant increases were observed for 8-oxo-dG. and 1,N-6-epsilon dA. concentrations in hepatic DNA of female rats exposed to the binary mixture (1000 ng/kg/day + 1000 mu g/kg/day) but not in rats exposed to PCB 126 (1000 ng/kg/day) or PCB 153 (1000 mu g/kg/day) for 14 and 31 wks. However, exposure to PCB 126 (1000 ng/kg/day) for 53 wks significantly increased 8-oxo-dG, 1,N-6-epsilon dA, AcrdG, and M1dG. Exposure to PCB 153 (1000 mu g/kg/day) for 53 wks increased 8-oxo-dG, and 1,N-6-epsilon dA. Exposure to the binary mixture for 53 wks increased 8-oxo-dG, 1,N-6-epsilon dA., AcrdG, 1,N-2-epsilon dG, and N-2,3-epsilon G significantly above control groups. Increased hepatic oxidative DNA adducts following exposure to PCB 126, PCB 153; or the binary mixture shows that an increase in DNA damage may play an important role in hepatic toxicity and carcinogenesis in female Sprague Dawley rats. C1 [Mutlu, Esra; Walker, Nigel J.] NIEHS, Natl Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Gao, Lina; Collins, Leonard B.; Hartwell, Hadley J.; Gold, Avram; Ball, Louise M.; Swenberg, James A.] Univ North Carolina Chapel Hill, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. [Olson, James R.] SUNY Buffalo, Dept Pharmacol & Toxicol, Buffalo, NY 14214 USA. [Sun, Wei] Univ North Carolina Chapel Hill, Dept Biostat, Chapel Hill, NC 27599 USA. [Swenberg, James A.] Univ North Carolina Chapel Hill, Dept Environm Sci & Engn, Gillings Sch Global Publ Hlth, Campus Box 7431, Chapel Hill, NC 27599 USA. RP Swenberg, JA (reprint author), Univ North Carolina Chapel Hill, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA.; Swenberg, JA (reprint author), Univ North Carolina Chapel Hill, Dept Environm Sci & Engn, Gillings Sch Global Publ Hlth, Campus Box 7431, Chapel Hill, NC 27599 USA. EM jswenber@email.unc.edu RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 FU NIEHS Superfund Basic Research Program [P42-ES05948]; NIEHS Center for Environmental Health and Susceptibility [P30 ES 10126] FX This work was supported by the NIEHS Superfund Basic Research Program P42-ES05948 and the NIEHS Center for Environmental Health and Susceptibility P30 ES 10126. NR 87 TC 0 Z9 0 U1 11 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD AUG PY 2016 VL 29 IS 8 BP 1335 EP 1344 DI 10.1021/acs.chemrestox.6b00146 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA DT6KQ UT WOS:000381593500010 PM 27436759 ER PT J AU Yao, XL Gordon, EM Barochia, AV Remaley, AT Levine, SJ AF Yao, Xianglan Gordon, Elizabeth M. Barochia, Amisha V. Remaley, Alan T. Levine, Stewart J. TI The A's Have It Developing Apolipoprotein A-I Mimetic Peptides Into a Novel Treatment for Asthma SO CHEST LA English DT Article DE airway hyperresponsiveness; airway inflammation; asthma; lipids ID NEUTROPHILIC AIRWAY INFLAMMATION; REVERSE CHOLESTEROL TRANSPORT; CARDIOVASCULAR-DISEASE; ENDOTOXIN EXPOSURE; UNITED-STATES; HDL; ACTIVATION; CELLS; ABCA1; MICE AB New treatments are needed for patients with asthma who are refractory to standard therapies, such as individuals with a phenotype of "type 2-low" inflammation. This important clinical problem could potentially be addressed by the development of apolipoprotein A-I (apoA-I) mimetic peptides. ApoA-I interacts with its cellular receptor, the ATP-binding cassette subfamily A, member 1 (ABCA1), to facilitate cholesterol efflux out of cells to form nascent high-density lipoprotein particles. The ability of the apoA-I/ABCA1 pathway to promote cholesterol efflux from cells that mediate adaptive immunity, such as antigen-presenting cells, can attenuate their function. Data from experimental murine models have shown that the apoA-I/ABCA1 pathway can reduce neutrophilic airway inflammation, primarily by suppressing the production of granulocyte-colony stimulating factor. Furthermore, administration of apoA-I mimetic peptides to experimental murine models of allergic asthma has decreased both neutrophilic and eosinophilic airway inflammation, as well as airway hyperresponsiveness and mucous cell metaplasia. Higher serum levels of apoA-I have also been associated with less severe airflow obstruction in patients with asthma. Collectively, these results suggest that the apoA-I/ABCA1 pathway may have a protective effect in asthma, and support the concept of advancing inhaled apoA-I mimetic peptides to clinical trials that can assess their safety and effectiveness. Thus, we propose that the development of inhaled apoA-I mimetic peptides as a new treatment could represent a clinical advance for patients with severe asthma who are unresponsive to other therapies. C1 [Yao, Xianglan; Gordon, Elizabeth M.; Barochia, Amisha V.; Levine, Stewart J.] NHLBI, Lab Asthma & Lung Inflammat, Cardiovasc & Pulm Branch, Div Intramural Res,NIH, Bldg 10, Bethesda, MD 20892 USA. [Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Cardiovasc & Pulm Branch, Div Intramural Res,NIH, Bldg 10, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, NIH, Bldg 10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health [1ZIAHL006054-06] FX This work was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health (project number 1ZIAHL006054-06). NR 49 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2016 VL 150 IS 2 BP 283 EP 288 DI 10.1016/j.chest.2016.05.035 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DS7AG UT WOS:000380934100016 PM 27327118 ER PT J AU Harari, S Elia, D Torre, O Bulgheroni, E Provasi, E Moss, J AF Harari, Sergio Elia, Davide Torre, Olga Bulgheroni, Elisabetta Provasi, Elena Moss, Joel TI Sirolimus Therapy for Patients With Lymphangioleiomyomatosis Leads to Loss of Chylous Ascites and Circulating LAM Cells SO CHEST LA English DT Editorial Material ID TUBEROUS SCLEROSIS COMPLEX; EFFICACY; TSC2 AB A young woman received a diagnosis of abdominal, sporadic lymphangioleiomyomatosis (LAM) and multiple abdominal lymphangioleiomyomas and was referred for recurrent chylous ascites responding only to a fat-free diet. On admission, pulmonary function test (PFT) results showed a moderate reduction in the transfer factor for carbon monoxide with normal exercise performance. The serum vascular endothelial growth factor D (VEGF-D) level was 2,209 pg/mL. DNA sequences, amplified at loci kg8, D16S3395, D16S3024, D16S521, and D16S291 on chromosome 16p13.3, showed a loss of heterozygosity (LOH) only for kg8. Fat-free total parenteral nutrition in association with sirolimus (2 mg po daily) was initiated. Serum sirolimus levels were maintained at concentrations between 5 and 15 ng/mL. After 1 month, reintroduction of a low-fat oral feeding was achieved without recurrence of ascites. PFT results were stable. Interestingly, clinical improvement was associated with a reduction in the VEGF-D serum level (1,558 pg/mL). LOH at the kg8 biomarker in blood LAM cells was no longer detected. C1 [Harari, Sergio; Elia, Davide; Torre, Olga] Osped San Giuseppe, MultiMed, Serv Fisiopatol Resp & Emoodinam Polmonare, Unita Pneumol & Terapia Semiintens Resp,IRCCS, Via S Vittore 12, I-20142 Milan, Italy. [Bulgheroni, Elisabetta; Provasi, Elena] Ist Nazl Genet Mol Romeo & Enrica Invernizzi, Milan, Italy. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Elia, D (reprint author), Osped San Giuseppe, MultiMed, Serv Fisiopatol Resp & Emoodinam Polmonare, Unita Pneumol & Terapia Semiintens Resp,IRCCS, Via S Vittore 12, I-20142 Milan, Italy. EM davide.elia@multimedica.it OI Harari, Sergio/0000-0001-8629-7391 FU Intramural Research Program, NIH, NHLBI FX The authors have reported to CHEST the following: J. M. was supported by the Intramural Research Program, NIH, NHLBI. None declared (S. H., D. E., O. T., E. B., E. P.). NR 11 TC 0 Z9 0 U1 2 U2 2 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2016 VL 150 IS 2 BP E29 EP E32 DI 10.1016/j.chest.2016.02.654 PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DS7AG UT WOS:000380934100001 PM 27502989 ER PT J AU Izzi, JM Beck, SE Adams, RJ Pate, KAM Hutchinson, EK AF Izzi, Jessica M. Beck, Sarah E. Adams, Robert J. Pate, Kelly A. Metcalf Hutchinson, Eric K. TI Serum Cobalamin (Vitamin B-12) Concentrations in Rhesus Macaques (Macaca mulatta) and Pigtailed Macaques (Macaca nemestrina) with Chronic Idiopathic Diarrhea SO COMPARATIVE MEDICINE LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; BABOON PAPIO-CYNOCEPHALUS; GASTROINTESTINAL-DISEASE; RISK-FACTORS; THERAPEUTIC IMPLICATIONS; ACID-CONCENTRATIONS; METHYLMALONIC ACID; DEFICIENCY STATES; CROHNS-DISEASE; CATS AB Chronic diarrhea poses a significant threat to the health of NHP research colonies, and its primary etiology remains unclear. In macaques, the clinical presentation of intractable diarrhea and weight loss that are accompanied by inflammatory infiltrates within the gastrointestinal tract closely resembles inflammatory bowel disease of humans, dogs, and cats, in which low serum and tissue cobalamin (vitamin B-12) levels are due to intestinal malabsorption. We therefore hypothesized that macaques with chronic idiopathic diarrhea (CID) have lower serum cobalamin concentrations than do healthy macaques. Here we measured serum cobalamin concentrations in both rhesus and pigtailed macaques with CID and compared them with those of healthy controls. Serum cobalamin levels were 2.5-fold lower in pigtailed macaques with CID than control animals but did not differ between rhesus macaques with CID and their controls. This finding supports the use of serum cobalamin concentration as an adjunct diagnostic tool in pigtailed macaques that present with clinical symptoms of chronic gastrointestinal disease. This use of serum vitamin B-12 levels has implications for the future use of parenteral cobalamin supplementation to improve clinical outcomes in this species. C1 [Izzi, Jessica M.; Beck, Sarah E.; Adams, Robert J.; Pate, Kelly A. Metcalf] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21218 USA. [Izzi, Jessica M.; Hutchinson, Eric K.] NIH, Div Vet Resources, Bldg 10, Bethesda, MD 20892 USA. RP Izzi, JM (reprint author), Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21218 USA.; Izzi, JM (reprint author), NIH, Div Vet Resources, Bldg 10, Bethesda, MD 20892 USA. EM jizzi13@gmail.com FU NIH ORIP grants [R25 OD10913, P40 OD013117, K01 OD018244] FX We thank our fellow laboratory animal medicine trainees, especially Cassandra Moats, Anna Goodroe, Peter Otovic, Theresa Meade, and Meghan Vermillion, and the veterinary technical staff at the Johns Hopkins University Research Farm for their aid in sample collection throughout the study. This study was funded in part by NIH ORIP grants R25 OD10913, P40 OD013117, and K01 OD018244. NR 55 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2016 VL 66 IS 4 BP 324 EP 332 PG 9 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA DT1KV UT WOS:000381242500007 PM 27538863 ER PT J AU Connolly, MA Trentalange, M Zeiss, CJ AF Connolly, Meghan A. Trentalange, Mark Zeiss, Caroline J. TI Long-Term Clinical Outcomes in Diabetic Rhesus Macaques (Macaca mulatta) Treated with Medroxyprogesterone Acetate for Endometriosis SO COMPARATIVE MEDICINE LA English DT Article ID CONDITION SCORING SYSTEM; ORAL-CONTRACEPTIVES; WEIGHT-GAIN; MELLITUS; METABOLISM; GLUCOSE; WOMEN; MODEL; USERS; RISK AB Depot medroxyprogesterone acetate (DMPA) is a common medical treatment for endometriosis in NHP. Because DMPA reportedly impairs glucoregulatory function in humans and rhesus macaques, as well as predisposes humans to diabetes mellitus (DM), we performed a retrospective study to further investigate its potential long-term clinical effects in animals with and without DM. Using a cohort of 29 rhesus macaques, we explored the hypotheses that DMPA treatment accelerates the onset of DM and that its use in rhesus macaques with endometriosis worsens clinical outcome measures (lifespan, body weight and body condition score). For both body weight and body condition score, a declining and statistically significant trend in mean values was evident as macaques developed either DM, or endometriosis or both. The addition of DMPA did not significantly alter this pattern. The presence of DM, endometriosis, or DMPA treatment statistically but not clinically significantly increased risk of death. Similarly, the presence of the 2 highly correlated variables endometriosis and DMPA treatment statistically but not clinically significantly increased the risk of incident DM. These results indicate that DMPA treatment was associated with worsening trends in lifespan and incident DM, however these trends did not achieve clinical significance in this cohort. C1 [Connolly, Meghan A.] NIH, Div Vet Resources, Bldg 10, Bethesda, MD 20892 USA. [Trentalange, Mark] Yale Univ, Yale Program Aging, Biostat Core, New Haven, CT USA. [Zeiss, Caroline J.] Yale Univ, Comparat Med Sect, New Haven, CT USA. RP Connolly, MA (reprint author), NIH, Div Vet Resources, Bldg 10, Bethesda, MD 20892 USA. EM meghan.connolly@nih.gov NR 44 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2016 VL 66 IS 4 BP 343 EP 348 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA DT1KV UT WOS:000381242500009 PM 27538865 ER PT J AU MacAllister, RP McCully, CML Bacher, J Thomas, ML Cruz, R Wangari, S Warren, KE AF MacAllister, Rhonda Pung McCully, Cynthia M. Lester Bacher, John Thomas, Marvin L., III Cruz, Rafael Wangari, Solomon Warren, Katherine E. TI Minimally Invasive Lumbar Port System for the Collection of Cerebrospinal Fluid from Rhesus Macaques (Macaca mulatta) SO COMPARATIVE MEDICINE LA English DT Article ID MONKEYS; DRUGS; MODEL AB Biomedical translational research frequently incorporates collection of CSF from NHP, because CSF drug levels are used as a surrogate for CNS tissue penetration in pharmacokinetic and dynamic studies. Surgical placement of a CNS ventricular catheter reservoir for CSF collection is an intensive model to create and maintain and thus may not be feasible or practical for short-term studies. Furthermore, previous NHP lumbar port models require laminectomy for catheter placement. The new model uses a minimally invasive technique for percutaneous placement of a lumbar catheter to create a closed, subcutaneous system for effective, repeated CSF sample collection. None of the rhesus macaques (Macaca mulatta; n = 10) implanted with our minimally invasive lumbar port (MILP) system experienced neurologic deficits, postoperative infection of the surgical site, or skin erosion around the port throughout the 21.7-mo study. Functional MILP systems were maintained in 70% of the macaques, with multiple, high-quality, 0.5- to 1.0-mL samples of CSF collected for an average of 3 mo by using aspiration or gravitational flow. Among these macaques, 57% had continuous functionality for a mean of 19.2 mo; 50% of the cohort required surgical repair for port repositioning and replacement during the study. The MILP was unsuccessful in 2 macaques, at an average of 9.5 d after surgery. Nonpatency in these animals was attributed to the position of the lumbar catheter. The MILP system is an appropriate replacement for temporary catheterization and previous models requiring laminectomy and is a short-term alternative for ventricular CSF collection systems in NHP. C1 [MacAllister, Rhonda Pung; McCully, Cynthia M. Lester; Cruz, Rafael; Wangari, Solomon; Warren, Katherine E.] NCI, Bethesda, MD 20892 USA. [MacAllister, Rhonda Pung] Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. [Bacher, John; Thomas, Marvin L., III] NIH, Off Res Serv, Bldg 10, Bethesda, MD 20892 USA. RP MacAllister, RP (reprint author), NCI, Bethesda, MD 20892 USA.; MacAllister, RP (reprint author), Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. EM macallis@ohsu.edu FU Nonhuman Primate Division (Laboratory Animal Science Program, National Cancer Institute) FX We thank the Nonhuman Primate Division (Laboratory Animal Science Program, National Cancer Institute) for their support and excellence in animal care. NR 16 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2016 VL 66 IS 4 BP 349 EP 352 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA DT1KV UT WOS:000381242500010 PM 27538866 ER PT J AU Chackerian, B Remaley, A AF Chackerian, Bryce Remaley, Alan TI Vaccine strategies for lowering LDL by immunization against proprotein convertase subtilisin/kexin type 9 SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review DE atherosclerosis; cholesterol; proprotein convertase subtilisin; kexin type 9; vaccine ID DENSITY-LIPOPROTEIN-RECEPTOR; VIRUS-LIKE PARTICLES; HIGH-RISK PATIENTS; STATIN THERAPY; CARDIOVASCULAR EVENTS; CHRONIC DISEASES; REDUCING LIPIDS; PCSK9; CHOLESTEROL; EFFICACY AB Purpose of reviewmAbs targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have the potential to become groundbreaking therapies for the treatment of hypercholesterolemia. However, one major drawback of mAb-based therapy for a chronic condition like dyslipidemia is its relatively high cost. This review summarizes two recent studies describing novel vaccine approaches for lowering LDL-cholesterol by active immunization against PCSK9.Recent findingsPCSK9 is a plasma protein secreted by the liver that controls cholesterol homeostasis by enhancing endosomal and lysosomal degradation of the LDL receptor. Two PCSK9 inhibitory mAbs (evolocumab and alirocumab) have recently been approved by the Food and Drug Administration and a third mAb (bococizumab) is in late stage clinical trials. Treatment with PCSK9 mAbs, in combination with statins, reduces LDL-cholesterol levels by as much as 40-60%. As an alternative to mAbs, there have been two recent studies describing the development of vaccines that target PCSK9. These studies have shown that PCSK9 vaccines can effectively induce high-titer antibody responses that reduce proatherogenic lipoproteins in animal models.SummaryA PCSK9 vaccine-based approach could serve as a more widely applicable and a more cost-effective approach than mAb therapy for controlling hypercholesteremia and associated cardiovascular disease. C1 [Chackerian, Bryce] Univ New Mexico, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Remaley, Alan] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Chackerian, B (reprint author), Univ New Mexico, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. EM BChackerian@salud.unm.edu FU National Heart, Lung and Blood Institute; NIH [R01 AI083305]; Intramural Research Program of NHLBI FX This work was supported in part by intramural research funds from the National Heart, Lung and Blood Institute. Research was also funded by NIH grant R01 AI083305 (to BC) and by the Intramural Research Program of NHLBI. NR 35 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0957-9672 EI 1473-6535 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD AUG PY 2016 VL 27 IS 4 BP 345 EP 350 DI 10.1097/MOL.0000000000000312 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA DS8NQ UT WOS:000381040500004 PM 27389630 ER PT J AU Goodman, MF McDonald, JP Jaszczur, MM Woodgate, R AF Goodman, Myron F. McDonald, John P. Jaszczur, Malgorzata M. Woodgate, Roger TI Insights into the complex levels of regulation imposed on Escherichia coli DNA polymerase V SO DNA REPAIR LA English DT Review DE Translesion DNA synthesis; Posttranslational regulation; Proteolysis; Y-family DNA polymerase ID UMUD MUTAGENESIS PROTEIN; SOS MUTAGENESIS; RECA PROTEIN; UV MUTAGENESIS; ERROR-PRONE; EVOLUTIONARY FITNESS; ULTRAVIOLET-LIGHT; CLPXP PROTEASE; BINDING-SITES; IN-VITRO AB It is now close to 40 years since the isolation of non-mutable umu/uvm strains of Escherichia coli and the realization that damage induced mutagenesis in E.coli is not a passive process. Early models of mutagenesis envisioned the Umu proteins as accessory factors to the cell's replicase that not only reduced its normally high fidelity, but also allowed the enzyme to traverse otherwise replication-blocking lesions in the genome. However, these models underwent a radical revision approximately 15 years ago, with the discovery that the Umu proteins actually encode for a DNA polymerase, E.coli pol V. The polymerase lacks 3' -> 5' exonucleolytic proofreading activity and is inherently error-prone when replicating both undamaged and damage DNA. So as to limit any "gratuitous" mutagenesis, the activity of pol V is strictly regulated in the cell at multiple levels. This review will summarize our current understanding of the myriad levels of regulation imposed on pol V including transcriptional control, posttranslational modification, targeted proteolysis, activation of the catalytic activity of pol V through protein-protein interactions and the very recently described intracellular spatial regulation of pol V. Remarkably, despite the multiple levels at which pol V is regulated, the enzyme is nevertheless able to contribute to the genetic diversity and evolutionary fitness of E.coli. Published by Elsevier B.V. C1 [Goodman, Myron F.] Univ Southern Calif, Dept Biol Sci, Univ Pk, Los Angeles, CA 90089 USA. [Goodman, Myron F.] Univ Southern Calif, Dept Chem, Univ Pk, Los Angeles, CA 90089 USA. [McDonald, John P.; Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. [Jaszczur, Malgorzata M.] Univ Southern Calif, Dept Biol Sci, Univ Pk, Los Angeles, CA 90089 USA. RP Goodman, MF (reprint author), Univ Southern Calif, Dept Biol Sci, Univ Pk, Los Angeles, CA 90089 USA.; Goodman, MF (reprint author), Univ Southern Calif, Dept Chem, Univ Pk, Los Angeles, CA 90089 USA.; Woodgate, R (reprint author), 9800 Med Ctr Dr,Bldg C,Rm 320, Bethesda, MD 20892 USA. EM mgoodman@usc.edu; woodgate@mail.nih.gov FU NIH/NICHD Intramural Research Program [ES012259, GM21422] FX This study was made possible by funding from the NIH/NICHD Intramural Research Program to R.W. and ES012259, GM21422 to M.F.G. We thank Alexandra Vaisman for generating the figures shown in this review article. NR 73 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD AUG PY 2016 VL 44 BP 42 EP 50 DI 10.1016/j.dnarep.2016.05.005 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA DT0KA UT WOS:000381171200006 PM 27236212 ER PT J AU Mattingly, CJ Boyles, R Lawler, CP Haugen, AC Dearry, A Haendel, M AF Mattingly, Carolyn J. Boyles, Rebecca Lawler, Cindy P. Haugen, Astrid C. Dearry, Allen Haendel, Melissa TI Laying a Community-Based Foundation for Data-Driven Semantic Standards in Environmental Health Sciences SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review ID ANTIBIOTIC-RESISTANCE; ONTOLOGY; BIOLOGY; UNIFICATION; KNOWLEDGE; PROJECT; DISEASE AB BACKGROUND: Despite increasing availability of environmental health science (EHS) data, development, and implementation of relevant semantic standards, such as ontologies or hierarchical vocabularies, has lagged. Consequently, integration and analysis of information needed to better model environmental influences on human health remains a significant challenge. OBJECTIVES: We aimed to identify a committed community and mechanisms needed to develop EHS semantic standards that will advance understanding about the impacts of environmental exposures on human disease. METHODS: The National Institute of Environmental Health Sciences sponsored the "Workshop for the Development of a Framework for Environmental Health Science Language" hosted at North Carolina State University on 15-16 September 2014. Through the assembly of data generators, users, publishers, and funders, we aimed to develop a foundation for enabling the development of community-based and data-driven standards that will ultimately improve standardization, sharing, and interoperability of EHS information. DISCUSSION: Creating and maintaining an EHS common language is a continuous and iterative process, requiring community building around research interests and needs, enabling integration and reuse of existing data, and providing a low barrier of access for researchers needing to use or extend such a resource. CONCLUSIONS: Recommendations included developing a community-supported web-based toolkit that would enable a) collaborative development of EHS research questions and use cases, b) construction of user-friendly tools for searching and extending existing semantic resources, c) education and guidance about standards and their implementation, and d) creation of a plan for governance and sustainability. C1 [Mattingly, Carolyn J.] North Carolina State Univ, Dept Biol Sci, Campus Box 7633, Raleigh, NC 27695 USA. [Mattingly, Carolyn J.] North Carolina State Univ, Ctr Human Hlth & Environm, Raleigh, NC USA. [Boyles, Rebecca; Lawler, Cindy P.; Haugen, Astrid C.; Dearry, Allen] NIEHS, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Haendel, Melissa] Oregon Hlth & Sci Univ, Lib, Portland, OR 97201 USA. [Haendel, Melissa] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. RP Mattingly, CJ (reprint author), North Carolina State Univ, Dept Biol Sci, Campus Box 7633, Raleigh, NC 27695 USA. EM cjmattin@ncsu.edu OI Boyles, Rebecca/0000-0003-0073-6854 FU National Institutes of Health, NIEHS; Office of the Associate Director for Data Science FX This work was supported by the National Institutes of Health, the NIEHS, and the Office of the Associate Director for Data Science. NR 29 TC 1 Z9 1 U1 4 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 2016 VL 124 IS 8 BP 1136 EP 1140 DI 10.1289/ehp.1510438 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DS4KL UT WOS:000380749900011 PM 26871594 ER PT J AU Auerbach, S Filer, D Reif, D Walker, V Holloway, AC Schlezinger, J Srinivasan, S Svoboda, D Judson, R Bucher, JR Thayer, KA AF Auerbach, Scott Filer, Dayne Reif, David Walker, Vickie Holloway, Alison C. Schlezinger, Jennifer Srinivasan, Supriya Svoboda, Daniel Judson, Richard Bucher, John R. Thayer, Kristina A. TI Prioritizing Environmental Chemicals for Obesity and Diabetes Outcomes Research: A Screening Approach Using ToxCast (TM) High-Throughput Data SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review ID PANCREATIC BETA-CELLS; INSULIN-SECRETION; RODENTICIDE VACOR; MATERNAL SMOKING; WEIGHT-GAIN; C-ELEGANS; FORMAMIDINE PESTICIDE; TRIPHENYLTIN IMPAIRS; OBESOGEN TRIBUTYLTIN; GLUCOSE-INTOLERANCE AB BACKGROUND: Diabetes and obesity are major threats to public health in the United States and abroad. Understanding the role that chemicals in our environment play in the development of these conditions is an emerging issue in environmental health, although identifying and prioritizing chemicals for testing beyond those already implicated in the literature is challenging. This review is intended to help researchers generate hypotheses about chemicals that may contribute to diabetes and to obesity-related health outcomes by summarizing relevant findings from the U.S. Environmental Protection Agency (EPA) ToxCast (TM) high-throughput screening (HTS) program. OBJECTIVES: Our aim was to develop new hypotheses around environmental chemicals of potential interest for diabetes-or obesity-related outcomes using high-throughput screening data. METHODS: We identified ToxCast (TM) assay targets relevant to several biological processes related to diabetes and obesity (insulin sensitivity in peripheral tissue, pancreatic islet and beta cell function, adipocyte differentiation, and feeding behavior) and presented chemical screening data against those assay targets to identify chemicals of potential interest. DISCUSSION: The results of this screening-level analysis suggest that the spectrum of environmental chemicals to consider in research related to diabetes and obesity is much broader than indicated by research papers and reviews published in the peer-reviewed literature. Testing hypotheses based on ToxCast (TM) data will also help assess the predictive utility of this HTS platform. CONCLUSIONS: More research is required to put these screening-level analyses into context, but the information presented in this review should facilitate the development of new hypotheses. C1 [Auerbach, Scott; Walker, Vickie; Bucher, John R.; Thayer, Kristina A.] NIEHS, Div Natl Toxicol Program, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Filer, Dayne; Judson, Richard] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Reif, David] North Carolina State Univ, Bioinformat Res Ctr, Dept Biol Sci, Raleigh, NC USA. [Holloway, Alison C.] McMaster Univ, Dept Obstet & Gynecol, Hamilton, ON, Canada. [Schlezinger, Jennifer] Boston Univ, Sch Med, Dept Environm Hlth, Boston, MA 02118 USA. [Srinivasan, Supriya] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. [Svoboda, Daniel] SciOme LLC, Res Triangle Pk, NC USA. RP Thayer, KA (reprint author), NIEHS, NTP Off Hlth Assessment & Translat OHAT, NTP, 530 Davis Dr,Room 2150 Mail Drop K2-04, Morrisville, NC 27560 USA. EM thayer@niehs.nih.gov FU National Institute of Environmental Health Sciences/National Institutes of Health; U.S. Environmental Protection Agency (EPA) FX This research was supported by the National Institute of Environmental Health Sciences/National Institutes of Health and the U.S. Environmental Protection Agency (EPA). NR 96 TC 2 Z9 2 U1 6 U2 10 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 2016 VL 124 IS 8 BP 1141 EP 1154 DI 10.1289/ehp.1510456 PG 14 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DS4KL UT WOS:000380749900012 PM 26978842 ER PT J AU Aaron, CP Chervona, Y Kawut, SM Roux, AVD Shen, MW Bluemke, DA Van Hee, VC Kaufman, JD Barr, RG AF Aaron, Carrie P. Chervona, Yana Kawut, Steven M. Roux, Ana V. Diez Shen, Mingwu Bluemke, David A. Van Hee, Victor C. Kaufman, Joel D. Barr, R. Graham TI Particulate Matter Exposure and Cardiopulmonary Differences in the Multi-Ethnic Study of Atherosclerosis SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID LEFT-VENTRICULAR MASS; POLLUTION MESA AIR; OBSTRUCTIVE-PULMONARY-DISEASE; SUBCLINICAL ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; PERCENT EMPHYSEMA; FLOW OBSTRUCTION; TERM EXPOSURE; PRESSURE; LUNG AB BACKGROUND: Particulate matter (PM) exposure may directly affect the pulmonary vasculature. Although the pulmonary vasculature is not easily measurable, differential associations for right ventricular (RV) and left ventricular (LV) mass may provide an indirect assessment of pulmonary vascular damage. OBJECTIVES: We tested whether long-term exposure to PM < 2.5 mu m (PM2.5) is associated with greater RV mass and RV mass/end-diastolic volume ratio relative to the LV. METHODS: The Multi-Ethnic Study of Atherosclerosis performed cardiac magnetic resonance (CMR) imaging among participants 45-84 years old without clinical cardiovascular disease in 2000-2002 in six U.S. cities. A fine-scale spatiotemporal model estimated ambient PM2.5 exposure in the year before CMR; individually weighted estimates accounted for indoor exposure to ambient PM2.5. Linear regression models were adjusted for demographics, anthropometrics, smoking status, cardiac risk factors, and LV parameters, with additional adjustment for city. RESULTS: The 4,041 included participants had a mean age of 61.5 years, and 47% were never smokers. The mean ambient PM2.5 was 16.4 mu g/m(3) and individually weighted PM2.5 was 11.0 mu g/m(3). PM2.5 exposure was associated with greater RV mass [ambient: 0.11 g per 5 mu g/m(3) (95% CI: -0.05, 0.27); individually weighted: 0.20 g per 5 mu g/m(3) (95% CI: 0.04, 0.36)] and a greater RV mass/end-diastolic volume ratio conditional on LV parameters. City-adjusted results for RV mass were of greater magnitude and were statistically significant for both measures of PM2.5, whereas those for RV mass/end-diastolic volume ratio were attenuated. CONCLUSIONS: Long-term PM2.5 exposures were associated with greater RV mass and RV mass/end-diastolic volume ratio conditional on the LV; however, additional adjustment for city attenuated the RV mass/end-diastolic volume findings. These findings suggest that PM2.5 exposure may be associated with subclinical cardiopulmonary differences in this general population sample. C1 [Aaron, Carrie P.; Chervona, Yana; Barr, R. Graham] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY USA. [Chervona, Yana] NYU, Dept Environm Med, 550 1St Ave, New York, NY 10016 USA. [Kawut, Steven M.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Roux, Ana V. Diez; Shen, Mingwu] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Bluemke, David A.] NIH, Radiol & Imaging Sci, Ctr Clin, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. [Van Hee, Victor C.; Kaufman, Joel D.] Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. [Van Hee, Victor C.; Kaufman, Joel D.] Univ Washington, Dept Med, Seattle, WA USA. [Van Hee, Victor C.; Kaufman, Joel D.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Barr, R. Graham] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. RP Aaron, CP (reprint author), Columbia Univ, Coll Phys & Surg, PH 9 East Room 105,630 West 168th St, New York, NY 10032 USA. EM cp2346@columbia.edu RI Kaufman, Joel/B-5761-2008; OI Kaufman, Joel/0000-0003-4174-9037; Bluemke, David/0000-0002-8323-8086 FU National Heart, Blood, and Lung Institute, National Institutes of Health (NHBLI/NIH) [N01-HC-95159, N01-HC-95169, R01-HL077612, RC1-HL100543, R01-HL086719]; U.S. Environmental Protection Agency (EPA) [R830543, R831697, K24-HL103844]; MESA Investigators; U.S. EPA; Actelion Pharmaceuticals US, Inc; United Therapeutics Corporation; Gilead Sciences, Inc.; Lung Biotechnology PBC; Pfizer Inc.; Ikaria, Inc.; Pulmonary Hypertension Association; Merck Co., Inc.; GeNO LLC; Bayer AG; European Respiratory Journal and Insmed Incorporated; Alpha1 Foundation FX The MESA study is conducted and supported by the National Heart, Blood, and Lung Institute, National Institutes of Health (NHBLI/NIH) (N01-HC-95159 through N01-HC-95165 and N01-HC-95169, R01-HL077612, RC1-HL100543, and R01-HL086719) and by the U.S. Environmental Protection Agency (EPA) (R830543, R831697, and K24-HL103844) and MESA Investigators. This publication was also developed under a STAR research assistance agreement, No. RD831697 (MESA Air), awarded by the U.S. EPA.; Y.C. reports employment by SafeBridge Consultants, Inc. since September 2013. S.M.K. reports grant support from Actelion Pharmaceuticals US, Inc; United Therapeutics Corporation; Gilead Sciences, Inc.; Lung Biotechnology PBC; Pfizer Inc.; Ikaria, Inc.; the Pulmonary Hypertension Association; Merck & Co., Inc.; GeNO LLC; and Bayer AG; travel reimbursement from the American College of Chest Physicians and the American Thoracic Society; and personal fees from the European Respiratory Journal and Insmed Incorporated. R.G.B. reports grant funding from the Alpha1 Foundation, travel reimbursement from the COPD Foundation and royalties from UpToDate, Inc. These funding sources did not influence the design, collection, analysis, interpretation of the data, or decision to publish this work. The other authors declare they have no actual or potential competing financial interests. NR 50 TC 1 Z9 1 U1 6 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 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 2016 VL 124 IS 8 BP 1166 EP 1173 DI 10.1289/ehp.1409451 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DS4KL UT WOS:000380749900014 PM 26859533 ER PT J AU Gassman, NR Coskun, E Jaruga, P Dizdaroglu, M Wilson, SH AF Gassman, Natalie R. Coskun, Erdem Jaruga, Pawel Dizdaroglu, Miral Wilson, Samuel H. TI Combined Effects of High-Dose Bisphenol A and Oxidizing Agent (KBrO3) on Cellular Microenvironment, Gene Expression, and Chromatin Structure of Ku70-deficient Mouse Embryonic Fibroblasts SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID BASE EXCISION-REPAIR; OXIDATIVE DNA-DAMAGE; ENDOCRINE DISRUPTORS; ESTROGEN RESPONSE; NA+/H+ EXCHANGER; INTRACELLULAR PH; LIVING CELLS; CANCER CELLS; MALE RATS; STRESS AB BACKGROUND: Exposure to bisphenol A (BPA) has been reported to alter global gene expression, induce epigenetic modifications, and interfere with complex regulatory networks of cells. In addition to these reprogramming events, we have demonstrated that BPA exposure generates reactive oxygen species and promotes cellular survival when co-exposed with the oxidizing agent potassium bromate (KBrO3). OBJECTIVES: We determined the cellular microenvironment changes induced by co-exposure of BPA and KBrO3 versus either agent alone. Methods: Ku70-deficient cells were exposed to 150 mu M BPA, 20 mM KBrO3, or co-exposed to both agents. Four and 24 hr post-damage initiation by KBrO3, with BPA-only samples timed to coincide with these designated time points, we performed whole-genome microarray analysis and evaluated chromatin structure, DNA lesion load, glutathione content, and intracellular pH. RESULTS: We found that 4 hr post-damage initiation, BPA exposure and co-exposure transiently condensed chromatin compared with untreated and KBrO3-only treated cells; the transcription of DNA repair proteins was also reduced. At this time point, BPA exposure and co-exposure also reduced the change in intracellular pH observed after treatment with KBrO3 alone. Twenty-four hours post-damage initiation, BPA-exposed cells showed less condensed chromatin than cells treated with KBrO3 alone; the intracellular pH of the co-exposed cells was significantly reduced compared with untreated and KBrO3-treated cells; and significant up-regulation of DNA repair proteins was observed after co-exposure. CONCLUSION: These results support the induction of an adaptive response by BPA co-exposure that alters the microcellular environment and modulates DNA repair. Further work is required to determine whether BPA induces similar DNA lesions in vivo at environmentally relevant doses; however, in the Ku70-deficient mouse embryonic fibroblasts, exposure to a high dose of BPA was associated with changes in the cellular microenvironment that may promote survival. C1 [Gassman, Natalie R.; Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Coskun, Erdem; Jaruga, Pawel; Dizdaroglu, Miral] NIST, Biomol Measurement Div, Gaithersburg, MD 20899 USA. [Coskun, Erdem] Gazi Univ, Fac Pharm, Ankara, Turkey. [Gassman, Natalie R.] Univ S Alabama, Dept Oncol Sci, Mitchell Canc Inst, Mobile, AL USA. RP Wilson, SH (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU National Institutes of Health, NIEHS [Z01-ES050158, Z01-ES050159]; NIEHS [1K99ES023813-01] FX This research was supported by research project numbers Z01-ES050158 and Z01-ES050159 (S.H.W.) in the intramural research program of the National Institutes of Health, NIEHS. N.R.G. is funded by NIEHS grant 1K99ES023813-01. NR 56 TC 2 Z9 2 U1 3 U2 7 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 2016 VL 124 IS 8 BP 1241 EP 1252 DI 10.1289/EHP237 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DS4KL UT WOS:000380749900023 PM 27082013 ER PT J AU Cui, YX Balshaw, DM Kwok, RK Thompson, CL Collman, GW Birnbaum, LS AF Cui, Yuxia Balshaw, David M. Kwok, Richard K. Thompson, Claudia L. Collman, Gwen W. Birnbaum, Linda S. TI The Exposome: Embracing the Complexity for Discovery in Environmental Health SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID DISEASE; LIFE; EPIDEMIOLOGY; POLLUTANTS; CHALLENGE; RISK AB Environmental exposures are ubiquitous and play a fundamental role in the development of complex human diseases. The exposome, which is defined as the totality of environmental exposures over the life course, allows for systematic evaluation of the relationship between exposures and associated biological consequences, and represents a powerful approach for discovery in environmental health research. However, implementing the exposome concept is challenged by the ability to accurately assess multiple exposures and the ability to integrate information across the exposure-disease continuum. On 14-15 January 2015, the National Institute of Environmental Health Sciences (NIEHS) held the Exposome Workshop where a group of international and U.S. scientists from different disciplines gathered to review the state of the science in research areas related to the exposome and to provide recommendations for incorporating the exposome concept into each research area. To move the field forward, the NIEHS is establishing a Children's Health Exposure Analysis Resource (CHEAR) to provide infrastructure support for access to laboratory and statistical analyses to children's health studies. It is recognized that incorporating the exposome concept into exposure and environmental health research will be a long journey and will require significant collaborative efforts from different scientific disciplines, nations, and stakeholders. C1 [Cui, Yuxia; Balshaw, David M.] NIEHS, Exposure Response & Technol Branch, Div Extramural Res & Training, NIH,US DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Kwok, Richard K.] NIEHS, Epidemiol Branch, Div Intramural Res, NIH,DHHS, Res Triangle Pk, NC 27709 USA. [Thompson, Claudia L.] NIEHS, Populat Hlth Branch, Div Extramural Res & Training, NIH,DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Collman, Gwen W.] NIEHS, Div Extramural Res & Training, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIEHS, Off Director, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP Balshaw, DM (reprint author), NIEHS, NIH, US Dept HHS, POB 12233,Mail Drop K3-04, Res Triangle Pk, NC 27709 USA. EM balshaw@niehs.nih.gov RI Kwok, Richard/B-6907-2017 OI Kwok, Richard/0000-0002-6794-8360 FU NIEHS, NIH FX The NIEHS Exposome Workshop was supported by the NIEHS, NIH. NR 25 TC 2 Z9 2 U1 6 U2 11 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 2016 VL 124 IS 8 BP A137 EP A140 DI 10.1289/EHP412 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DS4KL UT WOS:000380749900003 PM 27479988 ER PT J AU Darney, SP AF Darney, Sally Perreault TI EHP Highlights of the Past Year SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Darney, Sally Perreault] NIEHS, Environm Hlth Perspect, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP Darney, SP (reprint author), NIEHS, Environm Hlth Perspect, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM sally.darney@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 2016 VL 124 IS 8 BP A132 EP A132 DI 10.1289/EHP777 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DS4KL UT WOS:000380749900001 PM 27479990 ER PT J AU Mason, JL Johnston, E Berndt, S Segal, K Lei, M Wiest, JS AF Mason, Julie L. Johnston, Elizabeth Berndt, Sam Segal, Katie Lei, Ming Wiest, Jonathan S. TI Labor and skills gap analysis of the biomedical research workforce SO FASEB JOURNAL LA English DT Article DE training; education; occupation; graduate students; postdoctoral fellows AB The United States has experienced an unsustainable increase of the biomedical research workforce over the past 3 decades. This expansion has led to a myriad of consequences, including an imbalance in the number of researchers and available tenure-track faculty positions, extended postdoctoral training periods, increasing age of investigators at first U.S. National Institutes of Health R01 grant, and exodus of talented individuals seeking careers beyond traditional academe. Without accurate data on the biomedical research labor market, challenges will remain in resolving these problems and in advising trainees of viable career options and the skills necessary to be productive in their careers. We analyzed workforce trends, integrating both traditional labor market information and real-time job data. We generated a profile of the current biomedical research workforce, performed labor gap analyses of occupations in the workforce at regional and national levels, and assessed skill transferability between core and complementary occupations. We conclude that although supply into the workforce and the number of job postings for occupations within that workforce have grown over the past decade, supply continues to outstrip demand. Moreover, we identify practical skill sets from real-time job postings to optimally equip trainees for an array of careers to effectively meet future workforce demand. C1 [Mason, Julie L.; Lei, Ming; Wiest, Jonathan S.] NCI, Ctr Canc Training, NIH, Bethesda, MD 20892 USA. [Johnston, Elizabeth; Segal, Katie] ICF Int, Cambridge, MA USA. [Berndt, Sam] ICF Int, Fairfax, VA USA. RP Mason, JL (reprint author), NCI, Ctr Canc Training, 9609 Med Ctr Dr,2W-120, Bethesda, MD 20892 USA. EM masonjl@mail.nih.gov FU NCI/NIH; NIH [HHSN261201200010I, HHSN261201500149P] FX The authors thank Misty Heggeness [U.S. National Institutes of Health (NIH) Office of the Director, Division of Biomedical Research Workforce), Patricia Labosky (NIH Office of the Director, Office of Strategic Coordination), and Randall Ribaudo (Human Workflows, LLC) for guidance and suggestions on this analysis, and Erika Ginsburg [NIH National Cancer Institute (NCI) Center for Cancer Training] for critically reviewing the manuscript. This research was supported by the Office of the Director, NCI/NIH. All authors are employees or contractors of NIH. ICF International acknowledges support from NIH Contract HHSN261201200010I. Access to Labor Insight, Burning Glass Technologies, was available through NIH Contract HHSN261201500149P. Any views expressed are those of the authors and not necessarily those of the NIH. The authors declare no conflicts of interest. NR 32 TC 1 Z9 1 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD AUG PY 2016 VL 30 IS 8 BP 2673 EP 2683 DI 10.1096/fj.201500067R PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DS7WP UT WOS:000380994000005 PM 27075242 ER PT J AU Almuzzaini, B Sarshad, AA Rahmanto, AS Hansson, ML Von Euler, A Sangfelt, O Visa, N Farrants, AKO Percipalle, P AF Almuzzaini, Bader Sarshad, Aishe A. Rahmanto, Aldwin S. Hansson, Magnus L. Von Euler, Anne Sangfelt, Olle Visa, Neus Farrants, Ann-Kristin Ostlund Percipalle, Piergiorgio TI In beta-actin knockouts, epigenetic reprogramming and rDNA transcription inactivation lead to growth and proliferation defects SO FASEB JOURNAL LA English DT Article DE genome-wide analysis; NM1; nuclear actin; rRNA synthesis ID POLYMERASE-I TRANSCRIPTION; RIBOSOMAL-RNA GENES; NUCLEOLAR TRANSCRIPTION; NUCLEAR ACTIN; CELL-GROWTH; FACTOR UBF; FACTOR SL1; MYOSIN-I; PROMOTER; COMPLEX AB Actin and nuclear myosin 1 (NM1) are regulators of transcription and chromatin organization. Using a genome-wide approach, we report here that beta-actin binds intergenic and genic regions across the mammalian genome, associated with both protein-coding and rRNA genes. Within the rDNA, the distribution of beta-actin correlated with NM1 and the other subunits of the B-WICH complex, WSTF and SNF2h. In beta-actin(-/-) mouse embryonic fibroblasts (MEFs), we found that rRNA synthesis levels decreased concomitantly with drops in RNA polymerase I (Pol I) and NM1 occupancies across the rRNA gene. Reintroduction of wild-type beta-actin, in contrast to mutated forms with polymerization defects, efficiently rescued rRNA synthesis underscoring the direct role for a polymerization-competent form of beta-actin in Pol I transcription. The rRNA synthesis defects in the beta-actin(-/-) MEFs are a consequence of epigenetic reprogramming with up-regulation of the repressive mark H3K4me1 (mono-methylation of lys4 on histone H3) and enhanced chromatin compaction at promoter-proximal enhancer (T0 sequence), which disturb binding of the transcription factor TTF1. We propose a novel genome-wide mechanism where the polymerase-associated beta-actin synergizes with NM1 to coordinate permissive chromatin with Pol I transcription, cell growth, and proliferation. C1 [Almuzzaini, Bader; Sarshad, Aishe A.; Rahmanto, Aldwin S.; Hansson, Magnus L.; Sangfelt, Olle; Percipalle, Piergiorgio] Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden. [Almuzzaini, Bader] King Abdullah Int Med Res Ctr, Natl Guard Hlth Affairs, Riyadh, Saudi Arabia. [Von Euler, Anne; Visa, Neus; Farrants, Ann-Kristin Ostlund; Percipalle, Piergiorgio] Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden. [Percipalle, Piergiorgio] New York Univ Abu Dhabi, Dept Biol, Div Sci, Abu Dhabi, U Arab Emirates. [Sarshad, Aishe A.] NIAMSD, NIH, Bethesda, MD USA. RP Percipalle, P (reprint author), New York Univ Abu Dhabi, Saadyiat Campus, Abu Dhabi 129188, U Arab Emirates. EM pp69@nyu.edu FU Swedish Research Council; Swedish Cancer Society; National Guard Health Affairs-King Abdullah International Medical Research Center; Karolinska Institute doctoral fellowship; Swedish Society for Medical Research; Radiumhemmets Forskningsfonder FX The authors thank C. Ampe (University of Ghent, Ghent, Belgium) and R. Treissman (London Research Institute, London, United Kingdom) for kindly providing the beta-actin+/+ MEFs, beta-actin-/- MEFs, and beta-actin constructs. The authors also thank M. Corcoran and M. Rahman (both from the Karolinska Institute) for technical help. This work was supported by grants from the Swedish Research Council and the Swedish Cancer Society to P.P., O.S., and N.V. B.A.M. was cofunded by National Guard Health Affairs-King Abdullah International Medical Research Center, and A.A.S. was cofunded by a Karolinska Institute doctoral fellowship. M.H. was supported by a postdoctoral fellowship from the Swedish Society for Medical Research. A.S.R. was supported by funds from Radiumhemmets Forskningsfonder. NR 48 TC 1 Z9 1 U1 2 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD AUG PY 2016 VL 30 IS 8 BP 2860 EP 2873 DI 10.1096/fj.201600280R PG 14 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DS7WP UT WOS:000380994000021 PM 27127100 ER PT J AU Karzai, FH Madan, RA Dahut, WL AF Karzai, Fatima H. Madan, Ravi A. Dahut, William L. TI Metabolic syndrome in prostate cancer: impact on risk and outcomes SO FUTURE ONCOLOGY LA English DT Review DE androgen-deprivation therapy; androgen receptor; cardiovascular risk; diabetes; gonadotropin-releasing hormone agonist/antagonist; hypertriglyceridemia; insulin resistance; metabolic syndrome; prostate cancer ID ANDROGEN-DEPRIVATION THERAPY; INSULIN-RESISTANCE; CARDIOVASCULAR MORTALITY; PELVIC LYMPHADENECTOMY; RADICAL PROSTATECTOMY; MEN; ASSOCIATION; CHEMOTHERAPY; BLOCKADE; ESTROGEN AB Androgen-deprivation therapy (ADT) is a fundamental element of treatment for nonlocalized prostate cancer and for patients with high-risk disease who are not candidates for radical treatment. ADT has been linked to metabolic syndrome, which involves changes in metabolic factors. While distinct from classic metabolic syndrome, this type does include changes in body composition, lipid profiles and insulin resistance. The constellation of risk factors may be associated with cardiovascular morbidity and the onset of diabetes mellitus. Physicians should discuss in detail the risk and benefits of ADT, as well as any needed lifestyle modifications with patients before beginning therapy. C1 [Karzai, Fatima H.; Madan, Ravi A.; Dahut, William L.] NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. RP Dahut, WL (reprint author), NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. EM dahutw@mail.nih.gov NR 55 TC 0 Z9 0 U1 1 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PD AUG PY 2016 VL 12 IS 16 BP 1947 EP 1955 DI 10.2217/fon-2016-0061 PG 9 WC Oncology SC Oncology GA DS8JS UT WOS:000381030000011 PM 27067408 ER PT J AU Bunch, H Lawney, BP Burkholder, A Ma, DD Zheng, XF Motola, S Fargo, DC Levine, SS Wang, YYE Hue, G AF Bunch, Heeyoun Lawney, Brian P. Burkholder, Adam Ma, Duanduan Zheng, Xiaofeng Motola, Shmulik Fargo, David C. Levine, Stuart S. Wang, Yaoyu E. Hue, Guang TI RNA polymerase II promoter-proximal pausing in mammalian long non-coding genes SO GENOMICS LA English DT Article DE Long non-coding RNAs; RNA polymerase II promoter-proximal pausing; TRIM28 ID POL-II; TRANSCRIPTIONAL ELONGATION; DIVERGENT TRANSCRIPTION; MEDIATOR COMPLEX; PREPARES GENES; P-TEFB; EXPRESSION; INITIATION; DROSOPHILA; RELEASE AB Mammalian genomes encode a large number of non-coding RNAs (ncRNAs) that greatly exceed mRNA genes. While the physiological and pathological roles of ncRNAs have been increasingly understood, the mechanisms of regulation of ncRNA expression are less clear. Here, our genomic study has shown that a significant number of long non-coding RNAs (lncRNAs, >1000 nucleotides) harbor RNA polymerase II (Pol II) engaged with the transcriptional start site. A pausing and transcriptional elongation factor for protein-coding genes, tripartite motif-containing 28 (TRIM28) regulates the transcription of a subset of lncRNAs in mammalian cells. In addition, the majority of lncRNAs in human and murine cells regulated by Pol II promoter-proximal pausing appear to function in stimulus-inducible biological pathways. Our findings suggest an important role of Pol II pausing for the transcription of mammalian lncRNA genes. (C) 2016 Elsevier Inc. All rights reserved. C1 [Bunch, Heeyoun] Harvard Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Lawney, Brian P.; Wang, Yaoyu E.] Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02130 USA. [Burkholder, Adam; Fargo, David C.] NIEHS, Integrat Bioinformat, NIH, Res Triangle Pk, NC 27705 USA. [Ma, Duanduan; Motola, Shmulik; Levine, Stuart S.] MIT, BioMicro Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Zheng, Xiaofeng; Hue, Guang] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, Res Triangle Pk, NC 27705 USA. RP Bunch, H (reprint author), Harvard Med Sch, Dept Genet & Complex Dis, Harvard Sch Publ Hlth, Goldenson Bldg,Room 559,220 Longwood Ave, Boston, MA 02115 USA. EM heeyounbunch@gmail.com OI Bunch, Heeyoun/0000-0003-0038-1985 FU Harvard Joint Center for Radiation Therapy FX We appreciate S. K. Calderwood in Beth Israel Deaconess Medical Center & Harvard Medical School for discussions and reading the manuscript and P. J. Park and L. Jung in Brigham Women Hospital & Harvard Medical School for providing initial bioinformatics analysis and discussions. We are grateful to D. J. Taatjes in the University of Colorado, Boulder and to J. Rinn in the Broad Institute for their critical reading and helpful comments of the manuscript. H.B. is grateful to D. Bunch, Joy, R. Baker, M. Seaquist, K. Perkins, D. Verrengia, G. Hugenberger, and P.S.C. for their loving support and encouragement throughout the work. This study was supported by grants from the Harvard Joint Center for Radiation Therapy to H.B. NR 59 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 EI 1089-8646 J9 GENOMICS JI Genomics PD AUG PY 2016 VL 108 IS 2 BP 64 EP 77 DI 10.1016/j.ygeno.2016.07.003 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DT4UX UT WOS:000381477700003 PM 27432546 ER PT J AU Baydyuk, M Xu, JH Wu, LG AF Baydyuk, Maryna Xu, Jianhua Wu, Ling-Gang TI The calyx of Held in the auditory system: Structure, function, and development SO HEARING RESEARCH LA English DT Review ID SYNAPTIC VESICLE ENDOCYTOSIS; PRESYNAPTIC CALCIUM CURRENT; READILY RELEASABLE POOL; SHORT-TERM DEPRESSION; RAT MEDIAL NUCLEUS; FAST CNS SYNAPSE; VENTRAL COCHLEAR NUCLEUS; BUSHY CELL AXONS; TRAPEZOID BODY; TRANSMITTER RELEASE AB The calyx of Held synapse plays an important role in the auditory system, relaying information about. sound localization via fast and precise synaptic transmission, which is achieved by its specialized structure and giant size. During development, the calyx of Held undergoes anatomical, morphological, and physiological changes necessary for performing its functions. The large dimensions of the calyx of Held nerve terminal are well suited for direct electrophysiological recording of many presynaptic events that are difficult, if not impossible to record at small conventional synapses. This unique accessibility has been used to investigate presynaptic ion channels, transmitter release, and short-term plasticity, providing invaluable information about basic presynaptic mechanisms of transmission at a central synapse. Here, we review anatomical and physiological specializations of the calyx of Held, summarize recent studies that provide new mechanisms important for calyx development and reliable synaptic transmission, and examine fundamental presynaptic mechanisms learned from studies using calyx as a model nerve terminal. This article is part of a Special Issue entitled . (C) 2016 Elsevier B.V. All rights reserved. C1 [Baydyuk, Maryna; Wu, Ling-Gang] NINDS, 35 Convent Dr,Bldg 35, Bethesda, MD 20892 USA. [Xu, Jianhua] Augusta Univ, Med Coll Georgia, Dept Neurosci & Regenerat Med, Augusta, GA 30912 USA. [Xu, Jianhua] Augusta Univ, Med Coll Georgia, Dept Neurol, Augusta, GA 30912 USA. [Baydyuk, Maryna] Georgetown Univ, Dept Biol, 3700 O St NW, Washington, DC 20057 USA. RP Baydyuk, M (reprint author), NINDS, 35 Convent Dr,Bldg 35, Bethesda, MD 20892 USA.; Baydyuk, M (reprint author), Georgetown Univ, Dept Biol, 3700 O St NW, Washington, DC 20057 USA. EM mb339@georgetown.edu FU NINDS Intramural Research Program FX This work was supported by the NINDS Intramural Research Program. NR 151 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 EI 1878-5891 J9 HEARING RES JI Hear. Res. PD AUG PY 2016 VL 338 SI SI BP 22 EP 31 DI 10.1016/j.heares.2016.03.009 PG 10 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA DT9RQ UT WOS:000381840400003 PM 27018297 ER PT J AU Singh, A Blaskovic, D Joo, J Yang, Z Jackson, SH Coleman, WG Yan, M AF Singh, Aparna Blaskovic, Dusan Joo, Jungsoo Yang, Zhen Jackson, Sharon H. Coleman, William G., Jr. Yan, Ming TI Investigating the Role of Helicobacter pylori PriA Protein SO HELICOBACTER LA English DT Article DE Helicobacter pylori; DNA helicase; replication fork stabilization ID VIVO EXPRESSION TECHNOLOGY; T-ANTIGEN GENE; ESCHERICHIA-COLI; DELAYED PHAGOCYTOSIS; GASTRIC SURFACE; DNA-REPAIR; GNOTOBIOTIC PIGLETS; BACTERIAL VIRULENCE; EPITHELIAL-CELLS; VIRAL-DNA AB BackgroundIn bacteria, PriA protein, a conserved DEXH-type DNA helicase, plays a central role in replication restart at stalled replication forks. Its unique DNA binding property allows it to recognize and stabilize stalled forks and the structures derived from them. PriA plays a very critical role in replication fork stabilization and DNA repair in E. coli and N. gonorrhoeae. In our in vivo expression technology screen, priA gene was induced in vivo when Helicobacter pylori infects mouse stomach. Materials and MethodsWe decided to elucidate the role of H. pylori PriA protein in survival in mouse stomach, survival in gastric epithelial cells and macrophage cells, DNA repair, acid stress, and oxidative stress. ResultsThe priA null mutant strain was unable to colonize mice stomach mucosa after long-term infections. Mouse colonization was observed after 1 week of infection, but the levels were much lower than the wild-type HpSS1 strain. PriA protein was found to be important for intracellular survival of epithelial cell-/macrophage cell-ingested H. pylori. Also, a priA null mutant was more sensitive to DNA-damaging agents and was much more sensitive to acid and oxidative stress as compared to the wild-type strain. ConclusionsThese data suggest that the PriA protein is needed for survival and persistence of H. pylori in mice stomach mucosa. C1 [Singh, Aparna; Blaskovic, Dusan; Joo, Jungsoo; Yang, Zhen; Coleman, William G., Jr.; Yan, Ming] NIDDK, NIH, Bethesda, MD 20892 USA. [Jackson, Sharon H.; Coleman, William G., Jr.] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD 20892 USA. RP Jackson, SH (reprint author), Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD 20892 USA.; Yan, M (reprint author), NIH, Kidney Dis, Bldg 10, Bethesda, MD 20892 USA. EM sjackson@mail.nih.gov; yanming@niddk.nih.gov FU intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases; intramural research program of the National Institute on Minority Health and Health Disparities FX This research was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, and the intramural research program of the National Institute on Minority Health and Health Disparities. We are thankful to Dr. Reed B. Wickner, NIDDK, NIH, for critical reading of the manuscript. NR 57 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1083-4389 EI 1523-5378 J9 HELICOBACTER JI Helicobacter PD AUG PY 2016 VL 21 IS 4 BP 295 EP 304 DI 10.1111/hel.12283 PG 10 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA DS0EU UT WOS:000380269000006 PM 26817518 ER PT J AU Talarico, S Safaeian, M Gonzalez, P Hildesheim, A Herrero, R Porras, C Cortes, B Larson, A Fang, FC Salama, NR AF Talarico, Sarah Safaeian, Mahboobeh Gonzalez, Paula Hildesheim, Allan Herrero, Rolando Porras, Carolina Cortes, Bernal Larson, Ann Fang, Ferric C. Salama, Nina R. TI Quantitative Detection and Genotyping of Helicobacter pylori from Stool using Droplet Digital PCR Reveals Variation in Bacterial Loads that Correlates with cagA Virulence Gene Carriage SO HELICOBACTER LA English DT Article DE Droplet digital PCR; stool-based assay; bacterial load; cagA gene; H; pylori ID POLYMERASE-CHAIN-REACTION; COMPLETE GENOME SEQUENCE; TYROSINE PHOSPHORYLATION; INFECTION; CHILDREN; DISEASE; PROTEIN; SAMPLES; CANCER; RISK AB BackgroundEpidemiologic studies of the carcinogenic stomach bacterium Helicobacter pylori have been limited by the lack of noninvasive detection and genotyping methods. We developed a new stool-based method for detection, quantification, and partial genotyping of H. pylori using droplet digital PCR (ddPCR), which allows for increased sensitivity and absolute quantification by PCR partitioning. Materials and MethodsStool-based ddPCR assays for H. pylori 16S gene detection and cagA virulence gene typing were tested using a collection of 50 matched stool and serum samples from Costa Rican volunteers and 29 H. pylori stool antigen-tested stool samples collected at a US hospital. ResultsThe stool-based H. pylori 16S ddPCR assay had a sensitivity of 84% and 100% and a specificity of 100% and 71% compared to serology and stool antigen tests, respectively. The stool-based cagA genotyping assay detected cagA in 22 (88%) of 25 stools from CagA antibody-positive individuals and four (16%) of 25 stools from CagA antibody-negative individuals from Costa Rica. All 26 of these samples had a Western-type cagA allele. Presence of serum CagA antibodies was correlated with a significantly higher load of H. pylori in the stool. ConclusionsThe stool-based ddPCR assays are a sensitive, noninvasive method for detection, quantification, and partial genotyping of H. pylori. The quantitative nature of ddPCR-based H. pylori detection revealed significant variation in bacterial load among individuals that correlates with presence of the cagA virulence gene. These stool-based ddPCR assays will facilitate future population-based epidemiologic studies of this important human pathogen. C1 [Talarico, Sarah; Salama, Nina R.] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. [Safaeian, Mahboobeh; Hildesheim, Allan] NCI, NIH, Rockville, MD USA. [Gonzalez, Paula; Herrero, Rolando; Porras, Carolina; Cortes, Bernal] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, Guanacaste, Costa Rica. [Gonzalez, Paula; Herrero, Rolando] Int Agcy Res Canc, Lyon, France. [Larson, Ann; Fang, Ferric C.] Harborview Med Ctr, Clin Microbiol Lab, Seattle, WA USA. [Larson, Ann; Fang, Ferric C.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Fang, Ferric C.; Salama, Nina R.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. RP Salama, NR (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,Mailstop C3-168, Seattle, WA 98109 USA. EM nsalama@fredhutch.org FU NIH [K01DK090103, R01AI054423]; NIH Intramural Research Program FX This work was supported by grants K01DK090103 and R01AI054423 from the NIH and by the NIH Intramural Research Program. We would like to thank Yoshio Yamaoka for providing Japanese H. pylori strains for testing of the cagA assays. We would also like to thank Tina Gall and Jennifer Taylor for their assistance in constructing the figures. NR 41 TC 1 Z9 1 U1 4 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1083-4389 EI 1523-5378 J9 HELICOBACTER JI Helicobacter PD AUG PY 2016 VL 21 IS 4 BP 325 EP 333 DI 10.1111/hel.12289 PG 9 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA DS0EU UT WOS:000380269000009 PM 26667241 ER PT J AU Hoye, BJ Munster, VJ Huig, N de Vries, P Oosterbeek, K Tijsen, W Klaassen, M Fouchier, RAM van Gils, JA AF Hoye, Bethany J. Munster, Vincent J. Huig, Naomi de Vries, Peter Oosterbeek, Kees Tijsen, Wim Klaassen, Marcel Fouchier, Ron A. M. van Gils, Jan A. TI Hampered Performance of Migratory Swans: Intra- and Inter-Seasonal Effects of Avian Influenza Virus SO INTEGRATIVE AND COMPARATIVE BIOLOGY LA English DT Article ID WILD BIRDS; NATURAL INFECTION; BLOOD PARASITES; BODY CONDITION; BEWICKS SWANS; DEER MICE; A VIRUS; HOST; POPULATION; SURVIVAL AB The extent to which animal migrations shape parasite transmission networks is critically dependent on a migrant's ability to tolerate infection and migrate successfully. Yet, sub-lethal effects of parasites can be intensified through periods of increased physiological stress. Long-distance migrants may, therefore, be especially susceptible to negative effects of parasitic infection. Although a handful of studies have investigated the short-term, transmission-relevant behaviors of wild birds infected with low-pathogenic avian influenza viruses (LPAIV), the ecological consequences of LPAIV for the hosts themselves remain largely unknown. Here, we assessed the potential effects of naturally-acquired LPAIV infections in Bewick's swans, a long-distance migratory species that experiences relatively low incidence of LPAIV infection during early winter. We monitored both foraging and movement behavior in the winter of infection, as well as subsequent breeding behavior and inter-annual resighting probability over 3 years. Incorporating data on infection history we hypothesized that any effects would be most apparent in naive individuals experiencing their first LPAIV infection. Indeed, significant effects of infection were only seen in birds that were infected but lacked antibodies indicative of prior infection. Swans that were infected but had survived a previous infection were indistinguishable from uninfected birds in each of the ecological performance metrics. Despite showing reduced foraging rates, individuals in the naive-infected category had similar accumulated body stores to re-infected and uninfected individuals prior to departure on spring migration, possibly as a result of having higher scaled mass at the time of infection. And yet individuals in the naive-infected category were unlikely to be resighted 1 year after infection, with 6 out of 7 individuals that never resighted again compared to 20 out of 63 uninfected individuals and 5 out of 12 individuals in the re-infected category. Collectively, our findings indicate that acute and superficially harmless infection with LPAIV may have indirect effects on individual performance and recruitment in migratory Bewick's swans. Our results also highlight the potential for infection history to play an important role in shaping ecological constraints throughout the annual cycle. C1 [Hoye, Bethany J.; Huig, Naomi; de Vries, Peter; Tijsen, Wim; Klaassen, Marcel] Netherlands Inst Ecol NIOO KNAW, Dept Anim Ecol, Wageningen, Netherlands. [Hoye, Bethany J.; Klaassen, Marcel] Deakin Univ, Sch Life & Environm Sci, Ctr Integrat Ecol, Geelong, Vic, Australia. [Munster, Vincent J.; Fouchier, Ron A. M.] Erasmus MC, Dept Virosci, Rotterdam, Netherlands. [Munster, Vincent J.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Oosterbeek, Kees] SOVON Texel, Dutch Ctr Field Ornithol, Den Burg, Texel, Netherlands. [van Gils, Jan A.] NIOZ Royal Netherlands Inst Sea Res, Dept Coastal Syst, Den Burg, Texel, Netherlands. [van Gils, Jan A.] Univ Utrecht, Den Burg, Texel, Netherlands. RP Hoye, BJ (reprint author), Netherlands Inst Ecol NIOO KNAW, Dept Anim Ecol, Wageningen, Netherlands.; Hoye, BJ (reprint author), Deakin Univ, Sch Life & Environm Sci, Ctr Integrat Ecol, Geelong, Vic, Australia. EM hoye.bethany@gmail.com RI Klaassen, Marcel/B-4325-2008; Fouchier, Ron/A-1911-2014; van Gils, Jan/B-5544-2008; OI Klaassen, Marcel/0000-0003-3907-9599; Fouchier, Ron/0000-0001-8095-2869; van Gils, Jan/0000-0002-4132-8243; KNAW, NIOO-KNAW/0000-0002-3835-159X NR 79 TC 1 Z9 1 U1 8 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1540-7063 EI 1557-7023 J9 INTEGR COMP BIOL JI Integr. Comp. Biol. PD AUG PY 2016 VL 56 IS 2 BP 317 EP 329 DI 10.1093/icb/icw038 PG 13 WC Zoology SC Zoology GA DT1YX UT WOS:000381279100018 PM 27252210 ER PT J AU Wang, GY Hu, FB Mistry, KB Zhang, CL Ren, FZ Huo, Y Paige, D Bartell, T Hong, XM Caruso, D Ji, ZC Chen, Z Ji, YL Pearson, C Ji, HK Zuckerman, B Cheng, TL Wang, XB AF Wang, Guoying Hu, Frank B. Mistry, Kamila B. Zhang, Cuilin Ren, Fazheng Huo, Yong Paige, David Bartell, Tami Hong, Xiumei Caruso, Deanna Ji, Zhicheng Chen, Zhu Ji, Yuelong Pearson, Colleen Ji, Hongkai Zuckerman, Barry Cheng, Tina L. Wang, Xiaobin TI Association Between Maternal Prepregnancy Body Mass Index and Plasma Folate Concentrations With Child Metabolic Health SO JAMA PEDIATRICS LA English DT Article ID NEURAL-TUBE DEFECTS; GESTATIONAL WEIGHT-GAIN; FOLIC-ACID; INSULIN-RESISTANCE; OFFSPRING OBESITY; CHILDBEARING AGE; UNITED-STATES; BIRTH-WEIGHT; PREGNANCY; PREVENTION AB IMPORTANCE Previous reports have linked maternal prepregnancy obesity with low folate concentrations and child overweight or obesity (OWO) in separate studies. To our knowledge, the role of maternal folate concentrations, alone or in combination with maternal OWO, in child metabolic health has not been examined in a prospective birth cohort. OBJECTIVE To test the hypotheses that maternal folate concentrations can significantly affect child metabolic health and that sufficient maternal folate concentrations can mitigate prepregnancy obesity-induced child metabolic risk. DESIGN, SETTING, AND PARTICIPANTS This prospective birth cohort study was conducted at the Boston Medical Center, Boston, Massachusetts. It included 1517 mother-child dyads recruited at birth from 1998 to 2012 and followed up prospectively up to 9 years from 2003 to 2014. MAIN OUTCOMES AND MEASURES Child body mass index z score calculated according to US reference data, OWO defined as a body mass index in the 85th percentile or greater for age and sex, and metabolic biomarkers (leptin, insulin, and adiponectin). RESULTS The mean (SD) age was 28.6 (6.5) years for mothers and 6.2 (2.4) years for the children. An L-shaped association between maternal folate concentrations and child OWO was observed: the risk for OWO was higher among those in the lowest quartile (Q1) as compared with those in Q2 through Q4, with an odds ratio of 1.45 (95% CI, 1.13-1.87). The highest risk for child OWO was found among children of obese mothers with low folate concentrations (odds ratio, 3.05; 95% CI, 1.91-4.86) compared with children of normal-weight mothers with folate concentrations in Q2 through Q4 after accounting for multiple covariables. Among children of obese mothers, their risk for OWO was associated with a 43% reduction (odds ratio, 0.57; 95% CI, 0.34-0.95) if their mothers had folate concentrations in Q2 through Q4 compared with Q1. Similar patterns were observed for child metabolic biomarkers. CONCLUSIONS AND RELEVANCE In this urban low-income prospective birth cohort, we demonstrated an L-shaped association between maternal plasma folate concentrations and child OWO and the benefit of sufficient folate concentrations, especially among obese mothers. The threshold concentration identified in this study exceeded the clinical definition of folate deficiency, which was primarily based on the hematological effect of folate. Our findings underscore the need to establish optimal rather than minimal folate concentrations for preventing adverse metabolic outcomes in the offspring. C1 [Wang, Guoying; Zhang, Cuilin; Bartell, Tami; Hong, Xiumei; Caruso, Deanna; Chen, Zhu; Ji, Yuelong; Cheng, Tina L.; Wang, Xiaobin] Johns Hopkins Univ, Dept Populat Family & Reprod Hlth, Bloomberg Sch Publ Hlth, Ctr Early Life Origins Dis, 615 N Wolfe St, Baltimore, MD 21205 USA. [Hu, Frank B.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Hu, Frank B.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hu, Frank B.] Harvard Med Sch, Dept Med, Brigham & Womens Hosp, Boston, MA USA. [Mistry, Kamila B.; Cheng, Tina L.; Wang, Xiaobin] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Gen Pediat & Adolescent Med, Baltimore, MD 21205 USA. [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Ren, Fazheng] China Agr Univ, Beijing Adv Innovat Ctr Food Nutr & Human Hlth, Beijing, Peoples R China. [Huo, Yong] Peking Univ, Hosp 1, Dept Cardiol, Beijing, Peoples R China. [Bartell, Tami] Ann & Robert H Lurie Childrens Hosp Chicago, Stanley Manne Childrens Res Inst, Chicago, IL 60611 USA. [Ji, Zhicheng; Ji, Hongkai] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Pearson, Colleen; Zuckerman, Barry] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. [Pearson, Colleen; Zuckerman, Barry] Boston Med Ctr, Boston, MA USA. RP Wang, XB (reprint author), Johns Hopkins Univ, Dept Populat Family & Reprod Hlth, Bloomberg Sch Publ Hlth, Ctr Early Life Origins Dis, 615 N Wolfe St, Baltimore, MD 21205 USA. EM xwang82@jhu.edu FU PERI grants from March of Dimes [20-FY02-56, 21-FY07-605]; National Institutes of Health [R21ES011666, R21HD066471, R01HD041702, U01AI090727, R21AI079872, R01HD086013]; Maternal and Child Health Bureau [R40MC27443]; intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX The Boston Birth Cohort is supported in part by the PERI grants 20-FY02-56 and 21-FY07-605 from the March of Dimes; grants R21ES011666, R21HD066471, R01HD041702, U01AI090727, R21AI079872, and R01HD086013 from the National Institutes of Health; and grant R40MC27443 from the Maternal and Child Health Bureau. Dr Zhang is supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 37 TC 1 Z9 1 U1 7 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD AUG PY 2016 VL 170 IS 8 AR e160845 DI 10.1001/jamapediatrics.2016.0845 PG 9 WC Pediatrics SC Pediatrics GA DS9XW UT WOS:000381137800002 PM 27295011 ER PT J AU McGowan, EC Peng, RD Salo, PM Zeldin, DC Keet, CA AF McGowan, Emily C. Peng, Roger D. Salo, Paivi M. Zeldin, Darryl C. Keet, Corinne A. TI Changes in Food-Specific IgE Over Time in the National Health and Nutrition Examination Survey (NHANES) SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Food allergy; NHANES; Food sensitization; Epidemiology ID PEANUT ALLERGEN; UNITED-STATES; PREVALENCE; CHILDREN; ANAPHYLAXIS; DIAGNOSIS; RISK; SENSITIZATION; ASTHMA; TRENDS AB BACKGROUND: Food allergy prevalence appears to have recently risen, with larger increases among non-Hispanic blacks. However, it is unclear whether these trends represent shifts in recognition of food allergy or in sensitization. OBJECTIVE: The objective of this study was to determine whether sensitization to common food allergens increased in US children from 1988-1994 to 2005-2006 and whether these trends differed by race and/or ethnicity. METHODS: Food-specific immunoglobulin E (IgE; to peanut, milk, egg, and shrimp) was measured by ImmunoCAP in stored sera from subjects aged 6-19 in the National Health and Nutrition Examination Survey (NHANES) III (1988-1994) and was compared with NHANES 2005-2006. Sensitization to foods was defined as overall (IgE >= 0.35 kU/L), moderate level (IgE >= 2 kU/L), and high level (IgE >= commonly used 95% predictive values). Sensitization to individual and combined foods was compared between surveys, with analyses further stratified by race and/or ethnicity. RESULTS: A total of 7896 subjects (NHANES III: n [4995, NHANES 2005-2006: n[2901) were included. In NHANES III, the prevalence of food sensitization was 24.3% (95% confidence interval [CI]: 22.1-26.5) compared with 21.6% (95% CI: 19.523.7) in NHANES 2005-2006. There were no significant changes in the prevalence of any level of milk, egg, or peanut sensitization, but shrimp sensitization at all levels decreased markedly; overall sensitization NHANES III: 11.2% (95% CI: 10.0-12.5) versus NHANES 2005-2006: 6.1% (95% CI: 4.5-7.7). There was a trend toward the increased prevalence of moderate-and high-level sensitization to the combination of milk, egg, and peanut among non-Hispanic blacks but not other groups. CONCLUSIONS: In contrast to our expectations, sensitization to common food allergens did not increase between the late 1980s/early 1990s and the mid-2000s among US 6-19 year olds, and in fact decreased to shrimp. (C) 2016 American Academy of Allergy, Asthma & Immunology C1 [McGowan, Emily C.] Johns Hopkins Univ, Sch Med, Div Allergy & Clin Immunol, Baltimore, MD USA. [McGowan, Emily C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Peng, Roger D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Salo, Paivi M.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Keet, Corinne A.] Johns Hopkins Univ, Sch Med, Div Pediat Allergy & Immunol, Baltimore, MD USA. RP Keet, CA (reprint author), Johns Hopkins Univ Hosp, CMSC 1102,600 N Wolfe St, Baltimore, MD 21202 USA. EM ckeet1@jhmi.edu FU National Institutes of Health (NIH) [1K23AI103187, 1KL2TR001077, R21AI107085]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES025041] FX This work was funded by the National Institutes of Health (NIH) through the following grants: (National Institute of Allergy and Infectious Diseases [NIAID]) 1K23AI103187, (National Center for Research Resources) 1KL2TR001077, and (NIAID) R21AI107085, and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES025041). The funders had no role in the design, analysis, or interpretation of this work. NR 38 TC 5 Z9 5 U1 5 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD AUG PY 2016 VL 4 IS 4 BP 713 EP 720 DI 10.1016/j.jaip.2016.01.017 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA DU0SZ UT WOS:000381916100022 PM 27133095 ER PT J AU Bernabe-Rubio, M Andres, G Casares-Arias, J Fernandez-Barrera, J Rangel, L Reglero-Real, N Gershlick, DC Fernandez, JJ Millan, J Correas, I Miguez, DG Alonso, MA AF Bernabe-Rubio, Miguel Andres, German Casares-Arias, Javier Fernandez-Barrera, Jaime Rangel, Laura Reglero-Real, Natalia Gershlick, David C. Fernandez, Jose J. Millan, Jaime Correas, Isabel Miguez, David G. Alonso, Miguel A. TI Novel role for the midbody in primary ciliogenesis by polarized epithelial cells SO JOURNAL OF CELL BIOLOGY LA English DT Article ID PRIMARY CILIUM; INTRAFLAGELLAR TRANSPORT; ASYMMETRIC INHERITANCE; CYTOKINETIC ABSCISSION; MEDIATED ABSCISSION; NEURAL PROGENITORS; MARKER PROMININ-1; CILIARY MEMBRANE; ANIMAL-CELLS; RAB8 GTPASE AB The primary cilium is a membrane protrusion that is crucial for vertebrate tissue homeostasis and development. Here, we investigated the uncharacterized process of primary ciliogenesis in polarized epithelial cells. We show that after cytokinesis, the midbody is inherited by one of the daughter cells as a remnant that initially locates peripherally at the apical surface of one of the daughter cells. The remnant then moves along the apical surface and, once proximal to the centrosome at the center of the apical surface, enables cilium formation. The physical removal of the remnant greatly impairs ciliogenesis. We developed a probabilistic cell population-based model that reproduces the experimental data. In addition, our model explains, solely in terms of cell area constraints, the various observed transitions of the midbody, the beginning of ciliogenesis, and the accumulation of ciliated cells. Our findings reveal a biological mechanism that links the three microtubule-based organelles-the midbody, the centrosome, and the cilium-in the same cellular process. C1 [Bernabe-Rubio, Miguel; Casares-Arias, Javier; Fernandez-Barrera, Jaime; Rangel, Laura; Reglero-Real, Natalia; Millan, Jaime; Correas, Isabel; Alonso, Miguel A.] CSIC, Ctr Biol Mol Severo Ochoa, Dept Cell Biol & Immunol, Madrid 28049, Spain. [Andres, German] CSIC, Ctr Biol Mol Severo Ochoa, Electron Microscopy Unit, Madrid 28049, Spain. Univ Autonoma Madrid, E-28049 Madrid, Spain. [Gershlick, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20892 USA. [Fernandez, Jose J.] CSIC, Ctr Nacl Biotecnol, Madrid 28049, Spain. [Miguez, David G.] Univ Autonoma Madrid, Dept Condensed Matter Phys, Inst Ciencias Mat Nicolas Cabrera, E-28049 Madrid, Spain. [Miguez, David G.] Univ Autonoma Madrid, Inst Fis Mat Condensada, E-28049 Madrid, Spain. RP Alonso, MA (reprint author), CSIC, Ctr Biol Mol Severo Ochoa, Dept Cell Biol & Immunol, Madrid 28049, Spain. EM maalonso@cbm.csic.es RI Alonso, Miguel/J-3945-2016; Fernandez, Jose-Jesus/A-5084-2008; Andres, German/E-2632-2016; OI Alonso, Miguel/0000-0002-7001-8826; Fernandez, Jose-Jesus/0000-0003-2222-3355; Andres, German/0000-0003-0265-5409; Casares Arias, Javier/0000-0003-3147-5730; Gershlick, David/0000-0002-0602-210X; Miguez Gomez, David/0000-0001-8065-1142 FU Spanish Ministerio de Economia y Competitividad/Fondo Europeo de Desarrollo Regional [BFU2012-32532, BFU2015-67266-R, BFU2014-53299-P, TIN-2012-37483-C03-02]; Comunidad de Madrid [S2010/BMD-2305]; Instituto de Investigaciones Sanitarias Jimenez Diaz; Ministerio de Economia y Competitividad [RYC-2010-07450]; Amarouto Program from the Comunidad de Madrid FX This work was supported by the following grants from the Spanish Ministerio de Economia y Competitividad/Fondo Europeo de Desarrollo Regional: BFU2012-32532 and BFU2015-67266-R to M.A. Alonso, BFU2014-53299-P to D.G. Miguez, and TIN-2012-37483-C03-02 to J.F. Fernandez. Grants from the Comunidad de Madrid (S2010/BMD-2305) to I. Correas and from Instituto de Investigaciones Sanitarias Jimenez Diaz to J. Millan are also acknowledged. M. Bernabe-Rubio and D.G. Miguez are the holders of a fellowship and a Ramon y Cajal contract (RYC-2010-07450), respectively, from the Ministerio de Economia y Competitividad. G. Andres was supported by the Amarouto Program from the Comunidad de Madrid. NR 68 TC 1 Z9 1 U1 3 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD AUG 1 PY 2016 VL 214 IS 3 BP 259 EP 273 DI 10.1083/jcb.201601020 PG 15 WC Cell Biology SC Cell Biology GA DS5OO UT WOS:000380831800007 PM 27458130 ER PT J AU Lippincott, MF Chan, YM Delaney, A Rivera-Morales, D Butler, JP Seminara, SB AF Lippincott, Margaret F. Chan, Yee-Ming Delaney, Angela Rivera-Morales, Dianali Butler, James P. Seminara, Stephanie B. TI Kisspeptin Responsiveness Signals Emergence of Reproductive Endocrine Activity: Implications for Human Puberty SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; FOLLICLE-STIMULATING-HORMONE; LUTEINIZING-HORMONE; MENSTRUAL-CYCLE; KISS-1 PEPTIDE; GPR54; SECRETION; RECEPTOR; WOMEN AB Context: Some patients with idiopathic hypogonadotropic hypogonadism (IHH) undergo spontaneous activation of their hypothalamic-pituitary-gonadal axis resulting in normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal. Objective: To assess the responsiveness of the GnRH neuronal network to exogenous kisspeptin administration in IHH patients who have undergone reversal. Participants: Six men with congenital IHH and evidence for reversal. Intervention: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to iv boluses of kisspeptin (0.24-2.4 nmol/kg) and GnRH (75 ng/kg). Results: Individuals with sustained reversal of their hypogonadotropism (spontaneous LH pulses) responded to exogenous kisspeptin with a GnRH-induced LH pulse. Individuals who had reversal but then subsequently suffered relapse of their IHH (loss of spontaneous LH pulsatility) did not respond to kisspeptin. Conclusions: The ability of kisspeptin to stimulate a GnRH-induced LH pulse correlates with the presence of endogenous LH pulses. These data suggest that reversal of hypogonadotropism, and by extension sexual maturation, may be due to the acquisition of kisspeptin responsiveness. C1 [Lippincott, Margaret F.; Chan, Yee-Ming; Rivera-Morales, Dianali; Seminara, Stephanie B.] Massachusetts Gen Hosp, Dept Med, Harvard Reprod Sci Ctr, Boston, MA 02114 USA. [Lippincott, Margaret F.; Chan, Yee-Ming; Rivera-Morales, Dianali; Seminara, Stephanie B.] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, Boston, MA 02114 USA. [Chan, Yee-Ming] Boston Childrens Hosp, Dept Med, Div Endocrinol, Boston, MA 02115 USA. [Butler, James P.] Brigham & Womens Hosp, Div Sleep Med, Boston, MA 02115 USA. Harvard Med Sch, Boston, MA 02115 USA. [Delaney, Angela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Genet Puberty & Reprod, Bethesda, MD 20892 USA. RP Seminara, SB (reprint author), Massachusetts Gen Hosp, 55 Fruit St,BHX 5, Boston, MA 02114 USA. EM Seminara.Stephanie@mgh.harvard.edu FU Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) [R01 HD043341, P50 HD028138]; Harvard Catalyst Harvard Clinical and Translational Science Center (National Center for Research Resources, National Institutes of Health) [UL1 RR 025758, UL1 TR000170]; Harvard Catalyst Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 RR 025758, UL1 TR000170]; Harvard Catalyst Harvard Clinical and Translational Science Center (Harvard University and its affiliated academic health care centers); NIH NICHD Grant [K24 HD067388, F32 HD078083]; Doris Duke Clinical Scientist Development Award [2013110]; Postdoctoral Fellowship Award for Clinical Research from the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery; NIH Intramural Research Program of NICHD FX This work was supported by grants R01 HD043341 and P50 HD028138 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) and the Harvard Catalyst Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Awards UL1 RR 025758 and UL1 TR000170 and financial contributions from Harvard University and its affiliated academic health care centers). S.B.S. was supported by the NIH NICHD Grant K24 HD067388. Y.-M.C. was supported by a Doris Duke Clinical Scientist Development Award (Grant 2013110). M.F.L. was supported by the NIH NICHD Grant F32 HD078083 and by a Postdoctoral Fellowship Award for Clinical Research from the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery. A.D. was supported by the NIH Intramural Research Program of NICHD. NR 44 TC 1 Z9 2 U1 3 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2016 VL 101 IS 8 BP 3061 EP 3069 DI 10.1210/jc.2016-1545 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU0YF UT WOS:000381930200014 PM 27214398 ER PT J AU Hernandez-Ramirez, LC Martucci, F Morgan, RML Trivellin, G Tilley, D Ramos-Guajardo, N Iacovazzo, D D'Acquisto, F Prodromou, C Korbonits, M AF Hernandez-Ramirez, Laura C. Martucci, Federico Morgan, Rhodri M. L. Trivellin, Giampaolo Tilley, Daniel Ramos-Guajardo, Nancy Iacovazzo, Donato D'Acquisto, Fulvio Prodromou, Chrisostomos Korbonits, Marta TI Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With Missense AIP Mutations SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RECEPTOR-INTERACTING-PROTEIN; MULTIPLE ENDOCRINE NEOPLASIA; ISOLATED PITUITARY-ADENOMA; YOUNG-PATIENTS; GENE-MUTATIONS; MACROADENOMAS; PREVALENCE; DIAGNOSIS; SEQUENCE; FAMILIES AB Context: The pathogenic effect of mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene (AIPmuts) in pituitary adenomas is incompletely understood. We have identified the primary mechanism of loss of function for missense AIPmuts. Objective: This study sought to analyze the mechanism/speed of protein turnover of wild-type and missense AIP variants, correlating protein half-life with clinical parameters. Design and Setting: Half-life and protein-protein interaction experiments and cross-sectional analysis of AIPmut positive patients' data were performed in a clinical academic research institution. Patients: Data were obtained from our cohort of pituitary adenoma patients and literature-reported cases. Interventions: Protein turnover of endogenous AIP in two cell lines and fifteen AIP variants over-expressed in HEK293 cells was analyzed via cycloheximide chase and proteasome inhibition. Glutathione-S-transferase pull-down and quantitative mass spectrometry identified proteins involved in AIP degradation; results were confirmed by coimmunoprecipitation and gene knockdown. Relevant clinical data was collected. Main Outcome Measures: Half-life of wild-type and mutant AIP proteins and its correlation with clinical parameters. Results: Endogenous AIP half-life was similar in HEK293 and lymphoblastoid cells (43.5 and 32.7 h). AIP variants were divided into stable proteins (median, 77.7 h; interquartile range [IQR], 60.7-92.9 h), and those with short (median, 27 h; IQR, 21.6-28.7 h) or very short (median, 7.7 h; IQR, 5.6-10.5 h) half-life; proteasomal inhibition rescued the rapid degradation of mutant proteins. The experimental half-life significantly correlated with age at diagnosis of acromegaly/gigantism (r = 0.411; P = .002). The FBXO3-containing SKP1-CUL1-F-box protein complex was identified as the E3 ubiquitin-ligase recognizing AIP. Conclusions: AIP is a stable protein, driven to ubiquitination by the SKP1-CUL1-F-box protein complex. Enhanced proteasomal degradation is a novel pathogenic mechanism for AIPmuts, with direct implications for the phenotype. C1 [Hernandez-Ramirez, Laura C.; Martucci, Federico; Trivellin, Giampaolo; Tilley, Daniel; Ramos-Guajardo, Nancy; Iacovazzo, Donato; Korbonits, Marta] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Ctr Endocrinol, London EC1M 6BQ, England. [D'Acquisto, Fulvio] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Ctr Biochem Pharmacol, London EC1M 6BQ, England. [Morgan, Rhodri M. L.; Prodromou, Chrisostomos] Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, Falmer, England. [Hernandez-Ramirez, Laura C.; Trivellin, Giampaolo] Eunice Kennedy Shriver Natl Inst Child Hlth andHu, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Morgan, Rhodri M. L.] Imperial Coll London, Dept Life Sci, Struct Biol Ctr, Prot Crystallog Facil, Flowers Bldg, London SW7 2AZ, England. RP Korbonits, M (reprint author), Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Ctr Endocrinol,Endocrinol & Metab, London EC1M 6BQ, England. EM m.korbonits@qmul.ac.uk OI Trivellin, Giampaolo/0000-0003-2384-4153; Korbonits, Marta/0000-0002-4101-9432; Hernandez-Ramirez, Laura C./0000-0002-6599-6406 FU Medical Research Council of the United Kingdom; Wellcome Trust [095605/Z11/Z]; National Institute of Health Research; Royal Society; Pfizer; National Council of Science and Technology; Secretariat of Public Education from the Mexican Government; Barts and The London Charity FX This work was supported by the Medical Research Council of the United Kingdom, Wellcome Trust, National Institute of Health Research, Barts and The London Charity, Royal Society, and Pfizer. L.C.H.-R. was supported by grants from the National Council of Science and Technology and the Secretariat of Public Education from the Mexican Government. C.P. is funded by the Wellcome Trust 095605/Z11/Z. NR 53 TC 1 Z9 1 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2016 VL 101 IS 8 BP 3144 EP 3154 DI 10.1210/jc.2016-1307 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU0YF UT WOS:000381930200023 PM 27253664 ER PT J AU Sleiman, S Halliday, CL Chapman, B Brown, M Nitschke, J Lau, AF Chen, SCA AF Sleiman, Sue Halliday, Catriona L. Chapman, Belinda Brown, Mitchell Nitschke, Joanne Lau, Anna F. Chen, Sharon C. -A. TI Performance of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Identification of Aspergillus, Scedosporium, and Fusarium spp. in the Australian Clinical Setting SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID SPECIES IDENTIFICATION; ACCURATE IDENTIFICATION; ROUTINE IDENTIFICATION; FILAMENTOUS FUNGI; MEDICAL MYCOLOGY; MOLDS; PSEUDALLESCHERIA; INFECTIONS; EPIDEMIOLOGY; BIOTYPER AB We developed an Australian database for the identification of Aspergillus, Scedosporium, and Fusarium species (n = 28) by matrix-assisted laser desorption ionization - time of flight mass spectrometry (MALDI-TOF MS). In a challenge against 117 isolates, species identification significantly improved when the in-house-built database was combined with the Bruker Filamentous Fungi Library compared with that for the Bruker library alone (Aspergillus, 93% versus 69%; Fusarium, 84% versus 42%; and Scedosporium, 94% versus 18%, respectively). C1 [Sleiman, Sue; Halliday, Catriona L.; Brown, Mitchell; Nitschke, Joanne; Chen, Sharon C. -A.] Univ Sydney, Westmead Hosp, Inst Clin Pathol & Med Res, Ctr Infect Dis & Microbiol Lab Serv, Westmead, NSW, Australia. [Chapman, Belinda] Univ Sydney, Westmead Inst Med Res, Westmead, NSW, Australia. [Lau, Anna F.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Chen, Sharon C. -A.] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. RP Chen, SCA (reprint author), Univ Sydney, Westmead Hosp, Inst Clin Pathol & Med Res, Ctr Infect Dis & Microbiol Lab Serv, Westmead, NSW, Australia.; Chen, SCA (reprint author), Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. EM sharon.chen@health.nsw.gov.au FU Intramural Research Program of the National Institutes of Health FX A.F.L. was supported by the Intramural Research Program of the National Institutes of Health. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. NR 34 TC 2 Z9 2 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2016 VL 54 IS 8 BP 2182 EP 2186 DI 10.1128/JCM.00906-16 PG 5 WC Microbiology SC Microbiology GA DT1YO UT WOS:000381278200037 PM 27252460 ER PT J AU Portier, CJ Armstrong, BK Baguley, BC Baur, X Belyaev, I Belle, R Belpoggi, F Biggeri, A Bosland, MC Bruzzi, P Budnik, LT Bugge, MD Burns, K Calaf, GM Carpenter, DO Carpenter, HM Lopez-Carrillo, L Clapp, R Cocco, P Consonni, D Comba, P Craft, E Dalvie, MA Davis, D Demers, PA De Roos, AJ DeWitt, J Forastiere, F Freedman, JH Fritschi, L Gaus, C Gohlke, JM Goldberg, M Greiser, E Hansen, J Hardell, L Hauptmann, M Huang, W Huff, J James, MO Jameson, CW Kortenkamp, A Kopp-Schneider, A Kromhout, H Larramendy, ML Landrigan, PJ Lash, LH Leszczynski, D Lynch, CF Magnani, C Mandrioli, D Martin, FL Merler, E Michelozzi, P Miligi, L Miller, AB Mirabelli, D Mirer, FE Naidoo, S Perry, MJ Petronio, MG Pirastu, R Portier, RJ Ramos, KS Robertson, LW Rodriguez, T Roosli, M Ross, MK Roy, D Rusyn, I Saldiva, P Sass, J Savolainen, K Scheepers, PTJ Sergi, C Silbergeld, EK Smith, MT Stewart, BW Sutton, P Tateo, F Terracini, B Thielmann, HW Thomas, DB Vainio, H Vena, JE Vineis, P Weiderpass, E Weisenburger, DD Woodruff, TJ Yorifuji, T Yu, IJ Zambon, P Zeeb, H Zhou, SF AF Portier, Christopher J. Armstrong, Bruce K. Baguley, Bruce C. Baur, Xaver Belyaev, Igor Belle, Robert Belpoggi, Fiorella Biggeri, Annibale Bosland, Maarten C. Bruzzi, Paolo Budnik, Lygia Therese Bugge, Merete D. Burns, Kathleen Calaf, Gloria M. Carpenter, David O. Carpenter, Hillary M. Lopez-Carrillo, Lizbeth Clapp, Richard Cocco, Pierluigi Consonni, Dario Comba, Pietro Craft, Elena Dalvie, Mohamed Aqiel Davis, Devra Demers, Paul A. De Roos, Anneclaire J. DeWitt, Jamie Forastiere, Francesco Freedman, Jonathan H. Fritschi, Lin Gaus, Caroline Gohlke, Julia M. Goldberg, Marcel Greiser, Eberhard Hansen, Johnni Hardell, Lennart Hauptmann, Michael Huang, Wei Huff, James James, Margaret O. Jameson, C. W. Kortenkamp, Andreas Kopp-Schneider, Annette Kromhout, Hans Larramendy, Marcelo L. Landrigan, Philip J. Lash, Lawrence H. Leszczynski, Dariusz Lynch, Charles F. Magnani, Corrado Mandrioli, Daniele Martin, Francis L. Merler, Enzo Michelozzi, Paola Miligi, Lucia Miller, Anthony B. Mirabelli, Dario Mirer, Franklin E. Naidoo, Saloshni Perry, Melissa J. Petronio, Maria Grazia Pirastu, Roberta Portier, Ralph J. Ramos, Kenneth S. Robertson, Larry W. Rodriguez, Theresa Roosli, Martin Ross, Matt K. Roy, Deodutta Rusyn, Ivan Saldiva, Paulo Sass, Jennifer Savolainen, Kai Scheepers, Paul T. J. Sergi, Consolato Silbergeld, Ellen K. Smith, Martyn T. Stewart, Bernard W. Sutton, Patrice Tateo, Fabio Terracini, Benedetto Thielmann, Heinz W. Thomas, David B. Vainio, Harri Vena, John E. Vineis, Paolo Weiderpass, Elisabete Weisenburger, Dennis D. Woodruff, Tracey J. Yorifuji, Takashi Yu, Il Je Zambon, Paola Zeeb, Hajo Zhou, Shu-Feng TI Differences in the carcinogenic evaluation of glyphosate between the International Agency for Research on Cancer (IARC) and the European Food Safety Authority (EFSA) SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Editorial Material ID HISTORICAL CONTROL DATA; LYMPHOMA C1 [Portier, Christopher J.] Environm Hlth Consultant, CH-3600 Thun, Switzerland. [Armstrong, Bruce K.] Univ Sydney, Sydney, NSW, Australia. [Baguley, Bruce C.] Univ Auckland, Auckland, New Zealand. [Baur, Xaver] Charite, Berlin, Germany. [Belyaev, Igor] Canc Res Inst, Bratislava, Slovakia. [Belle, Robert] Univ Paris 06, Sorbonne Univ, UMR8227, UPMC, Roscoff, France. [Belpoggi, Fiorella; Mandrioli, Daniele] CesareMaltoni Canc Res Ctr, Bologna, Italy. [Biggeri, Annibale] Univ Florence, Inst Canc Prevent & Res, I-50121 Florence, Italy. [Bosland, Maarten C.] Univ Illinois, Chicago, IL USA. [Bruzzi, Paolo] San Martino IST Hosp, Natl Canc Res Inst, Genoa, Italy. [Budnik, Lygia Therese] Univ Hamburg, Hamburg, Germany. [Bugge, Merete D.] Natl Inst Occupat Hlth, STAMI, Oslo, Norway. [Burns, Kathleen] Sciencecorps, Lexington, MA USA. [Calaf, Gloria M.] Univ Tarapaca, Inst Alta Invest, Arica, Chile. [Carpenter, David O.] Univ Albany, Inst Hlth & Environm, Rensselaer, NY USA. [Carpenter, Hillary M.] Toxicologist, Maplewood, MN USA. [Lopez-Carrillo, Lizbeth] Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [Clapp, Richard] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Cocco, Pierluigi] Univ Cagliari, Dept Publ Hlth Clin & Mol Med, Cagliari, Italy. [Consonni, Dario] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Dept Prevent Med, Milan, Italy. [Comba, Pietro] Ist Super Sanita, Dept Environm & Primary Prevent, Rome, Italy. [Craft, Elena] Environm Def Fund, Austin, TX USA. [Dalvie, Mohamed Aqiel] Univ Cape Town, Ctr Environm & Occupat Hlth, Cape Town, South Africa. [Davis, Devra] Environm Hlth Trust, Jackson Hole, WY USA. [Davis, Devra] Hebrew Univ Jerusalem, Hadassah Med Sch, Jerusalem, Israel. [Demers, Paul A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [De Roos, Anneclaire J.] Drexel Univ, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [DeWitt, Jamie] E Carolina Univ, Brody Sch Med, Greenville, NC USA. [Forastiere, Francesco] Lazio Reg Hlth Serv, Dept Epidemiol, Rome, Italy. [Freedman, Jonathan H.] Univ Louisville, Sch Med, Louisville, KY 40292 USA. [Fritschi, Lin] Curtin Univ, Sch Publ Hlth, Perth, WA, Australia. [Gaus, Caroline] Univ Queensland, Dept Environm Toxicol, Brisbane, Qld, Australia. [Gohlke, Julia M.] Virginia Tech, Dept Populat Hlth Sci, Blacksburg, VA USA. [Goldberg, Marcel] Paris Descartes Univ, Paris, France. [Greiser, Eberhard] Epi Consult GmbH, Musweiler, Germany. [Hansen, Johnni] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Hardell, Lennart] Univ Hosp, Orebra, Sweden. [Hauptmann, Michael] Netherlands Canc Inst, Biostat Branch, Amsterdam, Netherlands. [Huang, Wei] Peking Univ, Fac Dept Occupat & Environm Hlth, Sch Publ Hlth, Beijing, Peoples R China. [Huff, James] NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. [James, Margaret O.] Univ Florida, Gainesville, FL USA. [Jameson, C. W.] CWJ Consulting LLC, Cape Coral, FL USA. [Kortenkamp, Andreas] Brunel Univ London, Inst Environm Hlth & Soc, London, England. [Kopp-Schneider, Annette] German Canc Res Ctr, Div Biostat, Heidelberg, Germany. [Kromhout, Hans] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Larramendy, Marcelo L.] Natl Univ La Plata, Natl Council Sci & Technol Res, La Plata, Buenos Aires, Argentina. [Landrigan, Philip J.] Icahn Sch Med Mt Sinai, Arnhold Inst Global Hlth, New York, NY USA. [Lash, Lawrence H.] Wayne State Univ, Sch Med, Dept Pharmacol, Detroit, MI 48201 USA. [Leszczynski, Dariusz] Univ Helsinki, Dept Biosci, Helsinki, Finland. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Magnani, Corrado] Univ Piemonte Orientale, Canc Epidemiol Unit, Novara, Italy. [Martin, Francis L.] Univ Lancaster, Ctr Biophoton, Lancaster LA1 4YW, England. [Merler, Enzo] Natl Hlth Serv, Occupat Hlth Unit, Dept Prevent, Padua, Italy. [Michelozzi, Paola] Dept Epidemiol Lazio Reg, Rome, Italy. [Miligi, Lucia] ISPO Canc Prevent & Res Inst, Occupat & Environm Epidemiol Unit, Florence, Italy. [Miller, Anthony B.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5S 1A1, Canada. [Mirabelli, Dario] Univ Turin, Unit Canc Epidemiol, Turin, Italy. [Mirabelli, Dario] CPO Piemonte, Turin, Italy. [Mirer, Franklin E.] CUNY, Sch Publ Hlth, Dept Environm & Occupat Hlth Sci, New York, NY USA. [Naidoo, Saloshni] Univ KwaZulu Natal, Sch Nursing & Publ Hlth, Durban, South Africa. [Perry, Melissa J.] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Environm & Occupat Hlth, Washington, DC USA. [Petronio, Maria Grazia] Local Hlth Author Empoli, Hlth & Environm Dept Prevent, Florence, Italy. [Pirastu, Roberta] Sapienza Rome Univ, Dept Biol & Biotechnol Charles Darwin, Rome, Italy. [Portier, Ralph J.] Louisiana State Univ, Dept Environm Sci, Sch Coast & Environm, Los Angeles, CA USA. [Ramos, Kenneth S.] Univ Arizona Hlth Sci, Ctr Appl Genet & Genom Med, Tucson, AZ USA. [Robertson, Larry W.] Univ Iowa, Iowa Superfund Res Program, Iowa City, IA USA. [Robertson, Larry W.] Univ Iowa, Interdisciplinary Grad Program Human Toxicol, Iowa City, IA USA. [Rodriguez, Theresa] Natl Autonomous Univ Nicaragua UNAN Leon, Ctr Res Hlth Work & Environm CISTA, Leon, Nicaragua. [Roosli, Martin] Univ Basel, Swiss Trop & Publ Hlth Inst, Associated Inst, Basel, Switzerland. [Ross, Matt K.] Mississippi State Univ, Coll Vet Med, Mississippi State, MS 39762 USA. [Roy, Deodutta] Florida Int Univ, Dept Environm & Occupat Hlth, Miami, FL 33199 USA. [Rusyn, Ivan] Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA. [Saldiva, Paulo] Univ Sao Paulo, Fac Med, Sao Paulo, Brazil. [Sass, Jennifer] Nat Resources Def Council, Washington, DC USA. [Sass, Jennifer] George Washington Univ, Washington, DC USA. [Savolainen, Kai] Finnish Inst Occupat Hlth, Nanosafety Res Ctr, Helsinki, Finland. [Scheepers, Paul T. J.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Sergi, Consolato] Univ Alberta, Dept Pathol, Edmonton, AB, Canada. [Silbergeld, Ellen K.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Smith, Martyn T.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Stewart, Bernard W.] Univ New South Wales, Fac Med, Randwick, NSW, Australia. [Sutton, Patrice] Univ Calif San Francisco, Program Reprod Hlth & Environm, San Francisco, CA 94143 USA. [Tateo, Fabio] Ist Geosce Georisorse CNR, Padua, Italy. [Terracini, Benedetto] Univ Turin, Turin, Italy. [Thielmann, Heinz W.] German Canc Res Ctr, Heidelberg, Germany. [Thielmann, Heinz W.] Heidelberg Univ, Fac Pharm, Bergheimer Str 58, D-69115 Heidelberg, Germany. [Thomas, David B.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Vainio, Harri] Kuwait Univ, Fac Publ Hlth, Kuwait, Kuwait. [Vena, John E.] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC USA. Imperial Coll London, Dept Environm Epidemiol, London, England. [Weiderpass, Elisabete] Canc Registry Norway, Inst Populat Based Canc Res, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Arctic Univ Norway, Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland. [Weisenburger, Dennis D.] City Hope Med Ctr, Dept Pathol, Duarte, CA USA. [Woodruff, Tracey J.] Univ Calif San Francisco, Program Reprod Hlth & Environm, San Francisco, CA 94143 USA. [Yorifuji, Takashi] Okayama Univ, Okayama, Japan. [Yu, Il Je] Hoseo Univ, Inst Nanoprod Safety Res, Asan, South Korea. [Zambon, Paola] Univ Padua, Padua, Italy. [Zeeb, Hajo] Leibniz Inst Prevent Res & Epidemiol, Dept Prevent & Evaluat, Bremen, Germany. [Zhou, Shu-Feng] Univ S Florida, Coll Pharm, Tampa, FL USA. RP Portier, CJ (reprint author), Environm Hlth Consultant, CH-3600 Thun, Switzerland. EM cportier@me.com RI Michelozzi, Paola/J-8608-2016; Consonni, Dario/K-7943-2016; Natarajan, Meena/J-9167-2012; Roosli, Martin/A-2658-2008; Weiderpass, Elisabete/M-4029-2016; Forastiere, Francesco/J-9067-2016; OI L Martin, Francis/0000-0001-8562-4944; Michelozzi, Paola/0000-0002-1646-2555; Consonni, Dario/0000-0002-8935-3843; Gohlke, Julia/0000-0002-6984-2893; DeWitt, Jamie/0000-0002-0440-4059; Natarajan, Meena/0000-0001-5652-9681; Roosli, Martin/0000-0002-7475-1531; Weiderpass, Elisabete/0000-0003-2237-0128; Forastiere, Francesco/0000-0002-9162-5684; Gaus, Caroline/0000-0002-0585-8511; Bruzzi, Paolo/0000-0002-7874-2077 FU NCI NIH HHS [P30 CA086862] NR 27 TC 4 Z9 4 U1 24 U2 34 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X EI 1470-2738 J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD AUG PY 2016 VL 70 IS 8 BP 741 EP 745 DI 10.1136/jech-2015-207005 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DR8MS UT WOS:000380152600002 PM 26941213 ER PT J AU Pan, BF Liu, XP Asai, Y Kurima, K Griffith, AJ Holt, JR AF Pan, Bifeng Liu, Xiao-Ping Asai, Yukako Kurima, Kiyoto Griffith, Andrew J. Holt, Jeffrey R. TI Cysteine Mutagenesis Reveals TMC1 Residues that Contribute to Mechanotransduction SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Meeting Abstract CT 70th Annual Meeting of the Society-of-General-Physiologists - Genetic and Animal Models for Ion Channel Function in Physiology and Disease CY SEP 07-11, 2016 CL Marine Biol Lab, Woods Hole, MA SP Soc Gen Physiologists HO Marine Biol Lab C1 [Pan, Bifeng; Liu, Xiao-Ping; Asai, Yukako; Holt, Jeffrey R.] Harvard Med Sch, Dept Otolaryngol, Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Kurima, Kiyoto; Griffith, Andrew J.] Natl Inst Deafness & Other Commun Disorders, Mol Biol & Genet Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1295 EI 1540-7748 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD AUG PY 2016 VL 148 IS 2 MA 65 BP 28A EP 28A PG 1 WC Physiology SC Physiology GA DS5OT UT WOS:000380832300074 ER PT J AU Rehermann, B AF Rehermann, Barbara TI Peptide-dependent HLA-KIR-mediated regulation of NK cell function SO JOURNAL OF HEPATOLOGY LA English DT Article ID INHIBITORY RECEPTOR; DIRECT BINDING; RECOGNITION; SELECTIVITY; ACTIVATION; INFECTION C1 [Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, DHHS,NIH, 10 Ctr Dr,Bldg 10,Rm 9B16, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, DHHS,NIH, 10 Ctr Dr,Bldg 10,Rm 9B16, Bethesda, MD 20892 USA. EM Rehermann@nih.gov FU NIDDK, NIH FX This work was supported by the intramural research program of NIDDK, NIH. NR 20 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD AUG PY 2016 VL 65 IS 2 BP 237 EP 239 DI 10.1016/j.jhep.2016.03.016 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DS2AH UT WOS:000380516900002 PM 27212248 ER PT J AU Lunemann, S Martrus, G Holzemer, A Chapel, A Ziegler, M Korner, C Beltran, WG Carrington, M Wedemeyer, H Altfeld, M AF Lunemann, Sebastian Martrus, Gloria Hoelzemer, Angelique Chapel, Anais Ziegler, Maja Koerner, Christian Beltran, Wilfredo Garcia Carrington, Mary Wedemeyer, Heiner Altfeld, Marcus TI Sequence variations in HCV core-derived epitopes alter binding of KIR2DL3 to HLA-C*03:04 and modulate NK cell function SO JOURNAL OF HEPATOLOGY LA English DT Article DE HCV; KIR; HLA; NK ID NATURAL-KILLER-CELLS; HEPATITIS-C VIRUS; MHC CLASS-I; IMMUNOGLOBULIN-LIKE RECEPTOR; CRYSTAL-STRUCTURE; INHIBITION; INFECTION; HLA; RECOGNITION; ACTIVATION AB Background & Aims: Both natural killer (NK) cells and human leukocyte antigen (HLA)/killer cell immunoglobulin like receptor (KIR) interactions have been shown to play an important role in the control, clearance and progression of hepatitis C virus (HCV) disease. Here we aimed at elucidating the effects of viral peptides derived from HCV on HLA stabilization, changes in KIR binding and primary NK cell function. Methods: Transporter for antigen presentation-deficient 722.221 cells stably transfected with HLA-C*03: 04 were used to screen 200 overlapping peptides, covering the non-structural protein 3 (NS3) and core protein of HCV genotype 1, for their ability to bind and stabilize HLA-C*03: 04. Binding of KIR2DL3 to the HLA-peptide complex was assessed using a KIR2DL3-IgG fusion construct. Primary NK cells were isolated from healthy donors to investigate the effects of identified peptides on KIR2DL3(+) NK cell function. Results: Thirty-one peptides able to stabilize HLA-C*03: 04 were identified. One 9mer peptide, YIPLVGAPL, resulted in significantly higher KIR2DL3 binding to HLA-C*03:04(+) 722.221 cells and suppression of primary KIR2DL3+ NK cell function. Interestingly this sequence exhibited a high frequency of mutations in different HCV genotypes. These genotype-specific peptides showed lower HLA-C*03: 04 stabilization, decreased binding of the inhibitory KIR2DL3 and lower inhibition of NK cell function. Conclusions: Taken together we show that a viral peptide derived from the core protein of HCV genotype 1 binding to HLA-C*03: 04 results in a sequence-dependent engagement of the inhibitory NK cell receptor KIR2DL3, while the large majority of the remain-ing 30 HLA-C*03: 04 binding HCV core peptides did not. These data show that sequence variations within HCV can modulate NK cell function, providing potential pathways for viral escape. Lay summary: We identified a HCV peptide that dampens NK cell responses, and thereby possibly prevents killing of infected cells through this part of the innate immune system. This is facilitated via presentation of the viral peptide on HLA*03: 04 to the inhibitory KIR receptor KIR2DL3 on NK cells. Naturally occurring sequence mutations in the peptide alter these interactions making the inhibition less efficient. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Lunemann, Sebastian; Martrus, Gloria; Chapel, Anais; Ziegler, Maja; Koerner, Christian; Altfeld, Marcus] Heinrich Pette Inst, Dept Virol Immunol, Hamburg, Germany. [Hoelzemer, Angelique] Univ Hosp Eppendorf, Dept Internal Med, Hamburg, Germany. [Wedemeyer, Heiner] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany. [Beltran, Wilfredo Garcia; Carrington, Mary] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Carrington, Mary] Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Altfeld, M (reprint author), Martinistr 52, D-20251 Hamburg, Germany. EM marcus.altfeld@hpi.uni-hamburg.de FU Deutsche Forschungsgemeinschaft [SFB841] FX This study was supported by the Deutsche Forschungsgemeinschaft (SFB841). NR 30 TC 2 Z9 2 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD AUG PY 2016 VL 65 IS 2 BP 252 EP 258 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DS2AH UT WOS:000380516900007 PM 27057987 ER PT J AU Ouchi, T Nakato, G Udey, MC AF Ouchi, Takeshi Nakato, Gaku Udey, Mark C. TI EpCAM Expressed by Murine Epidermal Langerhans Cells Modulates Immunization to an Epicutaneously Applied Protein Antigen SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID ADHESION MOLECULE EPCAM; DERMAL DENDRITIC CELLS; SCALDED-SKIN SYNDROME; TIGHT JUNCTION; EP-CAM; CONTACT HYPERSENSITIVITY; BULLOUS IMPETIGO; IN-VIVO; DISTINCT; IDENTIFICATION AB Langerhans cells (LCs) induce type 2 antibodies reactive with protein antigens that are applied to murine skin in the absence of adjuvant after extending their dendrites through tight junctions to acquire antigens and migrating to regional lymph nodes. In response to contact sensitizers, epithelial cell adhesion molecule (EpCAM) on LCs promotes LC dendrite mobility and LC migration. In epithelial cells, EpCAM regulates expression and distribution of selected tight junctions-associated claudins. To determine if EpCAM regulates claudins in LC and immune responses to externally applied proteins, we studied conditional knockout mice with EpCAM-deficient LCs. Although LC claudin-1 levels were dramatically reduced in the absence of EpCAM, conditional knockout mice with EpCAM-deficient LCs and control LC dendrites docked with epidermal tight junctions with equal efficiencies and ingested surface proteins. Topical immunization of conditional knockout mice with EpCAM-deficient LCs with ovalbumin led to increased induction of type 2 Ova-specific antibodies and enhanced proliferation of ovalbumin-reactive T cells associated with increased accumulation of LCs in lymph nodes. These results suggest that, in the absence of strong adjuvants, EpCAM-deficient LCs exhibit increased migration to regional lymph nodes. EpCAM appears to differentially regulate LC mobility/migration in the setting of limited inflammation as compared with the intense inflammation triggered by contact sensitizers. C1 [Ouchi, Takeshi; Nakato, Gaku; Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 4,Room 4N222, Bethesda, MD 20892 USA. RP Udey, MC (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 4,Room 4N222, Bethesda, MD 20892 USA. EM udeym@mail.nih.gov FU Intramural NIH HHS [Z01 SC003669-19, Z99 CA999999, Z01 SC003669-18] NR 44 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2016 VL 136 IS 8 BP 1627 EP 1635 DI 10.1016/j.jid.2016.04.005 PG 9 WC Dermatology SC Dermatology GA DS2HE UT WOS:000380585200088 PM 27106675 ER PT J AU Ishitsuka, Y Huebner, AJ Rice, RH Koch, PJ Speransky, VV Steven, AC Roop, DR AF Ishitsuka, Yosuke Huebner, Aaron J. Rice, Robert H. Koch, Peter J. Speransky, Vladislav V. Steven, Alasdair C. Roop, Dennis R. TI Lce1 Family Members Are Nrf2-Target Genes that Are Induced to Compensate for the Loss of Loricrin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID CORNIFIED CELL-ENVELOPE; ANTIOXIDANT RESPONSIVE ELEMENTS; NF-E2-RELATED FACTOR-2; STRUCTURAL PROTEINS; BINDING PROTEINS; BARRIER FUNCTION; NRF2; ACTIVATION; IDENTIFICATION; PSORIASIS AB Loricrin is a major component of the cornified cell envelope, a highly insoluble structure composed of covalently cross-linked proteins. Although loricrin knockout mice only exhibit a mild transient phenotype at birth, they show a marked delay in the formation of an epidermal barrier in utero. We recently discovered that induction of a compensatory response to repair the defective barrier is initiated by amniotic fluid via activation of NF-E2-related factor 2 and identified Sprr2d and Sprr2h as direct transcriptional targets. Proteomic analysis suggested that other proteins were also incorporated into the loricrin knockout cell envelope, in addition to the small proline rich proteins. Here we present evidence suggesting that the late cornified envelope 1 proteins are also compensatory components as determined by their localization within the loricrin knockout cell envelope via immunoelectron microscopy. We also demonstrate that late cornified envelope 1 genes are upregulated at the transcriptional level in loricrin knockout mouse skin and confirm that late cornified envelope 1 genes are transcriptional targets of NRF2. Our present study further highlights the complexity and importance of a compensatory mechanism that evolved in terrestrial animals to ensure the formation of a functional epidermal barrier. C1 [Ishitsuka, Yosuke; Huebner, Aaron J.; Koch, Peter J.; Roop, Dennis R.] Univ Colorado, Dept Dermatol, Anschutz Med Campus,Res Complex 1 North, Aurora, CO 80045 USA. [Ishitsuka, Yosuke; Huebner, Aaron J.; Koch, Peter J.; Roop, Dennis R.] Univ Colorado, Charles C Gates Ctr Regenerat Med, Anschutz Med Campus,Res Complex 1 North, Aurora, CO 80045 USA. [Rice, Robert H.] Univ Calif Davis, Dept Environm Toxicol, Davis, CA 95616 USA. [Speransky, Vladislav V.] Ted Pella, Life Sci, Redding, CA USA. [Steven, Alasdair C.] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Roop, DR (reprint author), Univ Colorado, Dept Dermatol, Anschutz Med Campus,Res Complex 1 North, Aurora, CO 80045 USA.; Roop, DR (reprint author), Univ Colorado, Charles C Gates Ctr Regenerat Med, Anschutz Med Campus,Res Complex 1 North, Aurora, CO 80045 USA. EM dennis.roop@ucdenver.edu FU NIBIB; NIAMS [AR47898] FX We thank Michal Jarnik for his contribution to the EM studies. This research was supported in part by the Intramural Research Programs of NIAMS and NIBIB, and a grant from NIAMS (AR47898) to DRR. We also thank the University of Colorado Skin Disease Research Center (P30AR057212) Morphology Phenotyping Core for assistance. NR 40 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2016 VL 136 IS 8 BP 1656 EP 1663 DI 10.1016/j.jid.2016.04.022 PG 8 WC Dermatology SC Dermatology GA DS2HE UT WOS:000380585200091 PM 27167730 ER PT J AU Li, L Kim, J Flowers, B Cataisson, C Yuspa, S AF Li, L. Kim, J. Flowers, B. Cataisson, C. Yuspa, S. TI Rho-associated protein kinase (ROCK) controls cellular homeostasis of mouse primary keratinocytes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Li, L.; Kim, J.; Flowers, B.; Cataisson, C.; Yuspa, S.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2016 VL 136 IS 8 MA LB793 BP B8 EP B8 PG 1 WC Dermatology SC Dermatology GA DS2HE UT WOS:000380585200040 ER PT J AU Nemeth, K Gorog, A Mezey, E Harsing, J Kuroli, E Rady, P Fischer, M Kovacs, L Sillo, P Tyring, SK Karpati, S AF Nemeth, K. Gorog, A. Mezey, E. Harsing, J. Kuroli, E. Rady, P. Fischer, M. Kovacs, L. Sillo, P. Tyring, S. K. Karpati, S. TI Detection of hair follicle-associated Merkel Cell Polyomavirus in an immunocompromised host with follicular spicules and alopecia and successful treatment with valganciclovir SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Nemeth, K.] Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA. [Nemeth, K.; Gorog, A.; Harsing, J.; Kuroli, E.; Sillo, P.; Karpati, S.] Semmelweis Univ, Dept Dermatol, Budapest, Hungary. [Mezey, E.] NIDCR, NIH, Bethesda, MD USA. [Fischer, M.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Kovacs, L.] Semmelweis Univ, Dept Pediat 1, Budapest, Hungary. [Rady, P.; Tyring, S. K.] UTHlth Med Sch, Dept Dermatol, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2016 VL 136 IS 8 MA LB807 BP B10 EP B10 PG 1 WC Dermatology SC Dermatology GA DS2HE UT WOS:000380585200053 ER PT J AU Nguyen, KD Lee, EE Tyring, SK North, JP Cockerell, CJ Buck, CB Wang, RC AF Nguyen, K. D. Lee, E. E. Tyring, S. K. North, J. P. Cockerell, C. J. Buck, C. B. Wang, R. C. TI A novel strain of HPyV7 causing a HIV/AIDS-associated pruritic rash SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Nguyen, K. D.; Lee, E. E.; Cockerell, C. J.; Wang, R. C.] Univ Texas Southwestern Med Ctr, Dept Dermatol, Dallas, TX USA. [Tyring, S. K.] Univ Texas Hlth Sci Ctr Houston, Dept Dermatol, Houston, TX 77030 USA. [North, J. P.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [North, J. P.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. [Buck, C. B.] NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2016 VL 136 IS 8 MA LB806 BP B10 EP B10 PG 1 WC Dermatology SC Dermatology GA DS2HE UT WOS:000380585200050 ER PT J AU Kim, SYH Wilson, R De Vries, R Ryan, KA Holloway, RG Kieburtz, K AF Kim, Scott Y. H. Wilson, Renee De Vries, Raymond Ryan, Kerry A. Holloway, Robert G. Kieburtz, Karl TI Are patients with amyotrophic lateral sclerosis at risk of a therapeutic misconception? SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID ONCOLOGY TRIALS; CLINICAL-TRIALS; DOUBLE-BLIND; BENEFIT AB Objectives To assess whether persons with amyotrophic lateral sclerosis (ALS) are at risk of a therapeutic misconception (TM) in which they misconceive research as treatment or overestimate the likelihood of its benefit. Methods 72 patients with ALS recruited via academic and patient organisations were surveyed using a hypothetical first-in-human intervention study scenario. We elicited their understanding of the purpose of the study ('purpose-of-research question') and then asked how they interpreted the question. We then asked for an estimate of the likelihood that their ALS would improve by participating and asked them to explain the meaning of their estimates. Results Although 10 of 72 (14%) subjects incorrectly said that the intervention study was 'mostly intending to help [me]' in response to the purpose-of-research question, 7 of those 10 thought that the question was asking them about their own motivations for participating. Overall, only one of 72 respondents (1.4%) both understood the purpose-of-research question as intended and gave the incorrect response. Subjects' mean estimate of likelihood of benefit was 31% (SD 26). This was due to 29 of 72 of respondents providing high estimates (50%-54% likelihood), which they said were expressions of hope and need for a positive attitude; among those who said their estimates meant 'those are the facts' or 'there is a lot of uncertainty', the estimates were much lower (12.6% and 18.5%, respectively). Conclusions In this group of patients with ALS considering a hypothetical first-in-human intervention study, apparent TM responses have alternative explanations and the risk of true TM appears low. C1 [Kim, Scott Y. H.] NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. [Wilson, Renee] Univ Rochester, Ctr Human Expt Therapeut, Rochester, NY USA. [De Vries, Raymond] Univ Michigan, Dept Learning Hlth Sci, Ann Arbor, MI 48109 USA. [De Vries, Raymond; Ryan, Kerry A.] Univ Michigan, Ctr Bioeth & Social Sci Med, Ann Arbor, MI 48109 USA. [Holloway, Robert G.] Univ Rochester, Dept Neurol, Rochester, NY USA. [Kieburtz, Karl] Univ Rochester, Clin & Translat Sci Inst, Rochester, NY USA. RP Kim, SYH (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. EM scott.kim@nih.gov FU National Institute for Neurological Disorders and Stroke [R01-NS062770]; CTSA award from the National Center for Research Resources [UL1 RR024160]; National Center for Advancing Translational Sciences; Intramural Research Program; National Institutes of Health, USA FX This work was supported in part by the National Institute for Neurological Disorders and Stroke (R01-NS062770), a CTSA award (UL1 RR024160) from the National Center for Research Resources and the National Center for Advancing Translational Sciences and the Intramural Research Program, all of the National Institutes of Health, USA. NR 27 TC 1 Z9 1 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD AUG PY 2016 VL 42 IS 8 BP 514 EP 518 DI 10.1136/medethics-2015-103319 PG 5 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DS7YG UT WOS:000380998600008 PM 26964569 ER PT J AU Kim, SYH De Vries, R Holloway, RG Kieburtz, K AF Kim, Scott Y. H. De Vries, Raymond Holloway, Robert G. Kieburtz, Karl TI Understanding the 'therapeutic misconception' from the research participant's perspective SO JOURNAL OF MEDICAL ETHICS LA English DT Editorial Material ID TRIALS C1 [Kim, Scott Y. H.] NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. [De Vries, Raymond] Univ Michigan, Ctr Bioeth & Social Sci, Ann Arbor, MI 48109 USA. [De Vries, Raymond] Univ Michigan, Dept Learning Hlth Sci, Ann Arbor, MI 48109 USA. [Holloway, Robert G.; Kieburtz, Karl] Univ Rochester, Dept Neurol, Rochester, NY USA. [Kieburtz, Karl] Univ Rochester, Ctr Human Expt Therapeut, Rochester, NY USA. RP Kim, SYH (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. EM scott.kim@nih.gov NR 13 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 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD AUG PY 2016 VL 42 IS 8 BP 522 EP 523 DI 10.1136/medethics-2016-103597 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DS7YG UT WOS:000380998600011 PM 27145809 ER PT J AU Hristovski, D Kastrin, A Dinevski, D Burgun, A Ziberna, L Rindflesch, TC AF Hristovski, Dimitar Kastrin, Andrej Dinevski, Dejan Burgun, Anita Ziberna, Lovro Rindflesch, Thomas C. TI Using Literature-Based Discovery to Explain Adverse Drug Effects SO JOURNAL OF MEDICAL SYSTEMS LA English DT Article DE Literature-based discovery; Text mining; Pharmacovigilance; Adverse drug effects; Adverse drug reactions; Pharmacogenomics ID PATIENT; RHABDOMYOLYSIS; PANCREATITIS; GENERATION; IRINOTECAN; KNOWLEDGE; IDENTIFY; TEXT; RATS AB We report on our research in using literature-based discovery (LBD) to provide pharmacological and/or pharmacogenomic explanations for reported adverse drug effects. The goal of LBD is to generate novel and potentially useful hypotheses by analyzing the scientific literature and optionally some additional resources. Our assumption is that drugs have effects on some genes or proteins and that these genes or proteins are associated with the observed adverse effects. Therefore, by using LBD we try to find genes or proteins that link the drugs with the reported adverse effects. These genes or proteins can be used to provide insight into the processes causing the adverse effects. Initial results show that our method has the potential to assist in explaining reported adverse drug effects. C1 [Hristovski, Dimitar] Univ Ljubljana, Fac Med, Inst Biostat & Med Informat, Ljubljana, Slovenia. [Kastrin, Andrej] Novo Mesto, Fac Informat Studies, Ljubljana, Slovenia. [Dinevski, Dejan] Univ Maribor, Fac Med, Maribor, Slovenia. [Burgun, Anita] Paris Descartes Univ, Georges Pompidou European Hosp, APHP, INSERM,UMRS 1138,Eq 22, Paris, France. [Ziberna, Lovro] Univ Ljubljana, Fac Med, Inst Pharmacol & Expt Toxicol, Ljubljana, Slovenia. [Rindflesch, Thomas C.] NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RP Hristovski, D (reprint author), Univ Ljubljana, Fac Med, Inst Biostat & Med Informat, Ljubljana, Slovenia. EM dimitar.hristovski@mf.uni-lj.si FU Intramural Research Program of the U.S. National Institutes of Health, National Library of Medicine FX This work was supported in part by the Intramural Research Program of the U.S. National Institutes of Health, National Library of Medicine. Authors would like to thank Celine Narjoz and Marie-Anne Loriot for suggesting the additional adverse drug reactions, which we used in this study. We are also grateful for the contribution of the medical students (Faculty of Medicine, University of Maribor) in the evaluation of the extracted relations. NR 26 TC 0 Z9 0 U1 6 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0148-5598 EI 1573-689X J9 J MED SYST JI J. Med. Syst. PD AUG PY 2016 VL 40 IS 8 AR 185 DI 10.1007/s10916-016-0544-z PG 5 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA DS3QG UT WOS:000380697200005 PM 27318993 ER PT J AU Ryerson, LZ Frohman, TC Foley, J Kister, I Weinstock-Guttman, B Tornatore, C Pandey, K Donnelly, S Pawate, S Bomprezzi, R Smith, D Kolb, C Qureshi, S Okuda, D Kalina, J Rimler, Z Green, R Monson, N Hoyt, T Bradshaw, M Fallon, J Chamot, E Bucello, M Beh, S Cutter, G Major, E Herbert, J Frohman, EM AF Ryerson, L. Zhovtis Frohman, T. C. Foley, J. Kister, I. Weinstock-Guttman, B. Tornatore, C. Pandey, K. Donnelly, S. Pawate, S. Bomprezzi, R. Smith, D. Kolb, C. Qureshi, S. Okuda, D. Kalina, J. Rimler, Z. Green, R. Monson, N. Hoyt, T. Bradshaw, M. Fallon, J. Chamot, E. Bucello, M. Beh, S. Cutter, G. Major, E. Herbert, J. Frohman, E. M. TI Extended interval dosing of natalizumab in multiple sclerosis SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID RECONSTITUTION INFLAMMATORY SYNDROME; TREATMENT INTERRUPTION; CONTROLLED TRIAL; DISEASE-ACTIVITY; MS PATIENTS; JC VIRUS; WITHDRAWAL; THERAPY; HOLIDAY; SAFETY AB Background Natalizumab (NTZ), a monoclonal antibody to human alpha(4)beta(1)/beta(7) integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days. Methods A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks. Results 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort. Conclusions Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID. C1 [Ryerson, L. Zhovtis; Kister, I.; Kalina, J.; Rimler, Z.; Fallon, J.; Herbert, J.] NYU, Dept Neurol, Langone Med Ctr, New York, NY 10016 USA. [Frohman, T. C.; Qureshi, S.; Okuda, D.; Monson, N.; Beh, S.; Frohman, E. M.] Univ Texas Southwestern Med Ctr, Dept Neurol, Dallas, TX USA. [Frohman, T. C.; Qureshi, S.; Okuda, D.; Monson, N.; Beh, S.; Frohman, E. M.] Univ Texas Southwestern Med Ctr, Dept Neurotherapeut, Dallas, TX USA. [Foley, J.; Hoyt, T.] Rocky Mt MS Clin, Salt Lake City, UT USA. [Weinstock-Guttman, B.; Kolb, C.; Bucello, M.] Univ Buffalo, Buffalo, NY USA. [Tornatore, C.] Georgetown Univ, Washington, DC USA. [Pandey, K.; Green, R.] Barnabas Hlth MS Ctr, Livingston, NJ USA. [Donnelly, S.] CUNY, Grad Ctr, New York, NY USA. [Pawate, S.; Bradshaw, M.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Bomprezzi, R.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Smith, D.] Multiple Sclerosis Ctr Connecticut, Norwich, CT USA. [Chamot, E.; Cutter, G.] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL 35294 USA. [Major, E.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Frohman, E. M.] Univ Texas Southwestern Med Ctr, Dept Ophthalmol, Dallas, TX USA. [Frohman, E. M.] Univ Texas Dallas, Dept Bioengn, Dallas, TX 75230 USA. [Frohman, E. M.] Univ Texas Dallas, Dept Behav & Brain Sci, Dallas, TX 75230 USA. RP Frohman, EM (reprint author), Univ Texas Southwestern Sch Med, Dept Neurol & Neurotherapeut, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM Elliot.frohman@utsouthwesternen.edu OI Ryerson , Lana/0000-0003-1868-3893; Kister, Ilya/0000-0003-3549-949X FU Biogen Idec; Novartis; Genzyme; Acorda; Guthy-Jackson Charitable Foundation; National Multiple Sclerosis Society; Serono; Navartis; Questcor Pharmaceuticals, Inc; Shire; TEVA; Biogen; EMD Serono; Acorda Therapeutics; TEVA Neuroscience; Genzyme Corp; Consortium of Multiple Sclerosis Centers; Cerespir Inc; Consortium of MS Centers; D3 (Drug Discovery and Development); Genentech; Innate Therapeutics; Jannsen Pharmaceuticals; Klein-Buendel Incorporated; Medimmune; Opexa Therapeutics; Receptos; Roche; Savara Inc; Spiniflex Pharmaceuticals; Somahlution; Teva pharmaceuticals; Transparency Life Sciences; PML Consortium; Takeda/Millennium Pharma; Glaxo Smith Klein; Genentech Roche; Sanofi Genzyme FX LZR has received research support from Biogen Idec. She has received compensation for advisory board and speaker activities from Biogen Idec and Teva. TCF has received speaker and consultant fees from Novartis, Genzyme and Acorda. IK is the member of scientific advisory board for Biogen Idec and received research support from Guthy-Jackson Charitable Foundation, National Multiple Sclerosis Society, Biogen-Idec, Serono and Navartis. JF has served as a consultant for and receives honoraria from Biogen, Genzyme, Teva, Novartis and Avanir. BW-G has participated in speaker's bureaus and served as a consultant for Biogen Idec, Teva Neuroscience, EMD Serono, Novartis, Genzyme & Sanofi, Acorda Therapeutics, Inc and Genentech. BW-G also has received grant/research support from the agencies listed in the previous sentence as well as Questcor Pharmaceuticals, Inc and Shire. She serves in the editorial board for BMJ Neurology, Journal of International MS and CNS Drugs. CT has received speaker and consulting fees from Biogen Idec. KP has received speaker and consulting fees from Acorda, TEVA and Biogen. DS has received speaker and consulting fees from Biogen Idec. CK has received speaker and consulting fees from Biogen, Teva, EMD Serono and Acorda. DO received lecture fees from Acorda Therapeutics, Genzyme and TEVA Neuroscience, consulting and advisory board fees from Genzyme, Novartis and TEVA Neuroscience, and research support from Biogen. EC reports grants from Genzyme Corp, grants from Consortium of Multiple Sclerosis Centers, grants from Biogen Idec, grants from National Multiple Sclerosis Society, outside the submitted work. MBu has received speaker and consulting fees from Genzyme, Teva and EMD Serono. GC has received consulting, speaking fees and advisory boards: Cerespir Inc, Consortium of MS Centers (grant), D3 (Drug Discovery and Development), Genzyme, Genentech, Innate Therapeutics, Jannsen Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Novartis, Opexa Therapeutics, Receptos, Roche, Savara Inc, Spiniflex Pharmaceuticals, Somahlution, Teva pharmaceuticals, Transparency Life Sciences. EM reports personal fees from PML Consortium, personal fees from Takeda/Millennium Pharma, personal fees from Glaxo Smith Klein, personal fees from Genentech Roche, personal fees from Sanofi Genzyme, outside the submitted work. JH has received research support from Biogen Idec. EMF has received speaker and consultant fees from Novartis, Genzyme, TEVA and Acorda. NR 28 TC 4 Z9 4 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD AUG PY 2016 VL 87 IS 8 BP 885 EP 889 DI 10.1136/jnnp-2015-312940 PG 5 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA DS1VP UT WOS:000380392200014 ER PT J AU Yucesoy, B Talzhanov, Y Barmada, MM Johnson, VJ Kashon, ML Baron, E Wilson, NW Frye, B Wang, W Fluharty, K Gharib, R Meade, J Germolec, D Luster, MI Nedorost, S AF Yucesoy, Berran Talzhanov, Yerkebulan Barmada, M. Michael Johnson, Victor J. Kashon, Michael L. Baron, Elma Wilson, Nevin W. Frye, Bonnie Wang, Wei Fluharty, Kara Gharib, Rola Meade, Jean Germolec, Dori Luster, Michael I. Nedorost, Susan TI Genetic Basis of Irritant Susceptibility in Health Care Workers SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; OF-FUNCTION MUTATIONS; CONTACT-DERMATITIS; ATOPIC-DERMATITIS; FACTOR RECEPTOR; JAPANESE POPULATION; PSORIASIS-VULGARIS; SKIN INFLAMMATION; FILAGGRIN GENE; IL22 GENE AB Objective: The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) within genes involved in inflammation, skin barrier integrity, signaling/pattern recognition, and antioxidant defense with irritant susceptibility in a group of health care workers. Methods: The 536 volunteer subjects were genotyped for selected SNPs and patch tested with three model irritants: sodium lauryl sulfate (SLS), sodium hydroxide (NaOH), and benzalkonium chloride (BKC). Genotyping was performed on genomic DNA using Illumina Goldengate custom panels. Results: The ACACB (rs2268387, rs16934132, rs2284685), NTRK2 (rs10868231), NTRK3 (rs1347424), IL22 (rs1179251), PLAU (rs2227564), EGFR (rs6593202), and FGF2 (rs308439) SNPs showed an association with skin response to tested irritants in different genetic models (all at P < 0.001). Functional annotations identified two SNPs in PLAU (rs2227564) and ACACB (rs2284685) genes with a potential impact on gene regulation. In addition, EGF (rs10029654), EGFR (rs12718939), CXCL12 (rs197452), and VCAM1 (rs3917018) genes showed an association with hand dermatitis (P < 0.005). Conclusions: The results demonstrate that genetic variations in genes related to inflammation and skin homeostasis can influence responses to irritants and may explain inter-individual variation in the development of subsequent contact dermatitis. C1 [Yucesoy, Berran; Kashon, Michael L.; Frye, Bonnie; Wang, Wei; Fluharty, Kara; Meade, Jean] NIOSH, Hlth Effects Lab Div, CDC, Morgantown, WV 26505 USA. [Talzhanov, Yerkebulan; Barmada, M. Michael] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15260 USA. [Johnson, Victor J.] BRT, Morrisville, NY USA. [Baron, Elma; Nedorost, Susan] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Wilson, Nevin W.] Univ Nevada, Sch Med, Dept Pediat, Reno, NV 89557 USA. [Gharib, Rola] West Virginia Univ, Sch Med, Dept Dermatol, Morgantown, WV USA. [Germolec, Dori] NIEHS, Toxicol Branch, DNTP, POB 12233, Res Triangle Pk, NC 27709 USA. [Luster, Michael I.] West Virginia Univ, Sch Publ Hlth, Morgantown, WV USA. RP Yucesoy, B (reprint author), NIOSH, Hlth Effects Lab Div, Morgantown, WV 26505 USA. EM berranyucesoy@gmail.com OI Barmada, M Michael/0000-0002-3604-6460 FU NIOSH [AES12007001-1-0-6]; NIEHS [AES12007001-1-0-6] FX This study was supported in part by an inter-agency agreement between NIOSH and NIEHS (AES12007001-1-0-6) as a collaborative National Toxicology Program research activity. NR 68 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD AUG PY 2016 VL 58 IS 8 BP 753 EP 759 DI 10.1097/JOM.0000000000000784 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DT0DP UT WOS:000381153200010 PM 27206134 ER PT J AU Lim, YH Ovejero, D Derrick, KM Collins, MT Choate, KA AF Lim, Young H. Ovejero, Diana Derrick, Kristina M. Collins, Michael T. Choate, Keith A. CA Yale Ctr Mendelian Genomics TI Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Review DE congenital melanocytic nevus; cutaneous skeletal hypophosphatemia syndrome; epidermal nevus; fibroblast growth factor-23; mosaicism; nevus syndrome; rickets ID EPIDERMAL NEVUS SYNDROME; D-RESISTANT RICKETS; X-LINKED HYPOPHOSPHATEMIA; VITAMIN-D METABOLISM; PHOSPHATE HOMEOSTASIS; PHAKOMATOSIS PIGMENTOKERATOTICA; POSTZYGOTIC HRAS; FGF23; PATHWAY; RAS AB Background: We recently demonstrated multilineage somatic mosaicism in cutaneous skeletal hypophosphatemia syndrome (CSHS), which features epidermal or melanocytic nevi, elevated fibroblast growth factor (FGF)-23, and hypophosphatemia, finding identical RAS mutations in affected skin and bone. Objective: We sought to: (1) provide an updated overview of CSHS; (2) review its pathobiology; (3) present a new patient with CSHS; and (4) discuss treatment modalities. Methods: We searched PubMed for ''nevus AND rickets,'' and ''nevus AND hypophosphatemia,'' identifying cases of nevi with hypophosphatemic rickets or elevated serum FGF-23. For our additional patient with CSHS, we performed histopathologic and radiographic surveys of skin and skeletal lesions, respectively. Sequencing was performed for HRAS, KRAS, and NRAS to determine causative mutations. Results: Our new case harbored somatic activating HRAS p.G13 R mutation in affected tissue, consistent with previous findings. Although the mechanism of FGF-23 dysregulation is unknown in CSHS, interaction between FGF and MAPK pathways may provide insight into pathobiology. Anti-FGF-23 antibody KRN-23 may be useful in managing CSHS. Limitations: Multilineage RAS mutation in CSHS was recently identified; further studies on mechanism are unavailable. Conclusion: Patients with nevi in association with skeletal disease should be evaluated for serum phosphate and FGF-23. Further studies investigating the role of RAS in FGF-23 regulation are needed. C1 [Lim, Young H.; Choate, Keith A.] Yale Univ, Sch Med, Dept Dermatol, 333 Cedar St, New Haven, CT 06510 USA. [Lim, Young H.; Choate, Keith A.] Yale Univ, Sch Med, Dept Pathol, 333 Cedar St, New Haven, CT 06519 USA. [Lim, Young H.; Choate, Keith A.] Yale Univ, Sch Med, Dept Genet, 333 Cedar St, New Haven, CT 06519 USA. [Ovejero, Diana; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Ovejero, Diana] Univ Autonoma Barcelona, Dept Med, Barcelona, Spain. [Derrick, Kristina M.] Albert Einstein Coll Med, Childrens Hosp Montefiore, Div Pediat Endocrinol, Bronx, NY 10467 USA. RP Choate, KA (reprint author), Yale Univ, Sch Med, Dept Dermatol, 333 Cedar St, New Haven, CT 06510 USA.; Choate, KA (reprint author), Yale Univ, Sch Med, Dept Pathol, 333 Cedar St, New Haven, CT 06519 USA.; Choate, KA (reprint author), Yale Univ, Sch Med, Dept Genet, 333 Cedar St, New Haven, CT 06519 USA. EM keith.choate@yale.edu FU Doris Duke Charitable Foundation; Medical Scientist Training Program at Yale University (National Institutes of Health) [T32 GM007205]; Yale Center for Mendelian Genomics (National Institutes of Health) [U54HG006504] FX Supported in part by a Clinical Scientist Development Award (Dr Choate) and Medical Student Research Fellowship (Mr Lim) from the Doris Duke Charitable Foundation, the Medical Scientist Training Program at Yale University (National Institutes of Health T32 GM007205) (Mr Lim), and the Yale Center for Mendelian Genomics (National Institutes of Health U54HG006504). NR 48 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD AUG PY 2016 VL 75 IS 2 BP 420 EP 427 DI 10.1016/j.jaad.2015.11.012 PG 8 WC Dermatology SC Dermatology GA DS4JV UT WOS:000380748300038 PM 27444071 ER PT J AU Pichard, DC Ombrello, AK Hoffmann, P Stone, DL Cowen, EW AF Pichard, Dominique C. Ombrello, Amanda K. Hoffmann, Patrycja Stone, Deborah L. Cowen, Edward W. TI Early-onset stroke, polyarteritis nodosa (PAN), and livedo racemosa SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material DE deficiency of adenosine deaminase 2; genodermatosis; livedo; polyarteritis nodosa; stroke ID DEAMINASE 2 DEFICIENCY; ADA2 DEFICIENCY; VASCULOPATHY; MUTATIONS; PHENOTYPE C1 [Pichard, Dominique C.; Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Ombrello, Amanda K.; Hoffmann, Patrycja; Stone, Deborah L.] NIH, Inflammatory Dis Sect, Natl Human Genome Res Inst, Bldg 10, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 15 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD AUG PY 2016 VL 75 IS 2 BP 449 EP 453 DI 10.1016/j.jaad.2016.01.057 PG 5 WC Dermatology SC Dermatology GA DS4JV UT WOS:000380748300048 PM 27444081 ER PT J AU Snider, TH Babin, MC Jett, DA Platoff, GE Yeung, DT AF Snider, Thomas H. Babin, Michael C. Jett, David A. Platoff, Gennady E., Jr. Yeung, David T. TI Toxicity and median effective doses of oxime therapies against percutaneous organophosphorus pesticide and nerve agent challenges in the Hartley guinea pig SO JOURNAL OF TOXICOLOGICAL SCIENCES LA English DT Article DE Nerve agent; Pesticide; Oxime; Therapy; ED50; Therapeutic index ID CHEMICAL-WARFARE; EFFICACY; ATTACK; RATS AB Anticholinesterases, such as organophosphorus pesticides and warfare nerve agents, present a significant health threat. Onset of symptoms after exposure can be rapid, requiring quick-acting, efficacious therapy to mitigate the effects. The goal of the current study was to identify the safest antidote with the highest therapeutic index (TI = oxime 24-hr LD50/oxime ED50) from a panel of four oximes deemed most efficacious in a previous study. The oximes tested were pralidoxime chloride (2-PAM CO, MMB4 DMS, HLo-7 DMS, and obidoxime Cl-2. The 24-hr median lethal dose (LD50) for the four by intramuscular (IM) injection and the median effective dose (ED50) were determined. In the ED50 study, male guinea pigs clipped of hair received 2x LD50 topical challenges of undiluted Russian VX (VR), VX, or phorate oxon (PHO) and, at the onset of cholinergic signs, IM therapy of atropine (0.4 mg/kg) and varying levels of oxime. Survival was assessed at 3 hr after onset clinical signs. The 3-hr 90th percentile dose (ED90) for each oxime was compared to the guinea pig pre-hospital human-equivalent dose of 2-PAM Cl, 149 mu mol/kg. The TI was calculated for each OP/oxime combination. Against VR, MMB4 DMS had a higher TI than HLo-7 DMS, whereas 2-PAM Cl and obidoxime Cl-2 were ineffective. Against VX, MMB4 DMS > HLo-7 DMS > 2-PAM Cl > obidoxime Cl. Against PHO, all performed better than 2-PAM Cl. MMB4 DMS was the most effective oxime as it was the only oxime with ED90 < 149 mu mol/kg against all three topical OPs tested. C1 [Snider, Thomas H.; Babin, Michael C.] Battelle Mem Inst, 505 King Ave,JM-7, Columbus, OH 43201 USA. [Jett, David A.; Yeung, David T.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Platoff, Gennady E., Jr.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Snider, TH (reprint author), Battelle Mem Inst, 505 King Ave,JM-7, Columbus, OH 43201 USA. EM snider-t@sbcglobal.net FU NIH Office of the Director (OD) [Y1-OD-0387-01]; NIH; NIAID; NINDS; DoD Defense Technical Information Center (DTIC) under the Chemical, Biological, Radiological & Nuclear Defense Information Analysis Center (CBRNIAC) program [SP0700-00-D-3180, 832/CB-10-0832, 0794, 689/CB-13-0689] FX This work was supported by the NIH Office of the Director through an interagency agreement (OD#: Y1-OD-0387-01) between the National Institute of Allergy and Infectious Diseases (NIAID) and Department of Defense (DoD) and prepared under the auspices of the NIH, NIAID, NINDS, and the DoD Defense Technical Information Center (DTIC) under the Chemical, Biological, Radiological & Nuclear Defense Information Analysis Center (CBRNIAC) program, Contract No. SP0700-00-D-3180, Delivery Order Number 0687, CBRNIAC Task 832/CB-10-0832 and SP0700-00-D-3180, Delivery Order Number 0794, CBRNIAC Task 689/CB-13-0689. NR 35 TC 1 Z9 1 U1 10 U2 10 PU JAPANESE SOC TOXICOLOGICAL SCIENCES PI TOKYO PA INTERNATIONAL MEDICAL INFORMATION CENTER, SHINANOMACHI RENGAKAN, 35 SHINANO-MACHI, SHINJUKU-KU, TOKYO, 160-0016, JAPAN SN 0388-1350 EI 1880-3989 J9 J TOXICOL SCI JI J. Toxicol. Sci. PD AUG PY 2016 VL 41 IS 4 BP 511 EP 521 PG 11 WC Toxicology SC Toxicology GA DS8WZ UT WOS:000381065000007 PM 27432237 ER PT J AU Cajka, T Davis, R Austin, KJ Newman, JW German, JB Fiehn, O Smilowitz, JT AF Cajka, Tomas Davis, Ryan Austin, Kathryn J. Newman, John W. German, J. Bruce Fiehn, Oliver Smilowitz, Jennifer T. TI Using a lipidomics approach for nutritional phenotyping in response to a test meal containing gamma-linolenic acid SO METABOLOMICS LA English DT Article DE Dihomo-gamma-linolenic acid; Gammalinolenic acid; Lipidomics; Liquid chromatography-mass spectrometry; Phenotyping; SWATH ID POLYUNSATURATED FATTY-ACIDS; MASS-SPECTROMETRY; GENE-CLUSTER; EICOSAPENTAENOIC ACID; ARACHIDONIC-ACID; METABOLISM; BIOSYNTHESIS; LIPIDS; SUPPLEMENTATION; PHOSPHOLIPIDS AB Introduction Plasma fatty acids are derived from preformed sources in the diet and de novo synthesis through the action of desaturase and elongase enzymes. Objective This study was designed to examine the elongation of gamma-linolenic acid (GLA, 18:3n6) into dihomo-gamma-linolenic acid (DGLA, 20:3n6) over an 8-h period using both targeted gas chromatography-flame ionization detection and untargeted liquid chromatography-mass spectrometry-based lipidomics utilizing the sequential window acquisition of all theoretical fragmention spectra (SWATH). Methods In a single blind, placebo-controlled, crossover design, seven healthy subjects consumed a test meal that consisted of GLA fat (borage oil) or a control fat (a mixture of corn, safflower, sunflower and extra-virgin light olive oils) on three separate test days for each test meal. Results Total plasma fatty acid concentrations and 366 unique lipid species were measured at 0, 2, 4, 6 and 8 h in response to the test meals. Mean plasma 18:3n6 was 7-fold higher to the GLA challenge compared with baseline and the control meal. By 8 h, mean plasma 20:3n6 was significantly higher in response to the GLA test meal than baseline and the control group. Five of the seven subjects were "responders'' in converting GLA into DGLA, but two subjects did not show this conversion. The conversion was independent of physical activity level. Conclusion Using polyunsaturated fatty acid metabolism as an example, this study demonstrates inter-individual differences in enzymatic capacities to inform exact nutritional and metabolic phenotyping that could be used for precision medicine. C1 [Cajka, Tomas; Newman, John W.; Fiehn, Oliver] Univ Calif Davis, NIH, West Coast Metabol Ctr, Davis, CA 95616 USA. [Davis, Ryan] Lipomics, 3410 Ind Blvd,Suite 103, West Sacramento, CA USA. [Austin, Kathryn J.; German, J. Bruce; Smilowitz, Jennifer T.] Univ Calif Davis, Dept Food Sci & Technol, Davis, CA 95616 USA. [Austin, Kathryn J.; German, J. Bruce; Smilowitz, Jennifer T.] Univ Calif Davis, Foods Hlth Inst, Davis, CA 95616 USA. [Newman, John W.] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. [Newman, John W.] USDA ARS, Obes & Metab Res Unit, Western Human Nutr Res Ctr, Davis, CA 95616 USA. [Fiehn, Oliver] King Abdulaziz Univ, Dept Biochem, Fac Sci, POB 80203, Jeddah 21589, Saudi Arabia. RP Smilowitz, JT (reprint author), Univ Calif Davis, Dept Food Sci & Technol, Davis, CA 95616 USA.; Smilowitz, JT (reprint author), Univ Calif Davis, Foods Hlth Inst, Davis, CA 95616 USA. EM jensm@ucdavis.edu RI Cajka, Tomas/A-8914-2008 OI Cajka, Tomas/0000-0002-9728-3355 FU National Institute of Environmental Health Sciences (NIEHS) [P42ES004699]; NIEHS [R01 ES002710]; NIEHS Superfund Research Program [P42 ES011269]; CHARGE [P01 ES11269]; West Coast Metabolomics Center (NIH) [U24 DK097154]; NIH [1S10RR031630-01, P20 HL113452]; USDA Agricultural Research Service Projects [5306-51000-016-00D, 5306-51000-019-00D, 2032-51530-022-00D] FX This project was made possible in part by support from the National Institute of Environmental Health Sciences (NIEHS) (P42ES004699), NIEHS R01 ES002710, NIEHS Superfund Research Program P42 ES011269; the CHARGE study (P01 ES11269); West Coast Metabolomics Center (NIH U24 DK097154) and instrument support (NIH 1S10RR031630-01), cardiovascular research (NIH P20 HL113452) and USDA Agricultural Research Service Projects 5306-51000-016-00D, 5306-51000-019-00D and 2032-51530-022-00D. We would like to thank Dr. Vincent Ziboh in loving memory for his inspiration and insight for this project. We would like to thank the staff at the USDA, ARS, Western Human Nutrition Research Center, Davis, CA, for clinical, laboratory and kitchen support. The USDA is an equal opportunity provider and employer. We thank the study participants for their time efforts to commit to the study procedures. NR 43 TC 0 Z9 0 U1 7 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1573-3882 EI 1573-3890 J9 METABOLOMICS JI Metabolomics PD AUG PY 2016 VL 12 IS 8 AR UNSP 127 DI 10.1007/s11306-016-1075-9 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DS9DO UT WOS:000381083100001 ER PT J AU Dropulic, LK Lederman, HM AF Dropulic, Lesia K. Lederman, Howard M. TI Overview of Infections in the Immunocompromised Host SO MICROBIOLOGY SPECTRUM LA English DT Article ID ORGAN-TRANSPLANT RECIPIENTS; STEM-CELL TRANSPLANTATION; EPSTEIN-BARR-VIRUS; TUMOR-NECROSIS-FACTOR; SYSTEMIC-LUPUS-ERYTHEMATOSUS; BONE-MARROW-TRANSPLANTATION; CHRONIC LYMPHOCYTIC-LEUKEMIA; RENAL-ALLOGRAFT RECIPIENTS; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; CHRONIC GRANULOMATOUS-DISEASE AB Understanding the components of the immune system that contribute to host defense against infection is key to recognizing infections that are more likely to occur in an immunocompromised patient. In this review, we discuss the integrated system of physical barriers and of innate and adaptive immunity that contributes to host defense. Specific defects in the components of this system that predispose to particular infections are presented. This is followed by a review of primary immunodeficiency diseases and secondary immunodeficiencies, the latter of which develop because of a specific illness or condition or are treatment-related. The effects of treatment for neoplasia, autoimmune diseases, solid organ and stem cell transplants on host defenses are reviewed and associated with susceptibility to particular infections. In conclusion, an approach to laboratory screening for a suspected immunodeficiency is presented. Knowledge of which host defects predispose to specific infections allows clinicians to prevent, diagnose, and manage infections in their immunocompromised patients most effectively. C1 [Dropulic, Lesia K.] NIAID, NIH, Div Intramural Res, Bethesda, MD 20892 USA. [Lederman, Howard M.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. [Lederman, Howard M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Lederman, Howard M.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. RP Dropulic, LK (reprint author), NIAID, NIH, Div Intramural Res, Bethesda, MD 20892 USA. EM dropulicl@niaid.nih.gov NR 336 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA EI 2165-0497 J9 MICROBIOL SPECTR JI Microbiol. Spectr. PD AUG PY 2016 VL 4 IS 4 AR UNSP DMIH2-0026-2016 DI 10.1128/microbiolspec.DMIH2-0026-2016 PG 43 WC Microbiology SC Microbiology GA DT9GI UT WOS:000381804000015 ER PT J AU Schug, TT Johnson, AF Birnbaum, LS Colborn, T Guillette, LJ Crews, DP Collins, T Soto, AM vom Saal, FS McLachlan, JA Sonnenschein, C Heindel, JJ AF Schug, Thaddeus T. Johnson, Anne F. Birnbaum, Linda S. Colborn, Theo Guillette, Louis J., Jr. Crews, David P. Collins, Terry Soto, Ana M. vom Saal, Frederick S. McLachlan, John A. Sonnenschein, Carlos Heindel, Jerrold J. TI Minireview: Endocrine Disruptors: Past Lessons and Future Directions SO MOLECULAR ENDOCRINOLOGY LA English DT Review ID NONMONOTONIC DOSE RESPONSES; TURTLE SEX DETERMINATION; PRENATAL BISPHENOL-A; IN-UTERO EXPOSURE; US POPULATION; POLYCHLORINATED-BIPHENYLS; REPRODUCTIVE HEALTH; JUVENILE ALLIGATORS; ESTROGENIC ACTIVITY; NEONATAL EXPOSURE AB Within the past few decades, the concept of endocrine-disrupting chemicals (EDCs) has risen from a position of total obscurity to become a focus of dialogue, debate, and concern among scientists, physicians, regulators, and the public. The emergence and development of this field of study has not always followed a smooth path, and researchers continue to wrestle with questions about the low-dose effects and nonmonotonic dose responses seen with EDCs, their biological mechanisms of action, the true pervasiveness of these chemicals in our environment and in our bodies, and the extent of their effects on human and wildlife health. This review chronicles the development of the unique, multidisciplinary field of endocrine disruption, highlighting what we have learned about the threat of EDCs and lessons that could be relevant to other fields. It also offers perspectives on the future of the field and opportunities to better protect human health. C1 [Schug, Thaddeus T.; Heindel, Jerrold J.] NIEHS, NIH, Div Extramural Res, Res Triangle Pk, NC 27560 USA. [Johnson, Anne F.] MDB Inc, Durham, NC 27713 USA. [Birnbaum, Linda S.] NCI, NIH, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Colborn, Theo] Endocrine Disrupt Exchange, Paonia, CO 81428 USA. [Guillette, Louis J., Jr.] Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. [Guillette, Louis J., Jr.] Hollings Marine Lab, Charleston, SC 29425 USA. [Crews, David P.] Univ Texas Austin, Sect Integrat Biol, Austin, TX 78712 USA. [Collins, Terry] Carnegie Mellon Univ, Dept Chem, 4400 5th Ave, Pittsburgh, PA 15213 USA. [Soto, Ana M.; Sonnenschein, Carlos] Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Medford, MA 02155 USA. [vom Saal, Frederick S.] Univ Missouri, Div Biol Sci & Dept, Columbia, MO 65211 USA. [McLachlan, John A.] Tulane Univ, Sch Med, Dept Pharmacol, New Orleans, LA 70118 USA. RP Schug, TT (reprint author), Div Extramural Res, 530 Davis Dr,Room 3041 Mail Drop K3-15, Morrisville, NC 27560 USA. EM schugt@niehs.nih.gov FU National Institutes of Health (NIH) Grants [ES023254, ES020662, ES08314]; National Science Foundation (NSF) Grant [IOS-1051623]; Avon Foundation FX This work was supported by National Institutes of Health (NIH) Grants ES023254 and ES020662 and the National Science Foundation (NSF) Grant IOS-1051623 (to D.C.) and by the NIH Grant ES08314, and the Avon Foundation (to A.M.S. and C.S.). NR 118 TC 6 Z9 6 U1 25 U2 41 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD AUG PY 2016 VL 30 IS 8 BP 833 EP 847 DI 10.1210/me.2016-1096 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU0ZB UT WOS:000381932700003 PM 27477640 ER PT J AU Radenkovic, D Kobayashi, H Remsey-Semmelweis, E Seifalian, AM AF Radenkovic, Dina Kobayashi, Hisataka Remsey-Semmelweis, Erno Seifalian, Alexander M. TI Quantum dot nanoparticle for optimization of breast cancer diagnostics and therapy in a clinical setting SO NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE LA English DT Article DE Quantum dots; Nanotechnology; Image-guided surgery; Cancer imaging; Nanoparticles; Breast cancer ID SENTINEL LYMPH-NODE; PRACTICE GUIDELINE UPDATE; VIVO REAL-TIME; IN-VIVO; BLUE-DYE; SILICA NANOPARTICLES; TOXICITY ASSESSMENT; AMERICAN SOCIETY; PHOTOTHERMAL THERAPY; ANTI-HER2 ANTIBODY AB Breast cancer is the most common cancer in the world. Sentinel lymph node (SLN) biopsy is used for staging of axillary lymph nodes. Organic dyes and radiocolloid are currently used for SLN mapping, but expose patients to ionizing radiation, are unstable during surgery and cause local tissue damage. Quantum dots (QD) could be used for SLN mapping without the need for biopsy. Surgical resection of the primary tumor is the optimal treatment for early-diagnosed breast cancer, but due to difficulties in defining tumor margins, cancer cells often remain leading to reoccurrences. Functionalized QD could be used for image-guided tumor resection to allow visualization of cancer cells. Near Infrared QD are photostable and have improved deep tissue penetration. Slow elimination of QD raises concerns of potential accumulation. Nevertheless, promising findings with cadmium-free QD in recent in vivo studies and first in-human trial suggest huge potential for cancer diagnostic and therapy. (C) 2016 Elsevier Inc. All rights reserved. C1 [Radenkovic, Dina; Seifalian, Alexander M.] UCL, UCL Med Sch, London, England. [Kobayashi, Hisataka] NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Remsey-Semmelweis, Erno; Seifalian, Alexander M.] NanoRegMed Ltd, London BioSci Innovat Ctr, London, England. RP Seifalian, AM (reprint author), UCL, London WC1E 6BT, England. EM a.seifalian@gmail.com OI seifalian, Alexander/0000-0002-8334-9376 NR 127 TC 3 Z9 3 U1 25 U2 30 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1549-9634 EI 1549-9642 J9 NANOMED-NANOTECHNOL JI Nanomed.-Nanotechnol. Biol. Med. PD AUG PY 2016 VL 12 IS 6 BP 1581 EP 1592 DI 10.1016/j.nano.2016.02.014 PG 12 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA DT8DF UT WOS:000381718600015 PM 27013132 ER PT J AU Early, R Bradley, BA Dukes, JS Lawler, JJ Olden, JD Blumenthal, DM Gonzalez, P Grosholz, ED Ibanez, I Miller, LP Sorte, CJB Tatem, AJ AF Early, Regan Bradley, Bethany A. Dukes, Jeffrey S. Lawler, Joshua J. Olden, Julian D. Blumenthal, Dana M. Gonzalez, Patrick Grosholz, Edwin D. Ibanez, Ines Miller, Luke P. Sorte, Cascade J. B. Tatem, Andrew J. TI Global threats from invasive alien species in the twenty-first century and national response capacities SO NATURE COMMUNICATIONS LA English DT Article ID PLANT INVASIONS; UNITED-STATES; BIOLOGICAL INVASIONS; CLIMATE-CHANGE; GREAT-BRITAIN; TRADE; BIODIVERSITY; RISK; INTRODUCTIONS; RICHNESS AB Invasive alien species (IAS) threaten human livelihoods and biodiversity globally. Increasing globalization facilitates IAS arrival, and environmental changes, including climate change, facilitate IAS establishment. Here we provide the first global, spatial analysis of the terrestrial threat from IAS in light of twenty-first century globalization and environmental change, and evaluate national capacities to prevent and manage species invasions. We find that one-sixth of the global land surface is highly vulnerable to invasion, including substantial areas in developing economies and biodiversity hotspots. The dominant invasion vectors differ between high-income countries (imports, particularly of plants and pets) and low-income countries (air travel). Uniting data on the causes of introduction and establishment can improve early-warning and eradication schemes. Most countries have limited capacity to act against invasions. In particular, we reveal a clear need for proactive invasion strategies in areas with high poverty levels, high biodiversity and low historical levels of invasion. C1 [Early, Regan] Univ Exeter, Ctr Ecol & Conservat, Penryn Campus, Penryn TR10 9FE, Cornwall, England. [Bradley, Bethany A.] Univ Massachusetts, Dept Environm Conservat, Amherst, MA 01003 USA. [Dukes, Jeffrey S.] Purdue Univ, Dept Forestry & Nat Resources, W Lafayette, IN 47907 USA. [Dukes, Jeffrey S.] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Lawler, Joshua J.] Univ Washington, Sch Environm & Forest Sci, Seattle, WA 98195 USA. [Olden, Julian D.] Univ Washington, Sch Aquat & Fishery Sci, Seattle, WA 98195 USA. [Blumenthal, Dana M.] USDA ARS, Rangeland Resources Res Unit, Ft Collins, CO USA. [Gonzalez, Patrick] Natl Pk Serv, Nat Resource Stewardship & Sci, Berkeley, CA 94720 USA. [Gonzalez, Patrick] Univ Calif Berkeley, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA. [Grosholz, Edwin D.] Univ Calif Davis, Dept Environm Sci & Policy, Davis, CA 95616 USA. [Ibanez, Ines] Univ Michigan, Sch Nat Resources & Environm, Ann Arbor, MI 48109 USA. [Miller, Luke P.] Stanford Univ, Hopkins Marine Stn, Pacific Grove, CA 93950 USA. [Sorte, Cascade J. B.] Univ Calif Irvine, Dept Ecol & Evolutionary Biol, Irvine, CA 92697 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton SO17 1BJ, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Flowminder Fdn, SE-11355 Stockholm, Sweden. RP Early, R (reprint author), Univ Exeter, Ctr Ecol & Conservat, Penryn Campus, Penryn TR10 9FE, Cornwall, England. EM r.early@exeter.ac.uk RI Gonzalez, Patrick/B-9479-2013 OI Gonzalez, Patrick/0000-0002-7105-0561 FU University of California, Santa Barbara; State of California; National Center for Ecological Analysis and Synthesis - National Science Foundation [EF-0553768]; NERC GW4+ DTP PhD 'Unexplained limits on species distributions. What do they mean for conservation?' FX We thank Ricardo Dobrovolski, Andy Nelson, Ben Halpern, Catarina Meireles, Sarah Ayton and Ryan Bird Rafalski for supplying or collating data, and Rashid Al Badwawi, Olga Dmitrieva, Manar Maraqa and Nazmi Sellami for help with translation. The analysis was conducted as part of the Climate Change & Invasive Species Working Group supported by the National Center for Ecological Analysis and Synthesis, a Center funded by the National Science Foundation (grant #EF-0553768), the University of California, Santa Barbara, and the State of California. The work was supported by the NERC GW4+ DTP PhD 'Unexplained limits on species distributions. What do they mean for conservation?' NR 76 TC 1 Z9 1 U1 62 U2 84 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 AUG PY 2016 VL 7 AR 12485 DI 10.1038/ncomms12485 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU1DG UT WOS:000381947800001 PM 27549569 ER PT J AU Martinez-Picado, J McLaren, PJ Erkizia, I Martin, MP Benet, S Rotger, M Dalmau, J Ouchi, D Wolinsky, SM Penugonda, S Gunthard, HF Fellay, J Carrington, M Izquierdo-Useros, N Telenti, A AF Martinez-Picado, Javier McLaren, Paul J. Erkizia, Itziar Martin, Maureen P. Benet, Susana Rotger, Margalida Dalmau, Judith Ouchi, Dan Wolinsky, Steven M. Penugonda, Sudhir Gunthard, Huldrych F. Fellay, Jacques Carrington, Mary Izquierdo-Useros, Nuria Telenti, Amalio TI Identification of Siglec-1 null individuals infected with HIV-1 SO NATURE COMMUNICATIONS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; DENDRITIC CELLS; TRANS-INFECTION; T-CELLS; PROTEIN; RECEPTORS; VARIANTS; CAPTURE; AIDS AB Siglec-1/CD169 is a myeloid-cell surface receptor critical for HIV-1 capture and infection of bystander target cells. To dissect the role of SIGLEC1 in natura, we scan a large population genetic database and identify a loss-of-function variant (Glu88Ter) that is found in B1% of healthy people. Exome analysis and direct genotyping of 4,233 HIV-1-infected individuals reveals two Glu88Ter homozygous and 97 heterozygous subjects, allowing the analysis of ex vivo and in vivo consequences of SIGLEC1 loss-of-function. Cells from these individuals are functionally null or haploinsufficient for Siglec-1 activity in HIV-1 capture and trans-infection ex vivo. However, Siglec-1 protein truncation does not have a measurable impact on HIV-1 acquisition or AIDS outcomes in vivo. This result contrasts with the known in vitro functional role of Siglec-1 in HIV-1 trans-infection. Thus, it provides evidence that the classical HIV-1 infectious routes may compensate for the lack of Siglec-1 in fuelling HIV-1 dissemination within infected individuals. C1 [Martinez-Picado, Javier; Erkizia, Itziar; Benet, Susana; Dalmau, Judith; Ouchi, Dan; Izquierdo-Useros, Nuria] Univ Autonoma Barcelona, AIDS Res Inst IrsiCaixa, Inst Invest Ciencies Salut Germans Trias & Pujol, Badalona 08916, Spain. [Martinez-Picado, Javier] ICREA, Barcelona 08010, Spain. [Martinez-Picado, Javier] Univ Vic, Cent Univ Catalonia UVic UCC, Barcelona 08500, Spain. [McLaren, Paul J.] Publ Hlth Agcy Canada, Natl HIV & Retrovirol Lab, Winnipeg, MB R3E 0W3, Canada. [McLaren, Paul J.] Univ Manitoba, Dept Med Microbiol & Infect Dis, Winnipeg, MB R3E 0J9, Canada. [Martin, Maureen P.; Carrington, Mary] Leidos Biomed Res Inc, Expt Immunol Lab, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Rotger, Margalida] Univ Hosp Ctr, Inst Microbiol, CH-1011 Lausanne, Switzerland. [Rotger, Margalida] Univ Lausanne, CH-1011 Lausanne, Switzerland. [Wolinsky, Steven M.; Penugonda, Sudhir] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [Gunthard, Huldrych F.] Univ Zurich, Div Infect Dis & Hosp Epidemiol, Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Gunthard, Huldrych F.] Univ Zurich, Inst Med Virol, CH-8057 Zurich, Switzerland. [Fellay, Jacques] Ecole Polytech Fed Lausanne, Sch Life Sci, CH-1015 Lausanne, Switzerland. [Fellay, Jacques] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Carrington, Mary] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Telenti, Amalio] J Craig Venter Inst, Genom Med, La Jolla, CA 92037 USA. RP Martinez-Picado, J; Izquierdo-Useros, N (reprint author), Univ Autonoma Barcelona, AIDS Res Inst IrsiCaixa, Inst Invest Ciencies Salut Germans Trias & Pujol, Badalona 08916, Spain.; Martinez-Picado, J (reprint author), ICREA, Barcelona 08010, Spain.; Martinez-Picado, J (reprint author), Univ Vic, Cent Univ Catalonia UVic UCC, Barcelona 08500, Spain.; Telenti, A (reprint author), J Craig Venter Inst, Genom Med, La Jolla, CA 92037 USA. EM jmpicado@irsicaixa.es; nizquierdo@irsicaixa.es; atelenti@jcvi.org RI SHCS, all/G-4072-2011; SHCS, int. coll. A/G-4083-2011; Izquierdo-Useros, Nuria/G-2534-2016; Martinez-Picado, Javier/G-5507-2012; Infektiologie, USZ/A-6921-2011; gunthard, huldrych/F-1724-2011; Fellay, Jacques/A-6681-2009 OI Izquierdo-Useros, Nuria/0000-0002-1039-1821; Martinez-Picado, Javier/0000-0002-4916-2129; gunthard, huldrych/0000-0002-1142-6723; Fellay, Jacques/0000-0002-8240-939X FU Spanish Secretariat of Science and Innovation [SAF2013-49042-R]; Gilead Fellowship Program [GLD1400271]; Mathilde Krim Fellowship [108676]; Spanish AIDS network 'Red Tematica Cooperativa de Investigacion en SIDA'; Swiss National Science Foundation [717, 148522]; SHCS research foundation; National Institute of Allergy and Infectious Diseases (NIAID) [U01-AI35042, U01-AI35039, U01-AI35040, U01-AI35041, UM1-AI35043]; National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research FX We thank the patients for participating in the SHCS and MACS. We thank Nimisha Chaturvedi and Victor Urrea for their excellent statistical assistance. The members of the SHCS are Aubert V., Battegay M., Bernasconi E., Boni J., Braun D.L., Bucher H.C., Burton-Jeangros C., Calmy A., Cavassini M., Dollenmaier G., Egger M., Elzi L., Fehr J., Fellay J., Furrer H. (Chairman of the Clinical and Laboratory Committee), Fux C. A., Gorgievski M., Gunthard H. (President of the SHCS), Haerry D. (deputy of 'Positive Council'), Hasse B., Hirsch H.H., Hoffmann M., Hosli I., Kahlert C., Kaiser L., Keiser O., Klimkait T., Kouyos R., Kovari H., Ledergerber B., Martinetti G., Martinez de Tejada B., Marzolini C., Metzner K., Muller N., Nadal D., Nicca D., Pantaleo G., Rauch A. (Chairman of the Scientific Board), Regenass S., Rudin C. (Chairman of the Mother & Child Sub-study), Schoni-Affolter F. (Head of Data Centre), Schmid P., Speck R., Stockle M., Tarr P., Trkola A., Vernazza P., Weber R., Yerly S. MACS Principal Investigators are: Johns Hopkins University Bloomberg School of Public Health (Joseph Margolick), U01-AI35042; Northwestern University (Steven Wolinsky), U01-AI35039; University of California, Los Angeles (Roger Detels), U01-AI35040; University of Pittsburgh (Charles Rinaldo), U01-AI35041; the Center for Analysis and Management of MACS, Johns Hopkins University Bloomberg School of Public Health (Lisa Jacobson), UM1-AI35043. J.M.-P. and N.I.-U. are supported by the Spanish Secretariat of Science and Innovation through Grant SAF2013-49042-R. N.I.-U. is supported by the Gilead Fellowship Program GLD1400271 and the Mathilde Krim Fellowship in basic biomedical research 108676 founded by 'AmfAR' AIDS research Foundation. JMP is supported by the Spanish AIDS network 'Red Tematica Cooperativa de Investigacion en SIDA'. Work at the laboratory of A.T. was financed by the Swiss National Science Foundation. The genetic analyses were realized within the framework of the Swiss HIV Cohort Study (SHCS Project number 717), which is supported by the Swiss National Science Foundation (Grant Number 148522) and by the SHCS research foundation. Some data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS). The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), U01-AI35042, U01-AI35039, U01-AI35040, U01-AI35041 and UM1-AI35043, with additional co-funding from the National Cancer Institute (NCI). This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. NR 24 TC 0 Z9 0 U1 5 U2 9 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 AUG PY 2016 VL 7 AR 12412 DI 10.1038/ncomms12412 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5MC UT WOS:000381526300001 PM 27510803 ER PT J AU Pankratz, N Schick, UM Zhou, Y Zhou, W Ahluwalia, TS Allende, ML Auer, PL Bork-Jensen, J Brody, JA Chen, MH Clavo, V Eicher, JD Grarup, N Hagedorn, EJ Hu, B Hunker, K Johnson, AD Leusink, M Lu, YC Lyytikainen, LP Manichaikul, A Marioni, RE Nalls, MA Pazoki, R Smith, AV van Rooij, FJA Yang, ML Zhang, XL Zhang, Y Asselbergs, FW Boerwinkle, E Borecki, IB Bottinger, EP Cushman, M de Bakker, PIW Deary, IJ Dong, LG Feitosa, MF Floyd, JS Franceschini, N Franco, OH Garcia, ME Grove, ML Gudnason, V Hansen, T Harris, TB Hofman, A Jackson, RD Jia, J Kahonen, M Launer, LJ Lehtimaki, T Liewald, DC Linneberg, A Liu, YM Loos, RJF Nguyen, VM Numans, ME Pedersen, O Psaty, BM Raitakari, OT Rich, SS Rivadeneira, F Di Sant, AMR Rotter, JI Starr, JM Taylor, KD Thuesen, BH Tracy, RP Uitterlinden, AG Wang, JS Wang, JD Dehghan, A Huo, Y Cupples, LA Wilson, JG Proia, RL Zon, LI O'Donnell, CJ Reiner, AP Ganesh, SK AF Pankratz, Nathan Schick, Ursula M. Zhou, Yi Zhou, Wei Ahluwalia, Tarunveer Singh Allende, Maria Laura Auer, Paul L. Bork-Jensen, Jette Brody, Jennifer A. Chen, Ming-Huei Clavo, Vinna Eicher, John D. Grarup, Niels Hagedorn, Elliott J. Hu, Bella Hunker, Kristina Johnson, Andrew D. Leusink, Maarten Lu, Yingchang Lyytikainen, Leo-Pekka Manichaikul, Ani Marioni, Riccardo E. Nalls, Mike A. Pazoki, Raha Smith, Albert Vernon van Rooij, Frank J. A. Yang, Min-Lee Zhang, Xiaoling Zhang, Yan Asselbergs, Folkert W. Boerwinkle, Eric Borecki, Ingrid B. Bottinger, Erwin P. Cushman, Mary de Bakker, Paul I. W. Deary, Ian J. Dong, Liguang Feitosa, Mary F. Floyd, James S. Franceschini, Nora Franco, Oscar H. Garcia, Melissa E. Grove, Megan L. Gudnason, Vilmundur Hansen, Torben Harris, Tamara B. Hofman, Albert Jackson, Rebecca D. Jia, Jia Kahonen, Mika Launer, Lenore J. Lehtimaki, Terho Liewald, David C. Linneberg, Allan Liu, Yongmei Loos, Ruth J. F. Nguyen, Vy M. Numans, Mattijs E. Pedersen, Oluf Psaty, Bruce M. Raitakari, Olli T. Rich, Stephen S. Rivadeneira, Fernando Di Sant, Amanda M. Rosa Rotter, Jerome I. Starr, John M. Taylor, Kent D. Thuesen, Betina Heinsbaek Tracy, Russell P. Uitterlinden, Andre G. Wang, Jiansong Wang, Judy Dehghan, Abbas Huo, Yong Cupples, L. Adrienne Wilson, James G. Proia, Richard L. Zon, Leonard I. O'Donnell, Christopher J. Reiner, Alex P. Ganesh, Santhi K. CA CHARGE Consortium Hematology TI Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; SUSCEPTIBILITY LOCI; LYMPHOCYTE EGRESS; CROHNS-DISEASE; FUNCTIONAL PREDICTIONS; CHARGE CONSORTIUM; KIDNEY-FUNCTION; LARGE-SCALE; DIFFERENTIATION AB Hematologic measures such as hematocrit and white blood cell ( WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals ( 37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait-locus associations ( CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count ( S1PR4), monocyte count ( BTBD8, NLRP12, and IL17RA), eosinophil count ( IRF1), and total WBC count ( MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury. C1 [Pankratz, Nathan] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Schick, Ursula M.; Lu, Yingchang; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA. [Schick, Ursula M.; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Zhou, Yi; Hagedorn, Elliott J.; Hu, Bella; Nguyen, Vy M.; Di Sant, Amanda M. Rosa; Zon, Leonard I.] Harvard Univ, Stem Cell & Regenerat Biol Dept, Cambridge, MA 02138 USA. [Zhou, Wei] Univ Michigan, Dept Computat Med & Biostat, Ann Arbor, MI 48109 USA. [Ahluwalia, Tarunveer Singh; Bork-Jensen, Jette; Grarup, Niels; Hansen, Torben; Pedersen, Oluf] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [Ahluwalia, Tarunveer Singh] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Allende, Maria Laura; Proia, Richard L.] NIDDKD, Genet Dev & Dis Branch, US Natl Inst Hlth, Bethesda, MD USA. [Auer, Paul L.] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Brody, Jennifer A.; Floyd, James S.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Ming-Huei; Eicher, John D.; Johnson, Andrew D.; Zhang, Xiaoling; Cupples, L. Adrienne; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Clavo, Vinna; Hunker, Kristina; Yang, Min-Lee; Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Clavo, Vinna; Hunker, Kristina; Yang, Min-Lee; Ganesh, Santhi K.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Eicher, John D.; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Intramural Res Program, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA. [Leusink, Maarten] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands. [Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Tampere, Finland. [Manichaikul, Ani; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Marioni, Riccardo E.; Deary, Ian J.; Liewald, David C.; Starr, John M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo E.] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo E.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Nalls, Mike A.] NIA, Neurogenet Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Pazoki, Raha; van Rooij, Frank J. A.; Franco, Oscar H.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; Dehghan, Abbas] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Fac Med, Kopavogur, Iceland. [Zhang, Xiaoling] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Zhang, Yan; Jia, Jia; Huo, Yong] Peking Univ, Hosp 1, Dept Cardiol, Beijing 100871, Peoples R China. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands. [Asselbergs, Folkert W.] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands. [Asselbergs, Folkert W.] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England. [Boerwinkle, Eric; Grove, Megan L.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Borecki, Ingrid B.; Feitosa, Mary F.; Wang, Judy] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Cushman, Mary] Univ Vermont, Dept Med, Div Hematol Oncol, Burlington, VT USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, Utrecht, Netherlands. [de Bakker, Paul I. W.; Numans, Mattijs E.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Dong, Liguang] Peking Univ, Shougang Hosp, Jin Ding St Community Hlth Ctr, Beijing, Peoples R China. [Franceschini, Nora] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Garcia, Melissa E.; Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Tampere, Finland. [Linneberg, Allan; Thuesen, Betina Heinsbaek] Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark. [Linneberg, Allan] Rigshosp, Dept Clin Expt Res, Glostrup, Denmark. [Linneberg, Allan] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Numans, Mattijs E.] Leiden Univ, Med Ctr, Publ Hlth & Primary Care, Leiden, Netherlands. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Rotter, Jerome I.; Taylor, Kent D.] Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA USA. [Rotter, Jerome I.; Taylor, Kent D.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Starr, John M.] Univ Edinburgh, Geriatr Med Unit, Edinburgh, Midlothian, Scotland. Univ Vermont, Coll Med, Dept Pathol & Lab Med, Colchester, VT USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Biochem, Colchester, VT USA. [Wang, Jiansong] Peking Univ, Shougang Hosp, Chron Dis Res Ctr, Beijing, Peoples R China. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [O'Donnell, Christopher J.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Intramural Res Program, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Boston Vet Adm Healthcare, Dept Med, Cardiol Sect, Boston, MA USA. [Reiner, Alex P.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Pankratz, N (reprint author), Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA.; Ganesh, SK (reprint author), Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA.; Ganesh, SK (reprint author), Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. EM nathan.pankratz.rps@gmail.com; sganesh@umich.edu RI Floyd, James/G-7563-2015; Johnson, Andrew/G-6520-2013; Grarup, Niels/K-2807-2015; Feitosa, Mary/K-8044-2012; OI Grarup, Niels/0000-0001-5526-1070; Feitosa, Mary/0000-0002-0933-2410; Pazoki, Raha/0000-0002-5142-2348; Manichaikul, Ani/0000-0002-5998-795X; Ahluwalia, Tarunveer Singh/0000-0002-7464-3354; Dehghan, Abbas/0000-0001-6403-016X; Linneberg, Allan/0000-0002-0994-0184 FU NIDDK Division of Intramural Research; US National Institutes of Health [N01AG12100, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268201200036C, HHSN268200800007C]; Clinical and Translational Science Institute [UL1TR000124]; Danish Heart Foundation [07-10-R61-A1754-B838-22392F]; Biobanking and BioMolecular resources Research Infrastructure-The Netherlands (BBMRI-NL) grant [NWO 184.021.007]; Health Insurance Foundation [2012B233]; Academy of Finland [134309, 126925, 121584, 124282, 129378, 117787, 41071]; US NIH [N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC25195, N02HL64278, N01AG62101, N01AG62103, N01AG62106]; NIH, US [HHSN268200782096C, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C, N01HC95159, N01HC95160, N01HC95161, N01HC95162, N01HC95163, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169, RR024156]; US, NIH [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C, RC2HL102924, CA137088, 5RC2HL102419, HL080295, HL087652, HL103612, HL105756, HL120393]; NIH US [AG023629, DK063491, R01DK089256, R01HL087700, R01HL088215, R01HL117078, 1R01AG032098-01A1, U01-HG005152, R25CA094880, R01HL122684, R01HL04880, R01HL32262, R01DK49216, R01HL10001, R01DK092760, R01OD017870] FX This work was supported by the following grants and contracts: US National Institutes of Health contracts (N01AG12100, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC25195, N02HL64278, N01AG62101, N01AG62103, N01AG62106, HHSN268200782096C, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C, N01HC95159, N01HC95160, N01HC95161, N01HC95162, N01HC95163, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169, RR024156, N02HL64278, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C, RC2HL102924, and CA137088); US National Institutes of Health grants (5RC2HL102419, HL080295, HL087652, HL103612, HL105756, HL120393, AG023629, DK063491, R01DK089256, R01HL087700, R01HL088215, R01HL117078, 1R01AG032098-01A1, U01-HG005152, R25CA094880, R01HL122684, R01HL04880, R01HL32262, R01DK49216, R01HL10001, R01DK092760, and R01OD017870); a Clinical and Translational Science Institute grant (UL1TR000124); a Danish Heart Foundation grant (07-10-R61-A1754-B838-22392F); a Biobanking and BioMolecular resources Research Infrastructure-The Netherlands (BBMRI-NL) grant (NWO 184.021.007); a Health Insurance Foundation grant (2012B233); and Academy of Finland grants (134309, 126925, 121584, 124282, 129378, 117787, and 41071).; This work was supported in part by the NIDDK Division of Intramural Research. NR 85 TC 2 Z9 2 U1 5 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD AUG PY 2016 VL 48 IS 8 BP 867 EP + DI 10.1038/ng.3607 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DS4ML UT WOS:000380755100010 ER PT J AU Shin, HY Willi, M Yoo, KH Zeng, XK Wang, CC Metser, G Hennighausen, L AF Shin, Ha Youn Willi, Michaela Yoo, Kyung Hyun Zeng, Xianke Wang, Chaochen Metser, Gil Hennighausen, Lothar TI Hierarchy within the mammary STAT5-driven Wap super-enhancer SO NATURE GENETICS LA English DT Article ID WHEY ACIDIC PROTEIN; DISTAL REGULATORY ELEMENTS; TRANSGENIC MICE; TRANSCRIPTION FACTOR; GENE-EXPRESSION; SIGNAL TRANSDUCER; GLAND DEVELOPMENT; CELL IDENTITY; T-CELLS; STAT5 AB Super-enhancers comprise dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate the role of super-enhancers in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-seq analysis for the master regulator STAT5A, the glucocorticoid receptor, H3K27ac and MED1 identified 440 mammary-specific super-enhancers, half of which were associated with genes activated during pregnancy. We interrogated the Wap super-enhancer, generating mice carrying mutations in STAT5-binding sites within its constituent enhancers. Individually, the most distal site displayed the greatest enhancer activity. However, combinatorial mutation analysis showed that the 1,000-fold induction in gene expression during pregnancy relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer. Altogether, these data suggest a temporal and functional enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insights into the regulation of cell-type-specific expression of hormone-sensing genes. C1 [Shin, Ha Youn; Willi, Michaela; Yoo, Kyung Hyun; Zeng, Xianke; Wang, Chaochen; Metser, Gil; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Willi, Michaela] Med Univ Innsbruck, Div Bioinformat, Bioctr, Innsbruck, Austria. RP Hennighausen, L (reprint author), NIDDK, Lab Genet & Physiol, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM lotharh@mail.nih.gov OI Willi, Michaela/0000-0002-2248-1998 FU IPR of the NIDDK/NIH FX We thank H. Smith from the NIDDK genomics core for never-ending help with next-generation sequencing and C. Liu from the NHLBI transgenic core for generating the CRISPR/Cas9-based mouse mutants. M.W. is a graduate student of the Individual Graduate Partnership Program (GPP) between NIH/NIDDK and the Medical University of Innsbruck. This work was performed in partial fulfillment of the graduation requirements for M.W. We thank K. Kang and S. Oh for discussions in the early stage of this project and Z. Trajanoski for advising M.W. during her graduate studies. This research was funded by the IPR of the NIDDK/NIH. NR 78 TC 13 Z9 13 U1 5 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD AUG PY 2016 VL 48 IS 8 BP 904 EP + DI 10.1038/ng.3606 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DS4ML UT WOS:000380755100014 PM 27376239 ER PT J AU Pearson, RD Amato, R Auburn, S Miotto, O Almagro-Garcia, J Amaratunga, C Suon, S Mao, S Noviyanti, R Trimarsanto, H Marfurt, J Anstey, NM William, T Boni, MF Dolecek, C Tran, HT White, NJ Michon, P Siba, P Tavul, L Harrison, G Barry, A Mueller, I Ferreira, MU Karunaweera, N Randrianarivelojosia, M Gao, Q Hubbart, C Hart, L Jeffery, B Drury, E Mead, D Kekre, M Campino, S Manske, M Cornelius, VJ MacInnis, B Rockett, KA Miles, A Rayner, JC Fairhurst, RM Nosten, F Price, RN Kwiatkowski, DP AF Pearson, Richard D. Amato, Roberto Auburn, Sarah Miotto, Olivo Almagro-Garcia, Jacob Amaratunga, Chanaki Suon, Seila Mao, Sivanna Noviyanti, Rintis Trimarsanto, Hidayat Marfurt, Jutta Anstey, Nicholas M. William, Timothy Boni, Maciej F. Dolecek, Christiane Hien Tinh Tran White, Nicholas J. Michon, Pascal Siba, Peter Tavul, Livingstone Harrison, Gabrielle Barry, Alyssa Mueller, Ivo Ferreira, Marcelo U. Karunaweera, Nadira Randrianarivelojosia, Milijaona Gao, Qi Hubbart, Christina Hart, Lee Jeffery, Ben Drury, Eleanor Mead, Daniel Kekre, Mihir Campino, Susana Manske, Magnus Cornelius, Victoria J. MacInnis, Bronwyn Rockett, Kirk A. Miles, Alistair Rayner, Julian C. Fairhurst, Rick M. Nosten, Francois Price, Ric N. Kwiatkowski, Dominic P. TI Genomic analysis of local variation and recent evolution in Plasmodium vivax SO NATURE GENETICS LA English DT Article ID DRUG-RESISTANCE GENES; DNA-SEQUENCING DATA; DUFFY-BLOOD-GROUP; MALARIA; FALCIPARUM; DIVERSITY; CHLOROQUINE; INFECTIONS; REVEALS; POLYMORPHISMS AB The widespread distribution and relapsing nature of Plasmodium vivax infection present major challenges for the elimination of malaria. To characterize the genetic diversity of this parasite in individual infections and across the population, we performed deep genome sequencing of > 200 clinical samples collected across the Asia-Pacific region and analyzed data on > 300,000 SNPs and nine regions of the genome with large copy number variations. Individual infections showed complex patterns of genetic structure, with variation not only in the number of dominant clones but also in their level of relatedness and inbreeding. At the population level, we observed strong signals of recent evolutionary selection both in known drug resistance genes and at new loci, and these varied markedly between geographical locations. These findings demonstrate a dynamic landscape of local evolutionary adaptation in the parasite population and provide a foundation for genomic surveillance to guide effective strategies for control and elimination of P. vivax. C1 [Pearson, Richard D.; Amato, Roberto; Miotto, Olivo; Drury, Eleanor; Mead, Daniel; Kekre, Mihir; Campino, Susana; Manske, Magnus; Cornelius, Victoria J.; MacInnis, Bronwyn; Rockett, Kirk A.; Miles, Alistair; Rayner, Julian C.; Kwiatkowski, Dominic P.] Wellcome Trust Sanger Inst, Cambridge, England. [Pearson, Richard D.; Amato, Roberto; Miotto, Olivo; Almagro-Garcia, Jacob; Hubbart, Christina; Hart, Lee; Jeffery, Ben; Cornelius, Victoria J.; Rockett, Kirk A.; Miles, Alistair; Kwiatkowski, Dominic P.] Wellcome Trust Ctr Human Genet, MRC Ctr Genom & Global Hlth, Oxford, England. [Auburn, Sarah; Marfurt, Jutta; Anstey, Nicholas M.; Price, Ric N.] Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia. [Auburn, Sarah; Marfurt, Jutta; Price, Ric N.] Charles Darwin Univ, Darwin, NT, Australia. [Miotto, Olivo; White, Nicholas J.] Mahidol Univ, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand. [Amaratunga, Chanaki] NIAID, NIH, Rockville, MD USA. [Suon, Seila] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. [Mao, Sivanna] Sampov Meas Referral Hosp, Pursat, Cambodia. [Noviyanti, Rintis; Trimarsanto, Hidayat] Eijkman Inst Mol Biol, Jakarta, Indonesia. [William, Timothy] Sabah Menzies Sch Hlth Res, Clin Res Unit, Infect Dis Soc, Kota Kinabalu, Sabah, Malaysia. [William, Timothy] Queen Elizabeth Hosp, Clin Res Ctr, Kota Kinabalu, Sabah, Malaysia. [Boni, Maciej F.; Dolecek, Christiane; Hien Tinh Tran] Univ Oxford, Clin Res Unit, Ho Chi Minh City, Vietnam. [Michon, Pascal; Siba, Peter; Tavul, Livingstone] Papua New Guinea Inst Med Res, Madang, Papua N Guinea. [Michon, Pascal] Divine Word Univ, Fac Med & Hlth Sci, Madang, Papua N Guinea. [Harrison, Gabrielle; Barry, Alyssa; Mueller, Ivo] Walter & Eliza Hall Inst Med Res, Div Populat Hlth & Immun, Parkville, Vic, Australia. [Harrison, Gabrielle; Barry, Alyssa; Mueller, Ivo] Univ Melbourne, Dept Med Biol, Parkville, Vic, Australia. [Ferreira, Marcelo U.] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo, Brazil. [Karunaweera, Nadira] Univ Colombo, Fac Med, Dept Parasitol, Colombo, Sri Lanka. [Randrianarivelojosia, Milijaona] Inst Pasteur Madagascar, Antananarivo, Madagascar. [Gao, Qi] Minist Hlth, Jiangsu Inst Parasit Dis, Key Lab Parasit Dis Control & Prevent, Prov Key Lab Parasite Mol Biol, Wuxi, Jiangsu, Peoples R China. [Nosten, Francois] Mahidol Univ, Mahidol Oxford Trop Med Res Unit, Shoklo Malaria Res Unit, Fac Trop Med, Mae Sot, Thailand. [Nosten, Francois; Price, Ric N.] Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England. RP Kwiatkowski, DP (reprint author), Wellcome Trust Sanger Inst, Cambridge, England.; Kwiatkowski, DP (reprint author), Wellcome Trust Ctr Human Genet, MRC Ctr Genom & Global Hlth, Oxford, England. EM dominic@sanger.ac.uk RI Ferreira, Marcelo/G-8289-2011; OI Ferreira, Marcelo/0000-0002-5293-9090; Auburn, Sarah/0000-0002-4638-536X; Rayner, Julian/0000-0002-9835-1014; Trimarsanto, Hidayat/0000-0003-2436-8283; Kwiatkowski, Dominic/0000-0002-5023-0176; Mead, Daniel/0000-0001-7717-4330; Manske, Magnus/0000-0001-5916-0947; Price, Richard/0000-0003-2000-2874 FU Wellcome Trust [098051, 090770/Z/09/Z, 091625]; Medical Research Council [G0600718]; UK Department for International Development [M006212]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank the patients and communities that provided samples for this study, and our many colleagues who supported this work in the field. Sequencing, data analysis and project coordination were funded by the Wellcome Trust (098051, 090770/Z/09/Z), the Medical Research Council (G0600718) and the UK Department for International Development (M006212). A.B. and I.M. acknowledge the Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Medical Research Institutes Infrastructure Support Scheme (NHMRC IRIISS). S.A. and R.N.P. are funded by the Wellcome Trust (Senior Fellowship in Clinical Science awarded to R.N.P., 091625). This study was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 53 TC 12 Z9 12 U1 4 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD AUG PY 2016 VL 48 IS 8 BP 959 EP 964 DI 10.1038/ng.3599 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA DS4ML UT WOS:000380755100022 PM 27348299 ER PT J AU Maguire, MG Martin, DF Ying, GS Jaffe, GJ Daniel, E Grunwald, JE Toth, CA Ferris, FL Fine, SL AF Maguire, Maureen G. Martin, Daniel F. Ying, Gui-shuang Jaffe, Glenn J. Daniel, Ebenezer Grunwald, Juan E. Toth, Cynthia A. Ferris, Frederick L., III Fine, Stuart L. CA Comparison Age-related Macular TI Five-Year Outcomes with Anti-Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration The Comparison of Age-Related Macular Degeneration Treatments Trials SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol ID OPTICAL COHERENCE TOMOGRAPHY; SUBFOVEAL CHOROIDAL NEOVASCULARIZATION; LONG-TERM OUTCOMES; PHOTODYNAMIC THERAPY; INTRAVITREAL RANIBIZUMAB; RANDOMIZED-TRIAL; CLINICAL-TRIALS; VISUAL-ACUITY; BEVACIZUMAB; VERTEPORFIN AB Purpose: To describe outcomes 5 years after initiating treatment with bevacizumab or ranibizumab for neovascular age-related macular degeneration (AMD). Design: Cohort study. Participants: Patients enrolled in the Comparison of AMD Treatments Trials. Methods: Patients were assigned randomly to ranibizumab or bevacizumab and to 1 of 3 dosing regimens. After 2 years, patients were released from the clinical trial protocol. At 5 years, patients were recalled for examination. Main Outcome Measures: Visual acuity (VA) and morphologic retinal features. Results: Visual acuity was obtained for 647 of 914 (71%) living patients with average follow-up of 5.5 years. The mean number of examinations for AMD care after the clinical trial ended was 25.3, and the mean number of treatments was 15.4. Most patients (60%) were treated 1 time or more with a drug other than their assigned drug. At the 5-year visit, 50% of eyes had VA of 20/40 or better and 20% had VA of 20/200 or worse. Mean change in VA was -3 letters from baseline and -11 letters from 2 years. Among 467 eyes with fluorescein angiography, mean total lesion area was 12.9 mm(2), a mean of 4.8 mm(2) larger than at 2 years. Geographic atrophy was present in 213 of 515 (41%) gradable eyes and was subfoveal in 85 eyes (17%). Among 555 eyes with spectral-domain optical coherence tomography, 83% had fluid (61% intraretinal, 38% subretinal, and 36% suberetinal pigment epithelium). Mean foveal total thickness was 278 mm, a decrease of 182 mm from baseline and 20 mm from 2 years. The retina was abnormally thin (<120 mm) in 36% of eyes. Between 2 and 5 years, the group originally assigned to ranibizumab for 2 years lost more VA than the bevacizumab group (-4 letters; P = 0.008). Otherwise, there were no statistically significant differences in VA or morphologic outcomes between drug or regimen groups. Conclusions: Vision gains during the first 2 years were not maintained at 5 years. However, 50% of eyes had VA of 20/40 or better, confirming antievascular endothelial growth factor therapy as a major long-term therapeutic advance for neovascular AMD. (C) 2016 by the American Academy of Ophthalmology. C1 [Maguire, Maureen G.; Ying, Gui-shuang; Daniel, Ebenezer; Grunwald, Juan E.] Univ Penn, Dept Ophthalmol, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. [Martin, Daniel F.] Cleveland Clin Fdn, Cole Eye Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Jaffe, Glenn J.; Toth, Cynthia A.] Duke Univ, Dept Ophthalmol, Durham, NC USA. [Ferris, Frederick L., III] NEI, NIH, Bethesda, MD 20892 USA. [Fine, Stuart L.] Univ Colorado, Dept Ophthalmol, Denver, CO 80202 USA. RP Maguire, MG (reprint author), Univ Penn, Dept Ophthalmol, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM maguirem@mail.med.upenn.edu NR 40 TC 6 Z9 6 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2016 VL 123 IS 8 BP 1751 EP 1761 DI 10.1016/j.ophtha.2016.03.045 PG 11 WC Ophthalmology SC Ophthalmology GA DS4MC UT WOS:000380754200032 ER PT J AU Willis, JR Vitale, S Morse, L Parke, DW Rich, WL Lum, F Cantrell, RA AF Willis, Jeffrey R. Vitale, Susan Morse, Lawrence Parke, David W., II Rich, William L. Lum, Flora Cantrell, Ronald A. TI The Prevalence of Myopic Choroidal Neovascularization in the United States Analysis of the IRIS (R) Data Registry and NHANES SO OPHTHALMOLOGY LA English DT Article ID PATHOLOGICAL MYOPIA; REFRACTIVE ERROR; RISK-FACTORS; EPIDEMIOLOGY; RETINOPATHY; PROGRESSION; POPULATION; EYE AB Purpose: To determine the prevalence of high myopia (HM), progressive high (degenerative) myopia (PHM), and myopic choroidal neovascularization (mCNV) in the United States. Design: Cross-sectional study. Participants: Individuals aged 18 years and older participating in the National Health and Nutrition Examination Survey (NHANES) and patients aged 18 years and older seen in clinics participating in the American Academy of Ophthalmology's Intelligent Research in Sight (IRIS (R)) Registry. Methods: We analyzed NHANES data from 2005 to 2008 to determine the prevalence of HM in the United States. This prevalence was then applied to estimates from the US Population Census (2014) to arrive at a population burden of HM at the diopter level in the United States. Data from the IRIS Registry were used to calculate the real-world prevalence rates of PHM and mCNV among patients with HM at the diopter level. This was subsequently applied to this reference population with HM to calculate the diopter-adjusted prevalence and population burden of PHM and mCNV in the United States in 2014. Main Outcome Measures: High myopia was defined as myopic refractive error of <= 6.0 diopters in the right eye. Progressive HM was defined as HM with the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) code of "360.21: Progressive High (Degenerative) Myopia." Myopic CNV was defined as HM with the presence of subretinal/choroidal neovascularization indicated by the ICD-9-CM diagnosis of "362.16: Retinal Neovascularization NOS." Results: The estimated diopter-adjusted prevalence of HM, PHM, and mCNV was 3.92% (95% confidence interval [CI], 2.82-5.60), 0.33% (95% CI, 0.21-0.55), and 0.017% (95% CI, 0.010-0.030), respectively, among adults in the United States aged 18 years and older in 2014. This translated into a population burden of approximately 9 614 719 adults with HM, 817 829 adults with PHM, and 41 111 adults with mCNV in the United States in 2014. Conclusions: Although HM and PHM impose a relatively large burden among adults in the United States, mCNV seems to be a rare disease. Relating data from the IRIS Registry and NHANES could be a novel method for assessing ophthalmic disease prevalence in the United States. Future studies should aim to better assess current treatment patterns and optimal management strategies of this condition. (C) 2016 by the American Academy of Ophthalmology. C1 [Willis, Jeffrey R.; Morse, Lawrence] Univ Calif Davis, Med Ctr, Dept Ophthalmol, Sacramento, CA 95817 USA. [Willis, Jeffrey R.; Cantrell, Ronald A.] Genentech Inc, San Francisco, CA 94080 USA. [Vitale, Susan] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Parke, David W., II; Rich, William L.; Lum, Flora] Amer Acad Ophthalmol, San Francisco, CA 94109 USA. RP Lum, F (reprint author), Amer Acad Ophthalmol, Div Qual & Data Sci, 655 Beach St, San Francisco, CA 94109 USA. EM flum@aao.org NR 26 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2016 VL 123 IS 8 BP 1771 EP 1782 DI 10.1016/j.ophtha.2016.04.021 PG 12 WC Ophthalmology SC Ophthalmology GA DS4MC UT WOS:000380754200035 PM 27342789 ER PT J AU Datiles, MB Ferris, F Ansari, RR Zigler, JS AF Datiles, Manuel B., III Ferris, Frederick, III Ansari, Rafat R. Zigler, J. Samuel, Jr. TI Re: Datiles et al.: Longitudinal study of age-related cataract using dynamic light scattering: loss of alpha-crystallin leads to nuclear cataract development (Ophthalmology 2016;123:248-54) REPLY SO OPHTHALMOLOGY LA English DT Letter C1 [Datiles, Manuel B., III; Ferris, Frederick, III] NEI, Off Clin Director, NIH, 10 Ctr Dr,Bldg 10,Room 1, Bethesda, MD 20892 USA. [Ansari, Rafat R.] NASA, Glenn Res Ctr, Cleveland, OH USA. [Zigler, J. Samuel, Jr.] Johns Hopkins Univ Hosp, Wilmer Eye Inst, Baltimore, MD 21287 USA. RP Datiles, MB (reprint author), NEI, Off Clin Director, NIH, 10 Ctr Dr,Bldg 10,Room 1, Bethesda, MD 20892 USA. EM Datilesm@nei.nih.gov NR 1 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2016 VL 123 IS 8 BP E48 EP E48 PG 1 WC Ophthalmology SC Ophthalmology GA DS4MC UT WOS:000380754200005 PM 27450826 ER PT J AU Aggarwal, SK Ghosh, A Cheng, MJ Luton, K Lowet, PF Berger, A AF Aggarwal, Sunil K. Ghosh, Amrita Cheng, M. Jennifer Luton, Kathleen Lowet, Peter F. Berger, Ann TI Initiating pain and palliative care outpatient services for the suburban underserved in Montgomery County, Maryland: Lessons learned at the NIH Clinical Center and MobileMed SO PALLIATIVE & SUPPORTIVE CARE LA English DT Article DE Palliative care; Pain management; Underserved; Maryland; Suburbanization of poverty AB Objective: With the ongoing expansion of palliative care services throughout the United States, meeting the needs of socioeconomically marginalized populations, as in all domains of healthcare, continues to be a challenge. Our specific aim here was to help meet some of these needs through expanding delivery of pain and palliative care services by establishing a new clinic for underserved patients and collecting descriptive data about its operation. Method: In November of 2014, the National Institutes of Health Clinical Center's Pain and Palliative Care Service (PPCS) launched a bimonthly offsite pain and palliative care outpatient clinic in collaboration with Mobile Medical Care Inc. (MobileMed), a private not-for-profit primary care provider in Montgomery County, Maryland, serving underserved area residents since 1968. Staffed by NIH hospice and palliative medicine clinical fellows and faculty, the clinic provides specialty pain and palliative care consultation services to patients referred by their primary care healthcare providers. A patient log was maintained, charts reviewed, and referring providers surveyed on their satisfaction with the service. Results: The clinic had 27 patient encounters with 10 patients (6 males, 4 females, aged 23-67) during its first 7 months of operation. The reason for referral for all but one patient was chronic pain of multiple etiologies. Patients had numerous psychosocial stressors and comorbidities. All primary care providers who returned surveys (n = 4) rated their level of satisfaction with the consultation service as very satisfied or extremely satisfied. Significance of Results: This brief descriptive report outlines the steps taken and logistical issues addressed to launch and continue the clinic, the characteristics of patients treated, and the results of quality-improvement projects. Lessons learned are highlighted and future directions suggested for the clinic and others that may come along like it. C1 [Aggarwal, Sunil K.; Ghosh, Amrita; Cheng, M. Jennifer; Berger, Ann] NIH, Ctr Clin, Pain & Palliat Care Serv, 10 Ctr Dr,2-1733 MSC 1517, Bethesda, MD 20892 USA. [Luton, Kathleen; Lowet, Peter F.] Mobile Med Care Inc, Bethesda, MD USA. RP Aggarwal, SK (reprint author), NIH, Ctr Clin, Pain & Palliat Care Serv, 10 Ctr Dr,2-1733 MSC 1517, Bethesda, MD 20892 USA. EM sunila@uw.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1478-9515 EI 1478-9523 J9 PALLIAT SUPPORT CARE JI Palliat. Support Care PD AUG PY 2016 VL 14 IS 4 BP 381 EP 386 DI 10.1017/S1478951515001030 PG 6 WC Health Policy & Services SC Health Care Sciences & Services GA DT2DH UT WOS:000381290500010 PM 26373835 ER PT J AU Adachi, K Klausner, JD Xu, JH Ank, B Bristow, CC Morgado, MG Watts, DH Weir, F Persing, D Mofenson, LM Veloso, VG Pilotto, JH Joao, E Gray, G Theron, G Santos, B Fonseca, R Kreitchmann, R Pinto, J Mussi-Pinhata, MM Ceriotto, M Machado, DM Bryson, YJ Grinsztejn, B Bastos, FI Siberry, G Nielsen-Saines, K AF Adachi, Kristina Klausner, Jeffrey D. Xu, Jiahong Ank, Bonnie Bristow, Claire C. Morgado, Mariza G. Watts, D. Heather Weir, Fred Persing, David Mofenson, Lynne M. Veloso, Valdilea G. Pilotto, Jose Henrique Joao, Esau Gray, Glenda Theron, Gerhard Santos, Breno Fonseca, Rosana Kreitchmann, Regis Pinto, Jorge Mussi-Pinhata, Marisa M. Ceriotto, Mariana Machado, Daisy Maria Bryson, Yvonne J. Grinsztejn, Beatriz Bastos, Francisco I. Siberry, George Nielsen-Saines, Karin CA NICHD HPTN 040 Study Team TI Chlamydia trachomatis and Neisseria gonorrhoeae in HIV-infected Pregnant Women and Adverse Infant Outcomes SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE HIV; pregnancy; chlamydia; gonorrhea; sexually transmitted infections; adverse infant outcomes ID ACTIVE ANTIRETROVIRAL THERAPY; PRETERM BIRTH; PERINATAL-MORTALITY; ASSOCIATION; CHILDREN; SYPHILIS; TRANSMISSION; METAANALYSIS; MORBIDITY; DISEASE AB Background: Sexually transmitted infections (STIs) in pregnancy such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) may lead to adverse infant outcomes. Methods: Individual urine specimens from HIV-infected pregnant women diagnosed with HIV during labor were collected at the time of infant birth and tested by polymerase chain reaction for CT and NG. Infant HIV infection was determined at 3 months with morbidity/mortality assessed through 6 months. Results: Of 1373 maternal urine samples, 277 (20.2%) were positive for CT and/or NG; 249 (18.1%) for CT, 63 (4.6%) for NG and 35 (2.5%) for both CT and NG. HIV infection was diagnosed in 117 (8.5%) infants. Highest rates of adverse outcomes (sepsis, pneumonia, congenital syphilis, septic arthritis, conjunctivitis, low birth weight, preterm delivery and death) were noted in infants of women with CT and NG (23/35, 65.7%) compared with NG (16/28, 57.1%), CT (84/214, 39.3%) and no STI (405/1096, 37%, P = 0.001). Death (11.4% vs. 3%, P = 0.02), low birth weight (42.9% vs. 16.9%, P = 0.001) and preterm delivery (28.6% vs. 10.2%, P = 0.008) were higher among infants of CT and NG-coinfected women. Infants who had any adverse outcome and were born to women with CT and/or NG were 3.5 times more likely to be HIV infected after controlling for maternal syphilis (odds ratio: 3.5, 95% confidence interval: 1.4-8.3). By adjusted multivariate logistic regression, infants born to mothers with any CT and/or NG were 1.35 times more likely to have an adverse outcome (odds ratio, 1.35; 95% confidence interval, 1.03-1.76). Conclusions: STIs in HIV-infected pregnant women are associated with adverse outcomes in HIV-exposed infected and uninfected infants. C1 [Adachi, Kristina; Klausner, Jeffrey D.; Ank, Bonnie; Bryson, Yvonne J.; Nielsen-Saines, Karin] David Geffen UCLA Sch Med, Los Angeles, CA USA. [Klausner, Jeffrey D.; Bristow, Claire C.] UCLA Fielding Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA USA. [Xu, Jiahong] WESTAT Corp, Rockville, MD 20850 USA. [Morgado, Mariza G.; Veloso, Valdilea G.; Grinsztejn, Beatriz; Bastos, Francisco I.] Fundacao Oswaldo Cruz FIOCRUZ, Rio De Janeiro, Brazil. [Watts, D. Heather] US Dept State, Off Global AIDS Coordinator, Washington, DC 20520 USA. [Weir, Fred; Persing, David] Cepheid, Sunnyvale, CA USA. [Mofenson, Lynne M.; Siberry, George] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Pilotto, Jose Henrique] Hosp Geral Nova Iguacu, DST AIDS, Rio De Janeiro, Brazil. [Joao, Esau] Hosp Fed Servidores Estado, Rio De Janeiro, Brazil. [Gray, Glenda] Univ Witwatersrand, SAMRC, Cape Town, South Africa. [Gray, Glenda] Univ Witwatersrand, Perinatal HIV Res Unit, Cape Town, South Africa. [Theron, Gerhard] Univ Stellenbosch, Tygerberg Hosp, Dept Obstet & Gynecol, Cape Town, South Africa. [Santos, Breno] Hosp Conceicao, Serv Infectol, Porto Alegre, RS, Brazil. [Fonseca, Rosana] Hosp Femina, Porto Alegre, RS, Brazil. [Kreitchmann, Regis] Irmandade Santa Casa de Misericordia Porto Alegre, Porto Alegre, RS, Brazil. [Pinto, Jorge] Univ Fed Minas Gerais, Dept Pediat, Belo Horizonte, MG, Brazil. [Mussi-Pinhata, Marisa M.] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pediat, Sao Paulo, Brazil. [Ceriotto, Mariana] Fdn Maternal & Infant Hlth FUNDASAMIN, Buenos Aires, DF, Argentina. [Machado, Daisy Maria] Univ Fed Sao Paulo, Escola Paulista Med, Sao Paulo, Brazil. RP Adachi, K (reprint author), David Geffen Sch Med UCLA, Dept Pediat, Div Infect Dis, 10833 Conte Ave,MDCC 22-442, Los Angeles, CA 90095 USA. EM kadachi@mednet.ucla.edu FU NICHD [HHSN267200800001C, N01-HD-8-0001, U01 AI047986]; National Institute of Allergy and Infectious Diseases (NIAID)/NIH; National Institutes of Health (NIH) [NIAIDU01 AI068632, UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health [AI068632]; Boehringer Ingelheim Pharmaceuticals Inc. (BIPI); GlaxoSmithKline on behalf of ViiV Healthcare; Cepheid, Sunnyvale, CA; UCLA Center for AIDS Research (CFAR) NIH/NIAID [AI028697] FX The NICHD HPTN 040 study was supported by NICHD Contract # HHSN267200800001C (NICHD Control # N01-HD-8-0001) and U01 AI047986 (Brazilian AIDS Prevention Trials International Network), National Institute of Allergy and Infectious Diseases (NIAID)/NIH. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers NIAIDU01 AI068632, UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH (AI068632). In addition, the parent study was supported in part by Boehringer Ingelheim Pharmaceuticals Inc. (BIPI), and GlaxoSmithKline on behalf of ViiV Healthcare. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and were fully responsible for all aspects of manuscript development. This particular sub-study was supported by Cepheid, Sunnyvale, CA, where CT and NG testing of specimens was performed. Support was also provided by the UCLA Center for AIDS Research (CFAR) NIH/NIAID AI028697. Support for Kristina Adachi's work on this sub-study was also provided in part by the UCLA Children's Discovery and Innovation Institute (CDI). The content, conclusions and opinions expressed in this article are those of the authors and do not necessarily represent those of the National Institutes of Health, the U.S. Department of Health and Human Services, or the U.S. Department of State, affiliated universities, programs or companies of the authors. NR 44 TC 2 Z9 2 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD AUG PY 2016 VL 35 IS 8 BP 894 EP 900 DI 10.1097/INF.0000000000001199 PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA DS4MK UT WOS:000380755000018 PM 27164464 ER PT J AU Chew, EY Clemons, TE Harrington, M Bressler, SB Elman, MJ Kim, JE Garfinkel, R Heier, JS Brucker, A Boyer, D AF Chew, Emily Y. Clemons, Traci E. Harrington, Molly Bressler, Susan B. Elman, Michael J. Kim, Judy E. Garfinkel, Richard Heier, Jeffrey S. Brucker, Alexander Boyer, David CA AREDS2-HOME Study Res Grp TI EFFECTIVENESS OF DIFFERENT MONITORING MODALITIES IN THE DETECTION OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION The Home Study, Report Number 3 SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE age-related macular degeneration; incident choroidal neovascularization; telemonitoring ID RANDOMIZED-TRIAL; EYE HOME; RANIBIZUMAB; DEVICE AB Purpose: To determine the effectiveness of different monitoring modalities to detect incident neovascularization associated with age-related macular degeneration (AMD). Methods: Secondary analyses compared the rates of detecting incident neovascular AMD in prescheduled office visits versus office visits triggered by monitoring device or by symptom realization in a randomized trial evaluating home telemonitoring device plus standard care (device arm) versus standard care alone. Results: At prescheduled office visits, neovascular AMD was detected in 14/1927 visits (0.7%, 95% confidence interval [CI]: 0.4%-1.1%) and 14/1949 visits (0.7%, 95% CI: 0.3%-1.1%) in the device and standard care alone arms, respectively. Thirty-seven participants with neovascular AMD were detected in 318 office visits (11.6%, 95% CI: 8.1%-15.2%) triggered by device or symptom realization and 17 neovascular AMD in 65 office visits (26%, 95% CI: 15.5%-36.8%) triggered by symptom realization in the device and standard care alone arms, respectively. The home device strategy had a higher neovascular-AMD detection rate than prescheduled office visits (relative risk = 16.0 [95% CI: 8.8-29.3]). Neovascular AMD detected at triggered visits were associated with less vision loss from baseline in the device arm versus standard care alone arm (-3 letters vs. -11.5 letters, respectively, P = 0.03). Conclusion: Telemonitoring may alter the management of patients with AMD and improve vision outcomes. C1 [Chew, Emily Y.] NEI, Clin Trials Branch, NIH, Bethesda, MD 20892 USA. [Clemons, Traci E.; Harrington, Molly] EMMES Corp, Rockville, MD USA. [Bressler, Susan B.] Johns Hopkins Univ, Wilmer Eye Inst, Retina Div, Baltimore, MD 21218 USA. [Elman, Michael J.] Elman Retina Grp, Baltimore, MD USA. [Kim, Judy E.] Med Coll Wisconsin, Dept Ophthalmol, Milwaukee, WI 53226 USA. [Garfinkel, Richard] Retina Grp Washington, Washington, DC USA. [Heier, Jeffrey S.] Ophthalm Consultants Boston, Boston, MA USA. [Brucker, Alexander] Scheie Eye Inst, Philadelphia, PA USA. [Boyer, David] Retina Vitreous Associates Med Grp, Los Angeles, CA USA. RP Chew, EY (reprint author), NEI, NIH, Bldg 10,CRC Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU Notal Vision Ltd; National Eye Institute, National Institutes of Health, Bethesda, Maryland (CTA) [CTA-00833]; National Eye Institute, National Institutes of Health [HHS-N-260-2005-00007-C, N01-EY-5-0007] FX Supported by Notal Vision Ltd through a clinical trial agreement with the National Eye Institute, National Institutes of Health, Bethesda, Maryland (CTA no: CTA-00833) and a service agreement with EMMES Corporation. The Age-Related Eye Disease Study 2 study is supported by the intramural program funds and contracts from the National Eye Institute, National Institutes of Health (contract nos: HHS-N-260-2005-00007-C, N01-EY-5-0007). NR 8 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD AUG PY 2016 VL 36 IS 8 BP 1542 EP 1547 PG 6 WC Ophthalmology SC Ophthalmology GA DS7MI UT WOS:000380967200033 PM 27243927 ER PT J AU Roux, A Jackson, SN Muller, L Barbacci, D O'Rourke, J Thanos, PK Volkow, ND Balaban, C Schultz, JA Woods, AS AF Roux, Aurelie Jackson, Sheller N. Muller, Ludovic Barbacci, Damon O'Rourke, Joseph Thanos, Panayotis K. Volkow, Nora D. Balaban, Carey Schultz, J. Albert Woods, Amina S. TI Ethanol Induced Brain Lipid Changes in Mice Assessed by Mass Spectrometry SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE lipids; alcohol; electrospray ionization; solid-phase extraction; mass spectrometry ID STIMULATES PHOSPHOLIPASE-D; INDUCED OXIDATIVE STRESS; PRIMARY RAT HEPATOCYTES; ADULT RATS; FATTY-ACIDS; INDUCED FLUIDIZATION; ALCOHOL-CONSUMPTION; PHYSICAL-PROPERTIES; CHOLESTEROL CONTENT; MEMBRANE-FLUIDITY AB Alcohol abuse is a chronic disease characterized by the consumption of alcohol at a level that interferes with physical and mental health and causes serious and persistent changes in the brain. Lipid metabolism is of particular interest due to its high concentration in the brain. Lipids are the main component of cell membranes, are involved in cell signaling, signal transduction, and energy storage. In this study, we analyzed lipid composition of chronically ethanol exposed mouse brains. Juvenile (JUV) and adult (ADU) mice were placed on a daily limited-access ethanol intake model for 52 days. After euthanasia, brains were harvested, and total lipids were extracted from brain homogenates. Samples were analyzed using high resolution mass spectrometry and processed by multivariate and univariate statistical analysis. Significant lipid changes were observed in different classes including sphingolipids, fatty acids, lysophosphatidylcholines, and other glycerophospholipids. C1 [Roux, Aurelie; Jackson, Sheller N.; Muller, Ludovic; Volkow, Nora D.; Woods, Amina S.] NIDA IRP, Struct Biol Unit, NIH, Baltimore, MD 21224 USA. [Muller, Ludovic] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [O'Rourke, Joseph; Thanos, Panayotis K.] Univ Buffalo, Dept Psychol, Behav Neuropharmacol & Neuroimaging Lab, Buffalo, NY 14260 USA. [Barbacci, Damon; Schultz, J. Albert] Ionwerks Inc, Houston, TX 77002 USA. [Balaban, Carey] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15260 USA. [Balaban, Carey] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA 15260 USA. [Balaban, Carey] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA 15260 USA. [Balaban, Carey] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15260 USA. RP Woods, AS (reprint author), NIDA IRP, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov FU NIDA SBIR Phase II grants [5R44DA030853-04, 5R44DA036263-04] FX Ionwerks gratefully acknowledges partial support for this work from NIDA SBIR Phase II grants 5R44DA030853-04 and 5R44DA036263-04. NR 77 TC 0 Z9 0 U1 6 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD AUG PY 2016 VL 7 IS 8 BP 1148 EP 1156 DI 10.1021/acschemneuro.6b00120 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA DT8CS UT WOS:000381717300016 PM 27269520 ER PT J AU Pletneva, NV Pletnev, S Pakhomov, AA Chertkova, RV Martynov, VI Muslinkina, L Dauter, Z Pletnev, VZ AF Pletneva, Nadya V. Pletnev, Sergei Pakhomov, Alexey A. Chertkova, Rita V. Martynov, Vladimir I. Muslinkina, Liya Dauter, Zbigniew Pletnev, Vladimir Z. TI Crystal structure of the fluorescent protein from Dendronephthya sp in both green and photoconverted red forms SO ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY LA English DT Article DE fluorescent photoconvertible proteins; green fluorescent protein; red fluorescent protein; three-dimensional structure; chromophore; beta-barrel; structure-function relationships; DendFP; DendRFP; DendGFP; Dendronephthya ID PHOTOINDUCED PEPTIDE CLEAVAGE; MICROSCOPY; CONVERSION; DENDRA2; STATE; GFP; CHROMOPHORE; MECHANISM; EVOLUTION; CELLS AB The fluorescent protein from Dendronephthya sp. (DendFP) is a member of the Kaede-like group of photoconvertible fluorescent proteins with a His62-Tyr63-Gly64 chromophore-forming sequence. Upon irradiation with UV and blue light, the fluorescence of DendFP irreversibly changes from green (506 nm) to red (578 nm). The photoconversion is accompanied by cleavage of the peptide backbone at the C-alpha-N bond of His62 and the formation of a terminal carboxamide group at the preceding Leu61. The resulting double C-alpha=C-beta bond in His62 extends the conjugation of the chromophore pi system to include imidazole, providing the red fluorescence. Here, the three-dimensional structures of native green and photoconverted red forms of DendFP determined at 1.81 and 2.14 angstrom resolution, respectively, are reported. This is the first structure of photoconverted red DendFP to be reported to date. The structure-based mutagenesis of DendFP revealed an important role of positions 142 and 193: replacement of the original Ser142 and His193 caused a moderate red shift in the fluorescence and a considerable increase in the photoconversion rate. It was demonstrated that hydrogen bonding of the chromophore to the Gln116 and Ser105 cluster is crucial for variation of the photoconversion rate. The single replacement Gln116Asn disrupts the hydrogen bonding of Gln116 to the chromophore, resulting in a 30-fold decrease in the photoconversion rate, which was partially restored by a further Ser105Asn replacement. C1 [Pletneva, Nadya V.; Pakhomov, Alexey A.; Chertkova, Rita V.; Martynov, Vladimir I.; Pletnev, Vladimir Z.] Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. [Pletnev, Sergei; Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne, IL 60439 USA. [Pletnev, Sergei] Leidos Biomed Res Inc, Basic Res Program, Argonne, IL 60439 USA. [Muslinkina, Liya] Russian Acad Sci, Arbuzov Inst Organ & Phys Chem, Kazan, Russia. RP Pletneva, NV; Pletnev, VZ (reprint author), Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. EM nadin.plet@gmail.com; vzpletnev@gmail.com RI Pakhomov, Alexey/D-7199-2012; Pletneva, Nadya/F-7839-2014; Pletnev, Vladimir/Q-6151-2016; Martynov, Vladimir/S-3483-2016 OI Martynov, Vladimir/0000-0003-4923-6842 FU Russian Science Foundation [14-14-00281]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; US Department of Energy, Office of Science and Office of Basic Energy Sciences [W-31-109-Eng-38] FX This research was supported by funding from the Russian Science Foundation (project 14-14-00281). X-ray data collection at the synchrotron station was supported in part by Federal funds from the National Cancer Institute, National Institutes of Health under contract No. HHSN261200800001E and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Diffraction experiments were carried out on synchrotron beamline 22-ID of the Southeast Regional Collaborative Access Team (SERCAT) located at the Advanced Photon Source, Argonne National Laboratory. Use of the APS was supported by the US Department of Energy, Office of Science and Office of Basic Energy Sciences under Contract No.W-31-109-Eng-38. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 37 TC 0 Z9 0 U1 10 U2 15 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2059-7983 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Struct. Biol. PD AUG PY 2016 VL 72 BP 922 EP 932 DI 10.1107/S205979831601038X PN 8 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA DS4TA UT WOS:000380773100003 PM 27487823 ER PT J AU Esser, L Shukla, S Zhou, F Ambudkar, SV Xia, D AF Esser, Lothar Shukla, Suneet Zhou, Fei Ambudkar, Suresh V. Xia, Di TI Crystal structure of the antigen-binding fragment of a monoclonal antibody specific for the multidrug-resistance-linked ABC transporter human P-glycoprotein SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS LA English DT Article DE monoclonal antibodies; UIC2/Fab; multidrug resistance; human ABC-dependent transporter P-glycoprotein; multidrug resistance ID DIFFERENTIAL IMMUNOREACTIVITY; CONFORMATIONAL-CHANGES; INSECT CELLS; COMPETITION; INHIBITION; EXPRESSION; MODE AB P-glycoprotein (P-gp) is a polyspecific ATP-dependent transporter linked to multidrug resistance in cancers that plays important roles in the pharmacokinetics of a large number of drugs. The drug-resistance phenotype of P-gp can be modulated by the monoclonal antibody UIC2, which specifically recognizes human P-gp in a conformation-dependent manner. Here, the purification, sequence determination and high-resolution structure of the Fab fragment of UIC2 (UIC2/Fab) are reported. Purified UIC2/Fab binds human P-gp with a 1: 1 stoichiometry. Crystals of UIC2/Fab are triclinic (space group P1), with unit-cell parameters a = 40.67, b = 44.91, c = 58.09 angstrom, alpha = 97.62, beta = 99.10, gamma = 94.09 degrees, and diffracted X-rays to 1.6 angstrom resolution. The structure was determined by molecular replacement and refined to 1.65 angstrom resolution. The asymmetric unit contains one molecule of UIC2/Fab, which exhibits a positively charged antigen-binding surface, suggesting that it might recognize an oppositely charged extracellular epitope of P-gp. C1 [Esser, Lothar; Shukla, Suneet; Zhou, Fei; Ambudkar, Suresh V.; Xia, Di] NCI, NIH, 37 Convent Dr,Bldg 37, Bethesda, MD 20892 USA. RP Xia, D (reprint author), NCI, NIH, 37 Convent Dr,Bldg 37, Bethesda, MD 20892 USA. EM dixia@helix.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX The authors wish to thank the staff of the SER-CAT beamline at APS, ANL for assistance in data collection. This study used the DNA Core of NCI and the high-performance Biowulf Linux cluster (http://hpc.nih.gov) at the NIH. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 23 TC 0 Z9 0 U1 8 U2 8 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2053-230X J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Commun. PD AUG PY 2016 VL 72 BP 636 EP 641 DI 10.1107/S2053230X16009778 PN 8 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA DS4SV UT WOS:000380772600009 PM 27487928 ER PT J AU Veronezi, BP Moffa, AH Carvalho, AF Galhardoni, R Simis, M Bensenor, IM Lotufo, PA Machado-Vieira, R Daskalakis, ZJ Brunoni, AR AF Veronezi, B. P. Moffa, A. H. Carvalho, A. F. Galhardoni, R. Simis, M. Bensenor, I. M. Lotufo, P. A. Machado-Vieira, R. Daskalakis, Z. J. Brunoni, A. R. TI Evidence for increased motor cortical facilitation and decreased inhibition in atypical depression SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article DE major depressive disorder; glutamate; gamma-aminobutyric acid; motor cortex excitability; transcranial magnetic stimulation ID TRANSCRANIAL MAGNETIC STIMULATION; MAJOR DEPRESSION; CORTEX EXCITABILITY; PREFRONTAL CORTEX; MOOD DISORDERS; DSM-IV; FEATURES; ORGANIZATION; ADOLESCENTS; RELIABILITY AB Objective: Major depressive disorder (MDD) is a clinically heterogeneous condition. However, the role of cortical glutamate and gamma-aminobutyric acid (GABA) receptor-mediated activity, implicated in MDD pathophysiology, has not been explored in different MDD subtypes. Our aim was to assess the atypical and melancholic depression subtypes regarding potential differences in GABA and glutamate receptor-mediated activity through established transcranial magnetic stimulation (TMS) neurophysiological measures from the motor cortex. Method: We evaluated 81 subjects free of antidepressant medication, including 21 healthy controls and 20 patients with atypical, 20 with melancholic, and 20 with undifferentiated MDD. Single and paired-pulse TMS paradigms were used to evaluate intracortical facilitation (ICF), cortical silent period (CSP), and short intracortical inhibition (SICI), which index glutamate, GABA(B) receptor-, and GABA(A) receptor-mediated activity respectively. Results: Patients with MDD demonstrated significantly decreased mean CSP values than healthy controls (Cohen's d = 0.22-0.3, P < 0.01 for all comparisons). Atypical depression presented a distinct cortical excitability pattern of decreased cortical inhibition and increased cortical facilitation, that is, an increased mean ICF and SICI ratios than other depression subtypes (d = 0.22-0.33, P < 0.01 for all comparisons). Conclusion: Different MDD subtypes may demonstrate different neurophysiology in relation to GABA(A) and glutamatergic activity. TMS as an investigational tool might be useful to distinguish between different MDD subtypes. C1 [Veronezi, B. P.; Moffa, A. H.; Bensenor, I. M.; Lotufo, P. A.; Brunoni, A. R.] Univ Sao Paulo, Univ Hosp, Interdisciplinary Ctr Appl Neuromodulat, Sao Paulo, Brazil. [Carvalho, A. F.] Univ Fed Ceara, Dept Psychiat, Fortaleza, Ceara, Brazil. [Moffa, A. H.] Univ Fed Ceara, Fac Med, Translat Psychiat Res Grp, Fortaleza, Ceara, Brazil. [Galhardoni, R.; Brunoni, A. R.] Univ Sao Paulo, Dept & Inst Psychiat, Lab Neurosci LIM 27, Serv Interdisciplinary Neuromodulat, Sao Paulo, Brazil. [Galhardoni, R.] Univ Sao Paulo, Sch Arts Sci & Humanities, Sao Paulo, Brazil. [Galhardoni, R.] Univ Sao Paulo, Dept Neurol, Pain Ctr, Sao Paulo, Brazil. [Galhardoni, R.] Univ City Sao Paulo UNICID, Med Sch, Sao Paulo, Brazil. [Simis, M.] Univ Sao Paulo, Sch Med, Clin Hosp, Inst Phys Med & Rehabil, Sao Paulo, Brazil. [Machado-Vieira, R.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Daskalakis, Z. J.] Univ Toronto, Temerty Ctr Therapeut Brain Intervent, Toronto, ON, Canada. [Daskalakis, Z. J.] Univ Toronto, Campbell Family Res Inst, Ctr Addict & Mental Hlth, Dept Psychiat, Toronto, ON, Canada. RP Brunoni, AR (reprint author), Interdisciplinary Ctr Appl Neuromodulat, Av Prof Lineu Prestes 2565,3o andar, BR-05508000 Sao Paulo, Brazil. EM brunoni@usp.br RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; Lotufo, Paulo/A-9843-2008; OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Lotufo, Paulo/0000-0002-4856-8450; Russowsky Brunoni, Andre/0000-0002-6310-3571 FU NARSAD Young Investigator from Brain & Behavior Research Foundation [20493]; Sao Paulo State Foundation [12/20911-5]; National Council for Scientific and Technological Development (CNPq) [470904]; CNPq scholarship grant; FAPESP scholarship grant [13/19759-7]; National Council for Scientific and Technological Development (CNPq; level II; Brazil) FX ARB is supported by the following grants: 2013 NARSAD Young Investigator from the Brain & Behavior Research Foundation (Grant Number 20493), 2012 FAPESP Young Researcher from the Sao Paulo State Foundation (Grant Number 12/20911-5), and National Council for Scientific and Technological Development (CNPq, Grant Number 470904). ARB also received equipment from the Soterix Company. AHM receives a CNPq scholarship grant. BPV receives a FAPESP scholarship grant (13/19759-7). AFC is the recipient of a research fellowship award from the National Council for Scientific and Technological Development (CNPq; level II; Brazil). NR 53 TC 0 Z9 0 U1 6 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-690X EI 1600-0447 J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD AUG PY 2016 VL 134 IS 2 BP 172 EP 182 DI 10.1111/acps.12565 PG 11 WC Psychiatry SC Psychiatry GA DT7SY UT WOS:000381688700009 PM 27028276 ER PT J AU Grantz, KL Grewal, J Albert, PS Wapner, R D'Alton, ME Sciscione, A Grobman, WA Wing, DA Owen, J Newman, RB Chien, EK Gore-Langton, RE Kim, S Zhang, CL Louis, GMB Hediger, ML AF Grantz, Katherine L. Grewal, Jagteshwar Albert, Paul S. Wapner, Ronald D'Alton, Mary E. Sciscione, Anthony Grobman, William A. Wing, Deborah A. Owen, John Newman, Roger B. Chien, Edward K. Gore-Langton, Robert E. Kim, Sungduk Zhang, Cuilin Louis, Germaine M. Buck Hediger, Mary L. TI Dichorionic twin trajectories: the NICHD Fetal Growth Studies SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE dichorionic; estimated fetal weight; fetal growth; twin ID BIRTH-WEIGHT; HEAD; GESTATIONS; RETARDATION; PREGNANCIES; PREDICTION; PATTERNS; DISEASE; HEALTH; RISK AB BACKGROUND: Systematic evaluation and estimation of growth trajectories in twins require ultrasound measurements across gestation that are performed in controlled clinical settings. Currently, there are few such data for contemporary populations. There is also controversy about whether twin fetal growth should be evaluated with the use of the same benchmarks as singleton growth. OBJECTIVES: Our objective was to define the trajectory of fetal growth in dichorionic twins empirically using longitudinal 2-dimensional ultrasonography and to compare the fetal growth trajectories for dichorionic twins with those based on a growth standard that was developed by our group for singletons. STUDY DESIGN: A prospective cohort of 171 women with twin gestations was recruited from 8 US sites from 2012-2013. After an initial sonogram at 11 weeks 0 days-13 weeks 6 days of gestation during which dichorionicity was confirmed, women were assigned randomly to 1 of 2 serial ultrasonography schedules. Growth curves and percentiles were estimated with the use of linear mixed models with cubic splines. Percentiles were compared statistically at each gestational week between the twins and 1731 singletons, after adjustment for maternal age, race/ethnicity, height, weight, parity, employment, marital status, insurance, income, education, and infant sex. Linear mixed models were used to test for overall differences between the twin and singleton trajectories with the use of likelihood ratio tests of interaction terms between spline mean structure terms and twin-singleton indicator variables. Singleton standards were weighted to correspond to the distribution of maternal race in twins. For those ultrasound measurements in which there were significant global tests for differences between twins and singletons, we tested for week-specific differences using Wald tests that were computed at each gestational age. In a separate analysis, we evaluated the degree of reclassification in small for gestational age, which was defined as < 10th percentile that would be introduced if fetal growth estimation for twins was based on an unweighted singleton standard. RESULTS: Women underwent a median of 5 ultrasound scans. The 50th percentile abdominal circumference and estimated fetal weight trajectories of twin fetuses diverged significantly beginning at 32 weeks of gestation; biparietal diameter in twins was smaller from 34-36 weeks of gestation. There were no differences in head circumference or femur length. The mean head circumference/abdominal circumference ratio was progressively larger for twins compared with singletons beginning at 33 weeks of gestation, which indicated a comparatively asymmetric growth pattern. At 35 weeks of gestation, the average gestational age at delivery for twins, the estimated fetal weights for the 10th, 50th, and 90th percentiles were 1960, 2376, and 2879 g for dichorionic twins, respectively, and 2180, 2567, and 3022 g for the singletons, respectively. At 32 weeks of gestation, the initial week when the mean estimated fetal weight for twins was smaller than that of singletons, 34% of twins would be classified as small for gestational age with the use of a singleton, non-Hispanic white standard. By 35 weeks of gestation, 38% of twins would be classified as small for gestational age. CONCLUSION: The comparatively asymmetric growth pattern in twin gestations, initially evident at 32 weeks of gestation, is consistent with the concept that the intrauterine environment becomes constrained in its ability to sustain growth in twin fetuses. Near term, nearly 40% of twins would be classified as small for gestational age based on a singleton growth standard. C1 [Grantz, Katherine L.; Grewal, Jagteshwar; Albert, Paul S.; Kim, Sungduk; Zhang, Cuilin; Louis, Germaine M. Buck; Hediger, Mary L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. [Wapner, Ronald; D'Alton, Mary E.] Columbia Univ, Med Ctr, New York, NY USA. [Sciscione, Anthony] Christiana Care Hlth Syst, Wilmington, DE USA. [Grobman, William A.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Wing, Deborah A.] Calif State Univ Long Beach, Irvine & Long Beach Mem Med Ctr, Long Beach, CA 90840 USA. [Owen, John] Univ Alabama Birmingham, Birmingham, AL USA. [Newman, Roger B.] Med Univ South Carolina, Charleston, SC 29425 USA. [Chien, Edward K.] Women & Infants Hosp Rhode Isl, Providence, RI 02908 USA. [Gore-Langton, Robert E.] Emmes Corp, Rockville, MD USA. RP Grantz, KL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. EM katherine.grantz@nih.gov OI owen, john/0000-0001-8854-2346; Grewal, Jagteshwar/0000-0002-0141-4876; Buck Louis, Germaine/0000-0002-1774-4490; Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275200800003IC, HHSN275200800014C, HHSN275200800012C, HHSN275200800028C, HHSN275201000009C] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract numbers: HHSN275200800013C; HHSN275200800002I; HHSN27500006; HHSN275200800003IC; HHSN275200800014C; HHSN275200800012C; HHSN275200800028C; HHSN275201000009C). NR 32 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 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD AUG PY 2016 VL 215 IS 2 AR 221.e1-e16 DI 10.1016/j.ajog.2016.04.044 PG 16 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DS5JN UT WOS:000380818200020 PM 27143399 ER PT J AU Hildesheim, A Gonzalez, P Kreimer, AR Wacholder, S Schussler, J Rodriguez, AC Porras, C Schiffman, M Sidawy, M Schiller, JT Lowy, DR Herrero, R AF Hildesheim, Allan Gonzalez, Paula Kreimer, Aimee R. Wacholder, Sholom Schussler, John Rodriguez, Ana C. Porras, Carolina Schiffman, Mark Sidawy, Mary Schiller, John T. Lowy, Douglas R. Herrero, Rolando CA Costa Rica HPV Vaccine Trial CVT TI Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE cervical cancer; clinical trial; human papillomaviruses; prevention; vaccines ID POOLED ANALYSIS; BROAD-SPECTRUM; TRIAL; NEOPLASIA; EFFICACY; PCR; WOMEN; ASSAY AB BACKGROUND: Human papillomavirus vaccines prevent human papillomavirus infection and cervical precancers. The impact of vaccinating women with a current infection or after treatment for an human papillomavirus-associated lesion is not fully understood. OBJECTIVES: To determine whether human papillomavirus-16/18 vaccination influences the outcome of infections present at vaccination and the rate of infection and disease after treatment of lesions. STUDY DESIGN: We included 1711 women (18 +/- 25 years) with carcinogenic human papillomavirus infection and 311 women of similar age who underwent treatment for cervical precancer and who participated in a community-based trial of the AS04-adjuvanted human papillomavirus-16/18 virus-like particle vaccine. Participants were randomized (human papillomavirus or hepatitis A vaccine) and offered 3 vaccinations over 6 months. Follow-up included annual visits (more frequently if clinically indicated), referral to colposcopy of high-grade and persistent low-grade lesions, treatment by loop electrosurgical excisional procedure when clinically indicated, and cytologic and virologic follow-up after treatment. Among women with human papillomavirus infection at the time of vaccination, we considered type-specific viral clearance, and development of cytologic (squamous intraepithelial lesions) and histologic (cervical intraepithelial neoplasia) lesions. Among treated women, we considered single-time and persistent human papillomavirus infection, squamous intraepithelial lesions, and cervical intraepithelial neoplasia 2 or greater. Outcomes associated with infections absent before treatment also were evaluated. Infection-level analyses were performed and vaccine efficacy estimated. RESULTS: Median follow-up was 56.7 months (women with human papillomavirus infection) and 27.3 months (treated women). There was no evidence of vaccine efficacy to increase clearance of human papillomavirus infections or decrease incidence of cytologic/histologic abnormalities associated with human papillomavirus types present at enrollment. Vaccine efficacy for human papillomavirus 16/18 clearance and against human papillomavirus 16/18 progression from infection to cervical intraepithelial neoplasia 2 or greater were -5.4% (95% confidence interval -19,10) and 0.3% (95% confidence interval -69,41), respectively. Among treated women, 34.1% had oncogenic infection and 1.6% had cervical intraepithelial neoplasia 2 or greater detected after treatment, respectively, and of these 69.8% and 20.0% were the result of new infections. We observed no significant effect of vaccination on rates of infection/lesions after treatment. Vaccine efficacy estimates for human papillomavirus 16/18 associated persistent infection and cervical intraepithelial neoplasia 2 or greater after treatment were 34.7% (95% confidence interval -131, 82) and -211% (95% confidence interval -2901, 68), respectively. We observed evidence for a partial and nonsignificant protective effect of vaccination against new infections absent before treatment. For incident human papillomavirus 16/18, human papillomavirus 31/33/45, and oncogenic human papillomavirus infections post-treatment, vaccine efficacy estimates were 57.9% (95% confidence interval -43, 88), 72.9% (95% confidence interval 29, 90), and 36.7% (95% confidence interval 1.5, 59), respectively. CONCLUSION: We find no evidence for a vaccine effect on the fate of detectable human papillomavirus infections. We show that vaccination does not protect against infections/lesions after treatment. Evaluation of vaccine protection against new infections after treatment and resultant lesions warrants further consideration in future studies. C1 [Hildesheim, Allan; Kreimer, Aimee R.; Wacholder, Sholom; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Gonzalez, Paula; Rodriguez, Ana C.; Porras, Carolina; Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Schussler, John] Informat Management Serv Inc, Silver Spring, MD USA. [Sidawy, Mary] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Schiller, John T.; Lowy, Douglas R.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Hildesheim, A (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM Hildesha@mail.nih.gov OI Schussler, John/0000-0002-8793-0766 FU NCI [N01-CP-11005]; National Institutes of Health Office of Research on Women's Health; GlaxoSmithKline Biologicals (GSK) [FDA BB-IND 7920]; GlaxoSmithKline; Merck FX The Costa Rica HPV Vaccine Trial is a long-standing collaboration between investigators in Costa Rica and the NCI. The trial is sponsored and funded by the NCI (contract N01-CP-11005), with funding support from the National Institutes of Health Office of Research on Women's Health. GlaxoSmithKline Biologicals (GSK) provided vaccine and support for aspects of the trial associated with regulatory submission needs of the company under a Clinical Trials Agreement (FDA BB-IND 7920) during the four-year, randomized blinded phase of our study. John T. Schiller and Douglas R. Lowy report that they are named inventors on US Government-owned HPV vaccine patents that are licensed to GlaxoSmithKline and Merck and for which the National Cancer Institute receives licensing fees. They are entitled to limited royalties as specified by federal law. The other authors declare that they have no conflicts of interest. The NCI and Costa Rica investigators are responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation of the manuscript. Registered with Clinicaltrials.gov NCT00128661. NR 17 TC 2 Z9 2 U1 2 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 AUG PY 2016 VL 215 IS 2 AR 212.e1-e15 DI 10.1016/j.ajog.2016.02.021 PG 15 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DS5JN UT WOS:000380818200016 PM 26892991 ER PT J AU Stern, JE McLain, AC Louis, GMB Luke, B Yeung, EH AF Stern, Judy E. McLain, Alexander C. Louis, Germaine M. Buck Luke, Barbara Yeung, Edwina H. TI Accuracy of self-reported survey data on assisted reproductive technology treatment parameters and reproductive history SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE assisted reproductive technology; intracytoplasmic sperm injection; participant self-report; patient communication; survey study ID IN-VITRO FERTILIZATION; INTRACYTOPLASMIC SPERM INJECTION; ASSESSMENT MONITORING-SYSTEM; BIRTH-DEFECTS; UNITED-STATES; UPSTATE KIDS; RISK; COHORT; CHILDREN; MASSACHUSETTS AB BACKGROUND: It is unknown whether data obtained from maternal self-report for assisted reproductive technology treatment parameters and reproductive history are accurate for use in research studies. OBJECTIVES: We evaluated the accuracy of self-reported in assisted reproductive technology treatment and reproductive history from the Upstate KIDS study in comparison with clinical data reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System. STUDY DESIGN: Upstate KIDS maternal questionnaire data from deliveries between 2008 and 2010 were linked to data reported to Society for Assisted Reproductive Technology Clinic Outcome Reporting System. The 617 index deliveries were compared as to treatment type (frozen embryo transfer and donor egg or sperm) and use of intracytoplasmic sperm injection and assisted hatching. Use of injectable medications, self-report for assisted reproductive technology, or frozen embryo transfer prior to the index deliveries were also compared. We report agreement in which both sources had yes or both no and sensitivity of maternal report using Society for Assisted Reproductive Technology Clinic Outcome Reporting System as the gold standard. Significance was determined using chi(2) at P < 0.05. RESULTS: Universal agreement was not reached on any parameter but was best for treatment type of frozen embryo transfer (agreement, 96%; sensitivity, 93%) and use of donor eggs (agreement, 97%; sensitivity, 82%) or sperm (agreement, 98%; sensitivity, 82%). Use of intracytoplasmic sperm injection (agreement, 78%: sensitivity, 78%) and assisted hatching (agreement, 57%; sensitivity, 38%) agreed less well with self-reported use (P <.0001). In vitro fertilization (agreement, 82%) and frozen embryo transfer (agreement, 90%) prior to the index delivery were more consistently reported than was use of injectable medication (agreement, 76%) (P <.0001). CONCLUSION: Women accurately report in vitro fertilization treatment but are less accurate about procedures handled in the laboratory (intracytoplasmic sperm injection or assisted hatching). Clinics might better communicate with patients on the use of these procedures, and researchers should use caution when using self-reported treatment data. C1 [Stern, Judy E.] Dartmouth Coll, Geisel Sch Med, Dept Ostet & Gynecol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. [McLain, Alexander C.] Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC USA. [Yeung, Edwina H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, Rockville, MD USA. [Luke, Barbara] Michigan State Univ, Dept Obstet, E Lansing, MI 48824 USA. [Luke, Barbara] Michigan State Univ, Dept Gynecol, E Lansing, MI 48824 USA. [Luke, Barbara] Michigan State Univ, Dept Reprod Biol, E Lansing, MI 48824 USA. RP Stern, JE (reprint author), Dartmouth Coll, Geisel Sch Med, Dept Ostet & Gynecol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM judy.e.stern@dartmouth.edu OI Yeung, Edwina/0000-0002-3851-2613; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275201200005C, HHSN267200700019C] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts HHSN275201200005C and HHSN267200700019C). NR 32 TC 1 Z9 1 U1 1 U2 1 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 AUG PY 2016 VL 215 IS 2 AR 219.e1-e6 DI 10.1016/j.ajog.2016.02.010 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DS5JN UT WOS:000380818200019 PM 26875948 ER PT J AU Thirunavukkarasu, S Khan, NS Song, CY Ghafoor, HU Brand, DD Gonzalez, FJ Malik, KU AF Thirunavukkarasu, Shyamala Khan, Nayaab S. Song, Chi Young Ghafoor, Hafiz U. Brand, David D. Gonzalez, Frank J. Malik, Kafait U. TI Cytochrome P450 1B1 Contributes to the Development of Angiotensin II-Induced Aortic Aneurysm in Male Apoe(-/-) Mice SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article; Proceedings Paper CT Meeting of the American-Society-of-Investigative-Pathology / Mini Symposium Sessions on Vascular Biology and Molecular Mechanisms of Diseases at Experimental Biology Meeting CY MAR 28-APR 01, 2015 CL Boston, MA SP Amer Soc Investigat Pathol ID SMOOTH-MUSCLE-CELLS; E-DEFICIENT MICE; INDUCED HYPERTENSION; OXIDATIVE STRESS; T-CELLS; CARDIOVASCULAR-DISEASE; CLINICAL-IMPLICATIONS; GENE-EXPRESSION; PDGFR-BETA; PATHOGENESIS AB Cytochrome P450 (CYP) 1B1 is implicated in vascular smooth muscle cell migration, proliferation, and hypertension. We assessed the contribution of CYP1B1 to angiotensin (Ang) II-induced abdominal aortic aneurysm (AAA). Male Apoe(-/-)/Cyp1b1(+/+) and Apoe(-/-)/Cyp1b1(-/-) mice were infused with Ang II or its vehicle for 4 weeks; another group of Apoe(-/-) /Cyp1b1(-/-) mice was coadministered the CYP1B1 inhibitor 2,3',4,5'-tetramethoxystilbene (TMS) every third day for 4 weeks. On day 28 of Ang II infusion, AAAs were analyzed by ultrasound and ex vivo by Vernier calipers, mice were euthanized, and tissues were harvested. Ang II produced AAAs in Apoe(-/-)/Cyp1b1(+/+) mice; mice treated with TMS or Apoe(-/-)/Cyp1b1(-/-) mice had reduced AAAs. Ang II enhanced infiltration of macrophages, T cells, and platelets and increased platelet derived growth factor D, Pdgfrb, Itga2, and matrix metalloproteinases 2 and 9 expression in aortic lesions; these changes were inhibited in mice treated with TMS and in Apoe(-/-)/Cyp1b1(-/-) mice. Oxidative stress resulted in cyclooxygenase-2 expression in aortic lesions. These effects were minimized in Apoe(-/-)/Cyp1b1+/+ mice treated with TMS and in Apoe(-/-)/Cyp1b1(-/-) mice and by concurrent treatment with the superoxide scavenger 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl. CYP1B1 contributed to the development of Ang II induced AAA and associated pathogenic events in mice, likely by enhancing oxidative stress and associated signaling events. Thus, CYP1B1 may serve as a target for therapeutic agents for AAA in males. C1 [Thirunavukkarasu, Shyamala; Khan, Nayaab S.; Song, Chi Young; Ghafoor, Hafiz U.; Malik, Kafait U.] Univ Tennessee, Hlth Sci Ctr, Coll Med, Dept Pharmacol, 874 Union Ave, Memphis, TN 38163 USA. [Brand, David D.] Univ Tennessee, Hlth Sci Ctr, Coll Med, Dept Med & Microbiol Immunol & Biochem, Memphis, TN USA. [Brand, David D.] Vet Affairs Med Ctr, Res Serv, Memphis, TN USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Malik, KU (reprint author), Univ Tennessee, Hlth Sci Ctr, Coll Med, Dept Pharmacol, 874 Union Ave, Memphis, TN 38163 USA. EM kmalik@uthsc.edu FU BLRD VA [I01 BX001193]; NHLBI NIH HHS [R01 HL079109] NR 60 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2016 VL 186 IS 8 BP 2204 EP 2219 DI 10.1016/j.ajpath.2016.04.005 PG 16 WC Pathology SC Pathology GA DS2ON UT WOS:000380623500020 PM 27301358 ER PT J AU Hughes, BL Clifton, RG Hauth, JC Leveno, KJ Myatt, L Reddy, UM Varner, MW Wapner, RJ Mercer, BM Peaceman, AM Ramin, SM Tolosa, JE Saade, G Sorokin, Y AF Hughes, Brenna L. Clifton, Rebecca G. Hauth, John C. Leveno, Kenneth J. Myatt, Leslie Reddy, Uma M. Varner, Michael W. Wapner, Ronald J. Mercer, Brian M. Peaceman, Alan M. Ramin, Susan M. Tolosa, Jorge E. Saade, George Sorokin, Yoram CA Eunice Kennedy Shriver Natl Inst TI Is Mid-trimester Insulin Resistance Predictive of Subsequent Puerperal Infection? A Secondary Analysis of Randomized Trial Data SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE insulin resistance; puerperal infection; pregnancy; predictor ID POLYCYSTIC-OVARY-SYNDROME; PRETERM PRELABOR RUPTURE; AMNIOTIC-FLUID; HISTOLOGICAL CHORIOAMNIONITIS; CEREBRAL-PALSY; TERM INFANTS; MEMBRANES; OBESITY; WOMEN; INTERLEUKIN-6 AB Objective The objective of this study was to examine whether there is an association between insulin resistance and subsequent development of puerperal infection by measuring insulin resistance in the mid-trimester using the homeostasis model assessment (HOMA:IR). Methods Secondary analysis of low-risk nulliparas enrolled in a multicenter preeclampsia prevention trial. HOMA: IR was measured on fasting plasma glucose and insulin concentrations among low-risk nulliparas between 22 and 26 weeks' gestation. Median HOMA:IR was compared between women who did and did not develop puerperal infection using Wilcoxon rank sum test. Logistic regression was used to control for potential confounders. Results Of 1,180 women with fasting glucose and insulin available, 121 (10.3%) had a puerperal infection. Median HOMA: IR was higher among those with subsequent puerperal infection (4.3 [interquartile, IQR: 2.2-20.5] vs. 2.6 [IQR: 1.5-6.7], p < 0.0001). After controlling for potentially confounding variables HOMA: IR was only marginally associated with an increased risk of development of puerperal infection, adjusted odds ratio: 1.01 (95% confidence interval: 1.00-1.02; p = 0.04) per unit increase. Elevated HOMA: IR performed poorly as a predictor of puerperal infection, with a positive predictive value of 15% and a negative predictive value of 92%. Conclusion Though associated with an increased risk of puerperal infection, insulin resistance, measured by HOMA: IR, is not a clinically useful predictor of puerperal infection. C1 [Hughes, Brenna L.] Brown Univ, Women & Infants Hosp, Dept Obstet & Gynecol, Providence, RI USA. [Clifton, Rebecca G.] George Washington Univ, Ctr Biostat, Washington, DC USA. [Hauth, John C.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Leveno, Kenneth J.] Univ Texas Southwestern Med Ctr, Dept Obstet & Gynecol, Dallas, TX USA. [Myatt, Leslie] Univ Cincinnati, Dept Obstet & Gynecol, Cincinnati, OH USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Varner, Michael W.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Wapner, Ronald J.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Mercer, Brian M.] Case Western Reserve Univ, Dept Obstet & Gynecol, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Peaceman, Alan M.] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Tolosa, Jorge E.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Saade, George] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Sorokin, Yoram] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. RP Hughes, BL (reprint author), Women & Infants Hosp Rhode Isl, Dept Obstet & Gynecol, 101 Dudley St, Providence, RI 02905 USA. EM bhughes@wihri.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD34208, HD27869, HD40485, HD40560, HD40544, HD34116, HD40512, HD21410, HD40545, HD40500, HD27915, HD34136, HD27860, HD53118, HD53097, HD27917, HD36801]; National Heart, Lung, and Blood Institute; National Center for Research Resources [M01 RR00080, UL1 RR024153, UL1 RR024989]; [K23HD062340-01] FX A portion of this work was funded by K23HD062340-01 (Hughes/Anderson). The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD34208, HD27869, HD40485, HD40560, HD40544, HD34116, HD40512, HD21410, HD40545, HD40500, HD27915, HD34136, HD27860, HD53118, HD53097, HD27917, and HD36801); the National Heart, Lung, and Blood Institute; and the National Center for Research Resources (M01 RR00080, UL1 RR024153, UL1 RR024989). Comments and views of the authors do not necessarily represent the views of the NICHD. NR 30 TC 0 Z9 0 U1 2 U2 2 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 EI 1098-8785 J9 AM J PERINAT JI Am. J. Perinatol. PD AUG PY 2016 VL 33 IS 10 BP 983 EP 990 DI 10.1055/s-0036-1583188 PG 8 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DS4TN UT WOS:000380774600010 PM 27120478 ER PT J AU Aliaga, S Zhang, J Long, DL Herring, AH Laughon, M Boggess, K Reddy, UM Grantz, KL AF Aliaga, Sofia Zhang, Jun Long, D. Leann Herring, Amy H. Laughon, Matthew Boggess, Kim Reddy, Uma M. Grantz, Katherine Laughon TI Center Variation in the Delivery of Indicated Late Preterm Births SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE late preterm birth; preterm birth; center variation; practice variation ID REGIONAL-VARIATION; UNITED-STATES; INFANTS; CARE; GESTATIONS; OUTCOMES; RATES; MORTALITY; TERM AB Objective Evidence for optimal timing of delivery for some pregnancy complications at late preterm gestation is limited. The purpose of this study was to identify center variation of indicated late preterm births. Study design We performed an analysis of singleton late pretermand term births from a large U.S. retrospective obstetrical cohort. Births associated with spontaneous preterm labor, major congenital anomalies, chorioamnionitis, and emergency cesarean were excluded. We used modified Poisson fixed effects logistic regression with interaction terms to assess center variation of indicated late preterm births associated with four medical/obstetric comorbidities after adjusting for socio-demographics, comorbidities, and hospital/provider characteristics. Results We identified 150,055 births from 16 hospitals; 9,218 were indicated late preterm births. We found wide variation of indicated late preterm births across hospitals. The extent of center variation was greater for births associated with preterm premature rupture of membranes (risk ratio [RR] across sites: 0.45-3.05), hypertensive disorders of pregnancy (RR across sites: 0.36-1.27), and placenta previa/abruption (RR across sites: 0.48-1.82). We found less center variation for births associated with diabetes (RR across sites: 0.65-1.39). Conclusion Practice variation in the management of indicated late preterm deliveries might be a source of preventable late preterm birth. C1 [Aliaga, Sofia; Laughon, Matthew] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Zhang, Jun] Shanghai Jiao Tong Univ, Xinhua Hosp, MOE Shanghai Key Lab Childrens Environm Hlth, Sch Med, Shanghai, Peoples R China. [Long, D. Leann; Herring, Amy H.] West Virginia Univ, Dept Biostat, Morgantown, WV USA. [Herring, Amy H.] Carolina Populat Ctr, Chapel Hill, NC USA. [Boggess, Kim] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. [Grantz, Katherine Laughon] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. RP Aliaga, S (reprint author), Pediat CB 7596,101 Manning Dr, Chapel Hill, NC 27599 USA. EM saliaga@med.unc.edu OI Grantz, Katherine/0000-0003-0276-8534 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C]; National Institute of General Medical Sciences [U54GM104942]; Faculty Development Award from North Carolina Children's Promise FX The data included in this article were obtained from the Consortium on Safe Labor, which was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through Contract number HHSN267200603425C. Institutions involved in the Consortium include, in alphabetical order, the following: Baystate Medical Center, Springfield, MA; Cedars-Sinai Medical Center Burnes Allen Research Center, Los Angeles, CA; Christiana Care Health System, Newark, DE; MedStar Georgetown University Hospital, Washington, DC; Indiana University Clarian Health, Indianapolis, IN; Intermountain Healthcare and the University of Utah, Salt Lake City, UT; Maimonides Medical Center, Brooklyn, NY; MetroHealth Medical Center, Cleveland, OH; Summa Health System, Akron City Hospital, Akron, OH; The EMMES Corporation, Rockville, MD (Data Coordinating System); University of Illinois at Chicago, Chicago, IL; University of Miami, Miami, FL; and University of Texas Health Science Center at Huston, Houston, TX. The named authors alone are responsible for the views expressed in this manuscript, which does not necessarily represent the decisions or the stated policy of the NICHD.; DL Long received support from a grant from the National Institute of General Medical Sciences (U54GM104942); her views expressed in this manuscript are not that of the NIH.; This study received supported from a Faculty Development Award from the North Carolina Children's Promise. NR 38 TC 0 Z9 0 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 EI 1098-8785 J9 AM J PERINAT JI Am. J. Perinatol. PD AUG PY 2016 VL 33 IS 10 BP 1008 EP 1016 DI 10.1055/s-0036-1582129 PG 9 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DS4TN UT WOS:000380774600014 PM 27120474 ER PT J AU Yao, XL Gordon, EM Figueroa, DM Barochia, AV Levine, SJ AF Yao, Xianglan Gordon, Elizabeth M. Figueroa, Debbie M. Barochia, Amisha V. Levine, Stewart J. TI Emerging Roles of Apolipoprotein E and Apolipoprotein A-I in the Pathogenesis and Treatment of Lung Disease SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Review DE apolipoprotein E; apolipoprotein A-I; lipid transport; lung disease ID APOE-DEFICIENT MICE; NEUTROPHILIC AIRWAY INFLAMMATION; DENSITY-LIPOPROTEIN RECEPTOR; INNATE IMMUNE-RESPONSES; MIMETIC PEPTIDE D-4F; PULMONARY-HYPERTENSION; KLEBSIELLA-PNEUMONIAE; BACTERIAL-INFECTIONS; ANTIGEN PRESENTATION; PEDIATRIC-PATIENTS AB Emerging roles are being recognized increasingly for apolipoproteins in the pathogenesis and treatment of lung diseases on the basis of their ability to suppress inflammation, oxidative stress, and tissue remodeling, and to promote adaptive immunity and host defense. Apolipoproteins, such as apolipoprotein E (apoE) and apolipoprotein A-I (apoA-I), are important components of lipoprotein particles that facilitate the transport of cholesterol, triglycerides, and phospholipids between plasma and cells. ApoE-containing lipoprotein particles are internalized into cells by low-density lipoprotein receptors (LDLRs), whereas apoA-I can interact with the ATP-binding cassette subfamily A member 1 (ABCA1) transporter to efflux cholesterol and phospholipids out of cells. ApoE and apoA-I also mediate receptor-independent effects, such as binding to and neutralizing LPS. Both apoE and apoA-I are expressed by lung cells, which allows apoE/LDLR- and apoA-I/ABCA1-dependent pathways to modulate normal lung health and the pathogenesis of respiratory diseases, including asthma, acute lung injury, cancer, emphysema, pulmonary fibrosis, and pulmonary hypertension. Data from human studies and research using experimental murine model systems have shown that both apoE and apoA-I pathways play primarily protective roles in lung biology and respiratory disease. Furthermore, apolipoprotein mimetic peptides, corresponding to the LDLR-binding domain of apoE or the class A amphipathic a-helical structure of apoA-I, have antiinflammatory and antioxidant effects that attenuate the severity of lung disease in murine models. Thus, the development of inhaled apolipoprotein mimetic peptides as a novel treatment paradigm could represent a significant advance for patients with respiratory disease who do not respond to current therapies. C1 [Yao, Xianglan; Gordon, Elizabeth M.; Figueroa, Debbie M.; Barochia, Amisha V.; Levine, Stewart J.] NHLBI, Lab Asthma & Lung Inflammat, Cardiovasc & Pulm Branch, Div Intramural Res,NIH, Bldg 10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Lab Asthma & Lung Inflammat, Cardiovasc & Pulm Branch, Div Intramural Res,NIH, Bldg 10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. NR 98 TC 1 Z9 1 U1 6 U2 7 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD AUG 1 PY 2016 VL 55 IS 2 BP 159 EP 169 DI 10.1165/rcmb.2016-0060TR PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA DT7XT UT WOS:000381702300002 PM 27073971 ER PT J AU Badri, MK Zhang, HH Ohyama, Y Venkitapathi, S Kamiya, N Takeda, H Ray, M Scott, G Tsuji, T Kunieda, T Mishina, Y Mochida, Y AF Badri, Mohammed K. Zhang, Honghao Ohyama, Yoshio Venkitapathi, Sundharamani Kamiya, Nobuhiro Takeda, Haruko Ray, Manas Scott, Greg Tsuji, Takehito Kunieda, Tetsuo Mishina, Yuji Mochida, Yoshiyuki TI Ellis Van Creveld2 is Required for Postnatal Craniofacial Bone Development SO ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY LA English DT Article DE cephalometric analysis; craniofacial bone; Ellis-van Creveld syndrome; EVC2; knockout (KO) mouse ID BOVINE CHONDRODYSPLASTIC DWARFISM; ACROFACIAL DYSOSTOSIS; GENE; GROWTH; MORPHOLOGY; MUTATIONS; CILIA; EVC2 AB Ellis-van Creveld (EvC) syndrome is a genetic disorder with mutations in either EVC or EVC2 gene. Previous case studies reported that EvC patients underwent orthodontic treatment, suggesting the presence of craniofacial bone phenotypes. To investigate whether a mutation in EVC2 gene causes a craniofacial bone phenotype, Evc2 knockout (KO) mice were generated and cephalometric analysis was performed. The heads of wild type (WT), heterozygous (Het) and homozygous Evc2 KO mice (1-, 3-, and 6-week-old) were prepared and cephalometric analysis based on the selected reference points on lateral X-ray radiographs was performed. The linear and angular bone measurements were then calculated, compared between WT, Het and KO and statistically analyzed at each time point. Our data showed that length of craniofacial bones in KO was significantly lowered by similar to 20% to that of WT and Het, the growth of certain bones, including nasal bone, palatal length, and premaxilla was more affected in KO, and the reduction in these bone length was more significantly enhanced at later postnatal time points (3 and 6 weeks) than early time point (1 week). Furthermore, bone-to-bone relationship to cranial base and cranial vault in KO was remarkably changed, i.e. cranial vault and nasal bone were depressed and premaxilla and mandible were developed in a more ventral direction. Our study was the first to show the cause-effect relationship between Evc2 deficiency and craniofacial defects in EvC syndrome, demonstrating that Evc2 is required for craniofacial bone development and its deficiency leads to specific facial bone growth defect. Anat Rec, 299:1110-1120, 2016. (C) 2016 Wiley Periodicals, Inc. C1 [Badri, Mohammed K.; Ohyama, Yoshio; Venkitapathi, Sundharamani; Mochida, Yoshiyuki] Boston Univ, Henry M Goldman Sch Dent Med, Dept Mol & Cell Biol, Boston, MA 02215 USA. [Badri, Mohammed K.] Taibah Univ, Coll Dent, Dept Pediat Dent & Orthodont, Al Madinah Al Munawarah, Saudi Arabia. [Zhang, Honghao; Kamiya, Nobuhiro; Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Kamiya, Nobuhiro; Ray, Manas; Scott, Greg; Mishina, Yuji] NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Takeda, Haruko] Univ Liege, GIGA R, Unit Anim Genom, B-4000 Liege, Belgium. [Takeda, Haruko] Univ Liege, Fac Vet Med, B-4000 Liege, Belgium. [Tsuji, Takehito; Kunieda, Tetsuo] Okayama Univ, Grad Sch Environm & Life Sci, Okayama, Japan. RP Mochida, Y (reprint author), 700 Albany St,W202D, Boston, MA 02118 USA. EM mochida@bu.edu FU NIH/NIDCR [DE019527, DE020843] FX Grant sponsor: NIH/NIDCR; Grant numbers: DE019527, DE020843. NR 28 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8486 EI 1932-8494 J9 ANAT REC JI Anat. Rec. PD AUG PY 2016 VL 299 IS 8 BP 1110 EP 1120 DI 10.1002/ar.23353 PG 11 WC Anatomy & Morphology SC Anatomy & Morphology GA DT7BU UT WOS:000381641900013 PM 27090777 ER PT J AU Sah, P Nussear, KE Esque, TC Aiello, CM Hudson, PJ Bansal, S AF Sah, Pratha Nussear, Kenneth E. Esque, Todd C. Aiello, Christina M. Hudson, Peter J. Bansal, Shweta TI Inferring social structure and its drivers from refuge use in the desert tortoise, a relatively solitary species SO BEHAVIORAL ECOLOGY AND SOCIOBIOLOGY LA English DT Article DE Behavioral stress response; Bipartite networks; Gopherus agassizii; Generalized linear mixed models; Modularity; Mycoplasma agassizii ID RESPIRATORY-TRACT DISEASE; JUVENILE GOPHER TORTOISES; LIZARD TILIQUA-RUGOSA; MOJAVE DESERT; BOVINE TUBERCULOSIS; CLIMATIC VARIATION; MOVEMENT PATTERNS; 2 POPULATIONS; HOME-RANGE; AGASSIZII AB For several species, refuges (such as burrows, dens, roosts, nests) are an essential resource for protection from predators and extreme environmental conditions. Refuges also serve as focal sites for social interactions, including mating, courtship, and aggression. Knowledge of refuge use patterns can therefore provide information about social structure, mating, and foraging success, as well as the robustness and health of wildlife populations, especially for species considered to be relatively solitary. In this study, we construct networks of burrow use to infer social associations in a threatened wildlife species typically considered solitary-the desert tortoise. We show that tortoise social networks are significantly different than null networks of random associations, and have moderate spatial constraints. We next use statistical models to identify major mechanisms behind individual-level variation in tortoise burrow use, popularity of burrows in desert tortoise habitat, and test for stressor-driven changes in refuge use patterns. We show that seasonal variation has a strong impact on tortoise burrow switching behavior. On the other hand, burrow age and topographical condition influence the number of tortoises visiting a burrow in desert tortoise habitat. Of three major population stressors affecting this species (translocation, drought, disease), translocation alters tortoise burrow switching behavior, with translocated animals visiting fewer unique burrows than residents. In a species that is not social, our study highlights the importance of leveraging refuge use behavior to study the presence of and mechanisms behind non-random social structure and individual-level variation. Our analysis of the impact of stressors on refuge-based social structure further emphasizes the potential of this method to detect environmental or anthropogenic disturbances. Adaptive and social behavior that affects fitness is now being increasingly incorporated in the conservation and management of wildlife species. However, direct observations of social interactions in species considered to be solitary are difficult, and therefore integration of behavior in conservation and management decisions in such species has been infrequent. For such species, we propose quantifying refuge use behavior as it can provide insights towards their (hidden) social structure, establish relevant contact patterns of infectious disease spread, and provide early warning signals of population stressors. Our study highlights this approach in a long-lived and threatened species, the desert tortoise. We provide evidence toward the presence of and identify mechanisms behind the social structure in desert tortoises formed by their burrow use preferences. We also show how individuals burrow use behavior responds to the presence of population stressors. C1 [Sah, Pratha; Bansal, Shweta] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Nussear, Kenneth E.] Univ Nevada, Dept Geog, Reno, NV 89557 USA. [Esque, Todd C.; Aiello, Christina M.] US Geol Survey, Western Ecol Res Ctr, Las Vegas Field Stn, Henderson, NV USA. [Aiello, Christina M.; Hudson, Peter J.] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Bansal, Shweta] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Bansal, S (reprint author), Georgetown Univ, Dept Biol, Washington, DC 20057 USA.; Bansal, S (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM shweta.bansal@georgetown.edu OI Sah, Pratha/0000-0001-8936-5871; Aiello, Christina/0000-0002-2399-5464; Bansal, Shweta/0000-0002-1740-5421 FU National Science Foundation [1216054]; Department of Defense, Ft. Irwin National Training Center; Ecosystems Mission Area of the U.S. Geological Survey FX This work was funded by the National Science Foundation Ecology of Infections Diseases grant 1216054 Invasion and Infection: Translocation and Transmission: An Experimental Study with Mycoplasma in Desert Tortoises. This work was also partially funded by a grant from the Department of Defense, Ft. Irwin National Training Center, and by the Ecosystems Mission Area of the U.S. Geological Survey. NR 75 TC 0 Z9 0 U1 19 U2 36 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-5443 EI 1432-0762 J9 BEHAV ECOL SOCIOBIOL JI Behav. Ecol. Sociobiol. PD AUG PY 2016 VL 70 IS 8 BP 1277 EP 1289 DI 10.1007/s00265-016-2136-9 PG 13 WC Behavioral Sciences; Ecology; Zoology SC Behavioral Sciences; Environmental Sciences & Ecology; Zoology GA DS0DQ UT WOS:000380266000015 ER PT J AU Detrait, ER Carr, GV Weinberger, DR Lamberty, Y AF Detrait, Eric R. Carr, Greg V. Weinberger, Daniel R. Lamberty, Yves TI Brain catechol-O-methyltransferase (COMT) inhibition by tolcapone counteracts recognition memory deficits in normal and chronic phencyclidine-treated rats and in COMT-Val transgenic mice SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE catechol-O-methyl transferase; cognitive enhancers; dopamine; entacapone; mouse; Novel Object Recognition; rat; tolcapone ID PREFRONTAL CORTEX; OBJECT RECOGNITION; PARKINSONS-DISEASE; COGNITIVE DEFICITS; SCHIZOPHRENIA; DOPAMINE; PERFORMANCE; RELEVANCE; MODELS AB The critical involvement of dopamine in cognitive processes has been well established, suggesting that therapies targeting dopamine metabolism may alleviate cognitive dysfunction. Catechol-O-methyl transferase ( COMT) is a catecholamine-degrading enzyme, the substrates of which include dopamine, epinephrine, and norepinephrine. The present work illustrates the potential therapeutic efficacy of COMT inhibition in alleviating cognitive impairment. A brainpenetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine-treated rats and COMT-Val transgenic mice. In a novel object recognition procedure, tolcapone counteracted a 24-h-dependent forgetting of a familiar object as well as phencyclidine-induced recognition deficits in the rats at doses ranging from 7.5 to 30 mg/kg. In contrast, entacapone, a COMT inhibitor that does not readily cross the blood-brain barrier, failed to show efficacy at doses up to 30 mg/kg. Tolcapone at a dose of 30 mg/kg also improved novel object recognition performance in transgenic mice, which showed clear recognition deficits. Complementing earlier studies, our results indicate that central inhibition of COMT positively impacts recognition memory processes and might constitute an appealing treatment for cognitive dysfunction related to neuropsychiatric disorders. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Detrait, Eric R.; Lamberty, Yves] UCB Biopharma Sprl, Neurosci Therapeut Area, Chemin Foriest, B-1420 Braine Lalleud, Belgium. [Carr, Greg V.; Weinberger, Daniel R.] Johns Hopkins Sch Med, Lieber Inst Brain Dev, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Neurosci, Inst Med Genet, Baltimore, MD USA. [Carr, Greg V.; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Detrait, ER (reprint author), UCB Biopharma Sprl, Neurosci Therapeut Area, Chemin Foriest, B-1420 Braine Lalleud, Belgium. EM edetrait@yahoo.fr RI Carr, Gregory/M-8821-2016 OI Carr, Gregory/0000-0002-6091-6729 FU Lieber Institute for Brain Development; Intramural Research Program of NIMH; UCB Biopharma FX Research funds were provided by the Lieber Institute for Brain Development, the Intramural Research Program of NIMH, and UCB Biopharma. NR 31 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0955-8810 EI 1473-5849 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD AUG PY 2016 VL 27 IS 5 BP 415 EP 421 DI 10.1097/FBP.0000000000000208 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA DS5GV UT WOS:000380810600002 PM 26919286 ER PT J AU Ann, J Sun, W Zhou, X Jung, A Baek, J Lee, S Kim, C Yoon, S Hong, S Choi, S Turcios, NA Herold, BKA Esch, TE Lewin, NE Abramovitz, A Pearce, LV Blumberg, PM Lee, J AF Ann, Jihyae Sun, Wei Zhou, Xing Jung, Aeran Baek, Jisoo Lee, Sunho Kim, Changhoon Yoon, Suyoung Hong, Sunhye Choi, Sun Turcios, Noe A. Herold, Brienna K. A. Esch, Timothy E. Lewin, Nancy E. Abramovitz, Adelle Pearce, Larry V. Blumberg, Peter M. Lee, Jeewoo TI Discovery of N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea as a potent TRPV1 antagonistic template SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Vanilloid receptor 1; TRPV1 antagonists; Analgesic ID PYRIDINE C-REGION; VANILLOID CAPSAICIN RECEPTORS; ANALGESIC AGENTS; AGONIST ACTIVITY; ANALOGS; 2-(3-FLUORO-4-METHYLSULFONYLAMINOPHENYL)PROPANAMIDES; MECHANISMS; DOCKING AB A series of homologous analogues of prototype antagonist 1 and its urea surrogate were investigated as hTRPV1 ligands. Through one-carbon elongation in the respective pharmacophoric regions, N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea was identified as a novel and potent TRPV1 antagonistic template. Its representative compound 27 showed a potency comparable to that of lead compound 1. Docking analysis of compound 27 in our hTRPV1 homology model indicated that its binding mode was similar with that of 1S. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Ann, Jihyae; Jung, Aeran; Baek, Jisoo; Lee, Sunho; Kim, Changhoon; Yoon, Suyoung; Lee, Jeewoo] Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. [Sun, Wei] Shenyang Pharmaceut Univ, Shenyang 110016, Peoples R China. [Zhou, Xing] Hainan Inst Mat Med, Haikou 570311, Peoples R China. [Hong, Sunhye; Choi, Sun] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Coll Pharm, Natl Leading Res Lab Mol Modeling & Drug Design, Seoul 120750, South Korea. [Turcios, Noe A.; Herold, Brienna K. A.; Esch, Timothy E.; Lewin, Nancy E.; Abramovitz, Adelle; Pearce, Larry V.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU Korea Science and Engineering Foundation (KOSEF) grant - Korea government (MOST) [NRF-2014M3A9B5073755]; National Leading Research Lab (NLRL) program [2011-0028885]; National Natural Science Foundation of China [81502927]; Liaoning ST Project [2014226032, 2015020733, 2015001002]; Hainan ST Project [KYYS-2014-66]; Intramural Research Program of the NIH, Center for Cancer Research, NCI in the USA [Z1A BC 005270] FX This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MOST) (NRF-2014M3A9B5073755), National Leading Research Lab (NLRL) program (2011-0028885), National Natural Science Foundation of China (81502927), Liaoning S&T Project (2014226032, 2015020733 and 2015001002), Hainan S&T Project (KYYS-2014-66), and in part by the Intramural Research Program of the NIH, Center for Cancer Research, NCI (Project Z1A BC 005270) in the USA. NR 32 TC 0 Z9 0 U1 4 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 1 PY 2016 VL 26 IS 15 BP 3603 EP 3607 DI 10.1016/j.bmcl.2016.06.010 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA DS2FA UT WOS:000380574100042 PM 27317643 ER PT J AU Wetzler, LM Feavers, IM Gray-Owen, SD Jerse, AE Rice, PA Deal, CD AF Wetzler, Lee M. Feavers, Ian M. Gray-Owen, Scott D. Jerse, Ann E. Rice, Peter A. Deal, Carolyn D. TI Summary and Recommendations from the National Institute of Allergy and Infectious Diseases (NIAID) Workshop "Gonorrhea Vaccines: the Way Forward" SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID SEXUALLY-TRANSMITTED INFECTIONS; NEISSERIA-GONORRHOEAE; GONOCOCCAL-INFECTION; ADAPTIVE IMMUNITY; POTENTIAL IMPACT; BINDING-PROTEIN; MALE-VOLUNTEERS; VACCINATION; MODEL; IMMUNOGENICITY AB There is an urgent need for the development of an antigonococcal vaccine due to the increasing drug resistance found in this pathogen. The U.S. Centers for Disease Control (CDC) have identified multidrug-resistant gonococci (GC) as among 3 "urgent" hazard-level threats to the U.S. population. In light of this, on 29 to 30 June 2015, the National Institute for Allergy and Infectious Diseases (NIAID) sponsored a workshop entitled "Gonorrhea Vaccines: the Way Forward." The goal of the workshop was to gather leaders in the field to discuss several key questions on the current status of gonorrhea vaccine research and the path forward to a licensed gonorrhea vaccine. Representatives from academia, industry, U.S. Government agencies, and a state health department were in attendance. This review summarizes each of the 4 scientific sessions and a series of 4 breakout sessions that occurred during the one and a half days of the workshop. Topics raised as high priority for future development included (i) reinvigoration of basic research to understand gonococcal infection and immunity to allow intervention in processes essential for infection; (ii) clinical infection studies to establish parallels and distinctions between in vitro and animal infection models versus natural human genital and pharyngeal infection and to inform in silico modeling of vaccine impact; and (iii) development of an integrated pipeline for preclinical and early clinical evaluation and direct comparisons of potential vaccine antigens and adjuvants and routes of delivery. C1 [Wetzler, Lee M.] Boston Univ, Sch Med, Dept Med, Infect Dis Sect, Boston, MA 02118 USA. [Feavers, Ian M.] Natl Inst Biol Stand & Controls, Ridge, Herts, England. [Gray-Owen, Scott D.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Jerse, Ann E.] Uniformed Serv Univ Hlth Sci, F Edward Herbert Sch Med, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Rice, Peter A.] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA 01605 USA. [Deal, Carolyn D.] NIAID, Div Microbiol & Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Wetzler, LM (reprint author), Boston Univ, Sch Med, Dept Med, Infect Dis Sect, Boston, MA 02118 USA. EM lwetzler@bu.edu FU NIAID NIH HHS [R01 AI114710] NR 36 TC 2 Z9 2 U1 5 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD AUG PY 2016 VL 23 IS 8 BP 656 EP 663 DI 10.1128/CVI.00230-16 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DS5NJ UT WOS:000380828700001 PM 27335384 ER PT J AU Tycko, R AF Tycko, Robert TI Molecular Structure of Aggregated Amyloid-beta: Insights from Solid-State Nuclear Magnetic Resonance SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID ALZHEIMERS-DISEASE BRAIN; ANGLE-SPINNING NMR; A-BETA; FIBRIL FORMATION; PRECURSOR PROTEIN; IN-REGISTER; EXPERIMENTAL CONSTRAINTS; ROTATIONAL RESONANCE; QUATERNARY STRUCTURE; ELECTRON-MICROSCOPY AB Amyloid-beta (A beta) peptides aggregate to form polymorphic amyloid fibrils and a variety of intermediate assemblies, including oligomers and protofibrils, both in vitro and in human brain tissue. Since the beginning of the 21st century, considerable progress has been made to characterize the molecular structures of A beta aggregates. Full molecular structural models based primarily on data from measurements using solid-state nuclear magnetic resonance (ssNMR) have been developed for several in vitro A beta fibrils and one metastable protofibril. Partial structural characterization of other aggregation intermediates has been achieved. One full structural model for fibrils derived frombrain tissue has also been reported. Future work is likely to focus on additional structures from brain tissue and on further clarification of non-fibrillar A beta aggregates. C1 [Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX Research on A beta structures in Dr. Tycko's laboratory is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health. NR 111 TC 0 Z9 0 U1 13 U2 21 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD AUG PY 2016 VL 6 IS 8 AR a024083 DI 10.1101/cshperspect.a024083 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DT7QJ UT WOS:000381681000001 ER PT J AU Hughes, HY Henderson, DK AF Hughes, Heather Y. Henderson, David K. TI Postexposure prophylaxis after hepatitis C occupational exposure in the interferon-free era SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE bloodborne pathogens; direct acting antiviral agents; hepatitis C virus; postexposure prophylaxis ID HCV GENOTYPE 1; HEALTH-CARE WORKERS; UNITED-STATES; VIRUS-INFECTION; NEEDLESTICK; MANAGEMENT; SOFOSBUVIR; VELPATASVIR; PROTECTION; MICRORNAS AB Purpose of review Healthcare personnel are at risk for occupational exposures to bloodborne pathogens. Primary prevention remains the first line of defense, but secondary prevention measures known to be effective should be implemented when percutaneous exposures occur. Hepatitis C virus (HCV) is a major infectious cause of liver-related morbidity and mortality. Chronic HCV treatment has changed dramatically, with many all-oral directly acting anti-HCV antiviral (DAA) regimens now available. Evidence for the use of DAAs as postexposure prophylaxis (PEP) after occupational exposures to HCV is summarized here. Recent findings Little new evidence supports the use of antivirals in acute HCV infection. Several preliminary studies have examined the use of DAAs or host target agents in chronic HCV treatment. Effective HCV PEP requirements likely include pan-genotypic activity and a high barrier to resistance. One investigational DAA has shown promising results as an efficacious option for all genotypes in chronic HCV treatment and may ultimately represent a potential HCV PEP agent. Summary Insufficient supporting data exist to endorse the use of DAAs for PEP after HCV occupational exposures; additional studies examining efficacy, duration, and cost-effectiveness are needed. Development of more oral drugs possessing a high barrier of resistance and equal activity against all HCV genotypes is anticipated. C1 [Hughes, Heather Y.] Charlie Norwood VA Med Ctr, Augusta, GA USA. [Henderson, David K.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Henderson, DK (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM DHenderson@cc.nih.gov NR 41 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0951-7375 EI 1473-6527 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD AUG PY 2016 VL 29 IS 4 BP 373 EP 380 DI 10.1097/QCO.0000000000000281 PG 8 WC Infectious Diseases SC Infectious Diseases GA DS3YQ UT WOS:000380719000008 PM 27306563 ER PT J AU Marongiu, M Deiana, M Marcia, L Sbardellati, A Asunis, I Meloni, A Angius, A Cusano, R Loi, A Crobu, F Fotia, G Cucca, F Schlessinger, D Crisponi, L AF Marongiu, Mara Deiana, Manila Marcia, Loredana Sbardellati, Andrea Asunis, Isadora Meloni, Alessandra Angius, Andrea Cusano, Roberto Loi, Angela Crobu, Francesca Fotia, Giorgio Cucca, Francesco Schlessinger, David Crisponi, Laura TI Novel action of FOXL2 as mediator of Col1a2 gene autoregulation SO DEVELOPMENTAL BIOLOGY LA English DT Article DE FOXL2; COL1A2; Transcriptional regulation; Ovary; ECM ID TRANSCRIPTION FACTOR FOXL2; GRANULOSA-CELL TUMORS; EPICANTHUS INVERSUS SYNDROME; FORKHEAD TRANSCRIPTION; I COLLAGEN; EXTRACELLULAR-MATRIX; OVARY; PROPEPTIDE; FOLLICLE; INTERACTS AB FOXL2 belongs to the evolutionarily conserved forkhead box (FOX) superfamily and is a master transcription factor in a spectrum of developmental pathways, including ovarian and eyelid development and bone, cartilage and uterine maturation. To analyse its action, we searched for proteins that interact with FOXL2. We found that FOXL2 interacts with specific C-terminal propeptides of several fibrillary collagens. Because these propeptides can participate in feedback regulation of collagen biosynthesis, we inferred that FOXL2 could thereby affect the transcription of the cognate collagen genes. Focusing on COL1A2, we found that FOXL2 indeed affects collagen synthesis, by binding to a DNA response element located about 65Kb upstream of this gene. According to our hypothesis we found that in Foxl2(-/-) mouse ovaries, Col1a2 was elevated from birth to adulthood. The extracellular matrix (ECM) compartmentalizes the ovary during folliculogenesis, (with type I, type III and type IV collagens as primary components), and ECM composition changes during the reproductive lifespan. In Foxl2(-/-) mouse ovaries, in addition to up-regulation of Col1a2, Col3a1, Col4a1 and fibronectin were also upregulated, while laminin expression was reduced. Thus, by regulating levels of extracellular matrix components, FOXL2 may contribute to both ovarian histogenesis and the fibrosis attendant on depletion of the follicle reserve during reproductive aging and menopause. (C) 2016 Elsevier Inc. All rights reserved. C1 [Marongiu, Mara; Deiana, Manila; Marcia, Loredana; Asunis, Isadora; Meloni, Alessandra; Angius, Andrea; Loi, Angela; Crobu, Francesca; Cucca, Francesco; Crisponi, Laura] CNR, Ist Ric Genet & Biomed, I-09042 Monserrato, Italy. [Sbardellati, Andrea; Cusano, Roberto; Fotia, Giorgio] Ctr Adv Studies Res & Dev Sardinia CRS4, Pula, Italy. [Marcia, Loredana; Cucca, Francesco] Univ Sassari, I-07100 Sassari, Italy. [Schlessinger, David] NIA, Genet Lab, IRP, NIH, Baltimore, MD 21224 USA. RP Crisponi, L (reprint author), CNR, Ist Ric Genet & Biomed, I-09042 Monserrato, Italy. EM laura.crisponi@irgb.cnr.it FU Comitato Telethon Fondazione Onlus; Telethon [GP0049Y01]; Sardinian Autonomous Region [L.R. 7/2009, cRP3-154]; CNR, Italy FX This work has been supported by Comitato Telethon Fondazione Onlus, with Telethon grant to LC no GP0049Y01 and in part by Sardinian Autonomous Region (L.R. 7/2009) grant cRP3-154 to FC and by CNR, Italy grant FaReBio2011 'Farmaci e Reti Biotecnologiche di Qualita' to FC. NR 68 TC 1 Z9 1 U1 4 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD AUG 1 PY 2016 VL 416 IS 1 BP 200 EP 211 DI 10.1016/j.ydbio.2016.05.022 PG 12 WC Developmental Biology SC Developmental Biology GA DS6BO UT WOS:000380866900019 PM 27212026 ER PT J AU Geva, S Cooper, JM Gadian, DG Mishkin, M Vargha-Khadem, F AF Geva, Sharon Cooper, Janine M. Gadian, David G. Mishkin, Mortimer Vargha-Khadem, Faraneh TI Impairment on a self-ordered working memory task in patients with early-acquired hippocampal atrophy SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Article DE Working memory; Hippocampus ID MEDIAL TEMPORAL-LOBE; SHORT-TERM-MEMORY; PREFRONTAL CORTEX; FRONTAL-LOBE; RELATIONAL INFORMATION; PARAHIPPOCAMPAL CORTEX; DEVELOPMENTAL AMNESIA; COGNITIVE-PROCESSES; RECOGNITION MEMORY; MACAQUE MONKEYS AB One of the features of both adult-onset and developmental forms of amnesia resulting from bilateral medial temporal lobe damage, or even from relatively selective damage to the hippocampus, is the sparing of working memory. Recently, however, a number of studies have reported deficits on working memory tasks in patients with damage to the hippocampus and in macaque monkeys with neonatal hippocampal lesions. These studies suggest that successful performance on working memory tasks with high memory load require the contribution of the hippocampus. Here we compared performance on a working memory task (the Self-ordered Pointing Task), between patients with early onset hippocampal damage and a group of healthy controls. Consistent with the findings in the monkeys with neonatal lesions, we found that the patients were impaired on the task, but only on blocks of trials with intermediate memory load. Importantly, only intermediate to high memory load blocks yielded significant correlations between task performance and hippocampal volume. Additionally, we found no evidence of proactive interference in either group, and no evidence of an effect of time since injury on performance. We discuss the role of the hippocampus and its interactions with the prefrontal cortex in serving working memory. (C) 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license. C1 [Geva, Sharon; Cooper, Janine M.; Mishkin, Mortimer; Vargha-Khadem, Faraneh] UCL, Inst Child Hlth, Cognit Neurosci & Neuropsychiat Sect, 30 Guilford St, London WC1N 1EH, England. [Gadian, David G.] UCL, Inst Child Hlth, Environm Imaging & Biophys Sect, 30 Guilford St, London WC1N 1EH, England. [Mishkin, Mortimer] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. [Cooper, Janine M.] Murdoch Childrens Res Inst, Australian Ctr Child Neuropsychol Studies, Flemington Rd, Parkville, Vic 3052, Australia. RP Geva, S (reprint author), UCL, Inst Child Hlth, Cognit Neurosci & Neuropsychiat Sect, 30 Guilford St, London WC1N 1EH, England. EM s.geva@ucl.ac.uk; janine.cooper@mcri.edu.au; d.gadian@ucl.ac.uk; mishkinm@mail.nih.gov; f.vargha-khadem@ucl.ac.uk FU Medical Research Council [G0300117-65439, G1002276-98624]; Intramural Research Program of the National Institute of Mental Health; NIH/DHHS; National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London FX This work was funded by the Medical Research Council (grants Nos. G0300117-65439 and G1002276-98624) and the Intramural Research Program of the National Institute of Mental Health, NIH/DHHS, and supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. NR 67 TC 1 Z9 1 U1 7 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 EI 1878-9307 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD AUG PY 2016 VL 20 BP 12 EP 22 DI 10.1016/j.dcn.2016.06.001 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DS5UH UT WOS:000380847600003 PM 27288821 ER PT J AU Singh, N Johnstone, DB Martin, KA Tempera, I Kaplan, MJ Denny, MF AF Singh, Namrata Johnstone, Duncan B. Martin, Kayla A. Tempera, Italo Kaplan, Mariana J. Denny, Michael F. TI Alterations in nuclear structure promote lupus autoimmunity in a mouse model SO DISEASE MODELS & MECHANISMS LA English DT Article DE Nucleus; Chromatin; Histone modifications; Calreticulin; Lamina; Autoantibody ID LAMIN-B-RECEPTOR; NEUTROPHIL EXTRACELLULAR TRAPS; MYELOPROLIFERATIVE NEOPLASMS; A-TYPE; H-Y; ERYTHEMATOSUS; AUTOANTIBODIES; ENVELOPE; DISEASE; CHROMATIN AB Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the development of autoantibodies that recognize components of the cell nucleus. The vast majority of lupus research has focused on either the contributions of immune cell dysfunction or the genetics of the disease. Because granulocytes isolated from human SLE patients had alterations in neutrophil nuclear morphology that resembled the Pelger-Huet anomaly, and had prominent mis-splicing of mRNA encoding the nuclear membrane protein lamin B receptor (LBR), consistent with their Pelger-Huet-like nuclear morphology, we used a novel mouse model system to test the hypothesis that a disruption in the structure of the nucleus itself also contributes to the development of lupus autoimmunity. The lupus-prone mouse strain New Zealand White (NZW) was crossed with c57Bl/6 mice harboring a heterozygous autosomal dominant mutation in Lbr (B6.Lbr(ic/+)), and the (NZWxB6.Lbr(ic))F-1 offspring were evaluated for induction of lupus autoimmunity. Only female (NZWxB6.Lbr(ic))F-1 mice developed lupus autoimmunity, which included splenomegaly, kidney damage and autoantibodies. Kidney damage was accompanied by immune complex deposition, and perivascular and tubule infiltration of mononuclear cells. The titers of anti-chromatin antibodies exceeded those of aged female MRL-Faslpr mice, and were predominantly of the IgG2 subclasses. The antinuclear antibody staining profile of female (NZWxB6.Lbr(ic))F-1 sera was complex, and consisted of an anti-nuclear membrane reactivity that colocalized with the A-type lamina, in combination with a homogeneous pattern that was related to the recognition of histones with covalent modifications that are associated with gene activation. An anti-neutrophil IgM recognizing calreticulin, but not myeloperoxidase (MPO) or proteinase 3 (PR3), was also identified. Thus, alterations in nuclear structure contribute to lupus autoimmunity when expressed in the context of a lupus-prone genetic background, suggesting a mechanism for the development of lupus autoimmunity in genetically predisposed individuals that is induced by the disruption of nuclear architecture. C1 [Singh, Namrata] Univ Iowa, Internal Med, Iowa City, IA 52242 USA. [Johnstone, Duncan B.] Temple Univ, Sch Med, Sect Nephrol Internal Med, Philadelphia, PA 19140 USA. [Martin, Kayla A.; Tempera, Italo] Temple Univ, Fels Inst Canc Res, Dept Immunol Microbiol, Philadelphia, PA 19140 USA. [Kaplan, Mariana J.] NIAMSD, Syst Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Denny, Michael F.] Temple Univ, Sch Med, Rheumatol Sect, Philadelphia, PA 19140 USA. RP Denny, MF (reprint author), Temple Univ, Sch Med, Rheumatol Sect, Philadelphia, PA 19140 USA. EM mikedenny@verizon.net FU National Institutes of Health, by a National Institute of Arthritis and Musculoskeletal and Skin Diseases New Investigator Grant [R03-AR061026]; Alliance for Lupus Research Target Identification in Lupus Grant; Department of Medicine at Temple University Faculty Research Development Award FX This work was supported by the National Institutes of Health, provided by a National Institute of Arthritis and Musculoskeletal and Skin Diseases New Investigator Grant [grant number R03-AR061026 to M.F.D.], the Alliance for Lupus Research Target Identification in Lupus Grant to M.F.D., and the Department of Medicine at Temple University Faculty Research Development Award to M.F.D. NR 91 TC 0 Z9 0 U1 1 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD AUG 1 PY 2016 VL 9 IS 8 BP 885 EP 897 DI 10.1242/dmm.024851 PG 13 WC Cell Biology; Pathology SC Cell Biology; Pathology GA DT8PW UT WOS:000381754600006 PM 27483354 ER PT J AU Lee, WH Lisanby, SH Laine, AF Peterchev, AV AF Lee, W. H. Lisanby, S. H. Laine, A. F. Peterchev, A. V. TI Comparison of electric field strength and spatial distribution of electroconvulsive therapy and magnetic seizure therapy in a realistic human head model SO EUROPEAN PSYCHIATRY LA English DT Article DE Unipolar depression; Mania and bipolar disorder; MRI; ECT; Transcranial magnetic stimulation (TMS) ID TREATMENT-RESISTANT DEPRESSION; ULTRABRIEF STIMULUS TECHNIQUE; ES ELECTROSHOCK APPARATUS; DIPOLE ESTIMATION ERRORS; SIEMENS KONVULSATOR-III; LOW CURRENT AMPLITUDE; EEG SOURCE ANALYSIS; BRAIN-STIMULATION; ANISOTROPIC CONDUCTIVITIES; ENDOGENOUS-DEPRESSION AB Background: This study examines the strength and spatial distribution of the electric field induced in the brain by electroconvulsive therapy (ECT) and magnetic seizure therapy (MST). Methods: The electric field induced by standard (bilateral, right unilateral, and bifrontal) and experimental (focal electrically administered seizure therapy and frontomedial) ECT electrode configurations as well as a circular MST coil configuration was simulated in an anatomically realistic finite element model of the human head. Maps of the electric field strength relative to an estimated neural activation threshold were used to evaluate the stimulation strength and focality in specific brain regions of interest for these ECT and MST paradigms and various stimulus current amplitudes. Results: The standard ECT configurations and current amplitude of 800-900 mA produced the strongest overall stimulation with median of 1.8-2.9 times neural activation threshold and more than 94% of the brain volume stimulated at suprathreshold level. All standard ECT electrode placements exposed the hippocampi to suprathreshold electric field, although there were differences across modalities with bilateral and right unilateral producing respectively the strongest and weakest hippocampal stimulation. MST stimulation is up to 9 times weaker compared to conventional ECT, resulting in direct activation of only 21% of the brain. Reducing the stimulus current amplitude can make ECT as focal as MST. Conclusions: The relative differences in electric field strength may be a contributing factor for the cognitive sparing observed with right unilateral compared to bilateral ECT, and MST compared to right unilateral ECT. These simulations could help understand the mechanisms of seizure therapies and develop interventions with superior risk/benefit ratio. (C) 2016 Elsevier Masson SAS. All rights reserved. C1 [Lee, W. H.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Lisanby, S. H.; Peterchev, A. V.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Lisanby, S. H.] Duke Univ, Dept Psychol & Neurosci, Durham, NC 27708 USA. [Lisanby, S. H.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Lisanby, S. H.] NIMH, NIH, Bethesda, MD 20892 USA. [Laine, A. F.] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. [Peterchev, A. V.] Duke Univ, Dept Biomed Engn, Durham, NC 27708 USA. [Peterchev, A. V.] Duke Univ, Dept Elect & Comp Engn, Durham, NC 27708 USA. RP Peterchev, AV (reprint author), Duke Univ, Dept Psychiat & Behav Sci, DUMC, Box 3620, Durham, NC 27710 USA. EM angel.peterchev@duke.edu OI Peterchev, Angel/0000-0002-4385-065X FU National Institutes of Health [R01MH091083] FX This work was supported by the National Institutes of Health under grant R01MH091083 and an ANSYS Strategic Research Partnership. The authors thank Drs. Paolo Maccarini and Murali Kadiramangalam for the ANSYS license donation. NR 73 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0924-9338 EI 1778-3585 J9 EUR PSYCHIAT JI Eur. Psychiat. PD AUG PY 2016 VL 36 BP 55 EP 64 DI 10.1016/j.eurpsy.2016.03.003 PG 10 WC Psychiatry SC Psychiatry GA DS2EI UT WOS:000380556000008 PM 27318858 ER PT J AU Patounakis, G Ozcan, MC Chason, RJ Norian, JM Payson, M DeCherney, AH Yauger, BJ AF Patounakis, George Ozcan, Meghan C. Chason, Rebecca J. Norian, John M. Payson, Mark DeCherney, Alan H. Yauger, Belinda J. TI Impact of a prior cesarean delivery on embryo transfer: a prospective study SO FERTILITY AND STERILITY LA English DT Article DE Embryo transfer; cesarean delivery; IVF; cesarean scar ID IN-VITRO FERTILIZATION; BODY-MASS INDEX; SUBSEQUENT FERTILITY; CLINICAL PREGNANCY; TRANSFER CATHETER; SECTION; COMPLICATIONS; METAANALYSIS; OUTCOMES; BLOOD AB Objective: To determine whether a history of prior cesarean delivery (CD) makes ET more difficult and impacts pregnancy outcomes. Design: Prospective cohort study. Setting: Tertiary care military facility. Patient(s): One hundred ninety-four patients with previous delivery undergoing IVF/intracytoplasmic sperm injection (ICSI)-ET. Intervention(s): None. Main Outcome Measure(s): Live birth (primary), positive hCG, clinical pregnancy, and time to perform ET. Result(s): There was no statistically significant difference between patients with a history of only vaginal deliveries versus those with a history of CD for live birth (39% vs. 32%), positive hCG (56% vs. 53%), or clinical pregnancy (49% vs. 41%). Embryo transfers took longer in the history of CD group (157 vs. 187 seconds) and were more likely to have mucus (27% vs. 45%) or blood (8% vs. 21%) on the catheter. Conclusion(s): Embryo transfers performed on patients with a prior CD took 30 seconds longer. They were also more likely to have blood or mucus on the catheter. Despite the apparently more difficult transfers, pregnancy outcomes were not different between the two groups. (C) 2016 by American Society for Reproductive Medicine. C1 [Patounakis, George; DeCherney, Alan H.] NICHHD, NIH, Bethesda, MD 20892 USA. [Ozcan, Meghan C.; Chason, Rebecca J.; Yauger, Belinda J.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Norian, John M.] HRC Fertil, Pasadena, CA USA. [Payson, Mark] Dominion Fertil, Arlington, VA USA. [Payson, Mark] Inova Fairfax Hosp Womens Ctr, Falls Church, VA USA. RP Yauger, BJ (reprint author), Walter Reed Natl Mil Med Ctr, Dept Obstet & Gynecol, 4494 North Palmer Rd, Bethesda, MD 20889 USA. EM belinda.j.yauger.mil@mail.mil FU Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported, in part, by the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 22 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD AUG PY 2016 VL 106 IS 2 BP 311 EP 316 DI 10.1016/j.fertnstert.2016.03.045 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DS4PQ UT WOS:000380763400018 PM 27087400 ER PT J AU Royster, GD Krishnamoorthy, K Csokmay, JM Yauger, BJ Chason, RJ DeCherney, AH Wolff, EF Hill, MJ AF Royster, Greene Donald Krishnamoorthy, Kavitha Csokmay, John M. Yauger, Belinda J. Chason, Rebecca J. DeCherney, Alan H. Wolff, Erin F. Hill, Micah J. TI Are intracytoplasmic sperm injection and high serum estradiol compounding risk factors for adverse obstetric outcomes in assisted reproductive technology? SO FERTILITY AND STERILITY LA English DT Article DE Elevated E-2; adverse obstetric outcomes; IVF; ICSI ID IN-VITRO FERTILIZATION; SINGLETON PREGNANCIES; PERINATAL OUTCOMES; CONCEIVED PREGNANCIES; EMBRYO IMPLANTATION; PREECLAMPSIA; METAANALYSIS AB Objective: To evaluate whether intracytoplasmic sperm injection (ICSI) use and E-2 on the final day of assisted reproductive technology (ART) stimulation are associated with adverse obstetric complications related to placentation. Design: Retrospective cohort study. Setting: Large private ART practice. Patient(s): A total of 383 women who underwent ART resulting in a singleton live birth. Intervention(s): None. Main Outcome Measure(s): Adverse placental outcomes composed of placenta accreta, placental abruption, placenta previa, intrauterine growth restriction, preeclampsia, gestational hypertension, and small for gestational age infants. Result(s): Patients with adverse placental outcomes had higher peak serum E-2 levels and were three times more likely to have used ICSI. Adverse placental outcomes were associated with increasing E-2 (odds ratio 1.36, 95% confidence interval 1.13-1.65) and ICSI (odds ratio 3.86, 95% confidence interval 1.61-9.27). Adverse outcomes increased when E-2 was >3,000 pg/mL and continued to increase in a linear fashion until E-2 was >5,000 pg/mL. The association of ICSI with adverse outcomes was independent of male factor infertility. Interaction testing suggested the adverse effect of E-2 was primarily seen in ICSI cycles, but not in conventional IVF cycles. Estradiol >5,000 pg/mL was associated with adverse placental events in 36% of all ART cycles and 52% of ICSI cycles. Conclusion(s): ICSI and elevated E-2 on the day of hCG trigger were associated with adverse obstetric outcomes related to placentation. The finding of a potential interaction of E-2 and ICSI with adverse placental events is novel and warrants further investigation. (C) 2016 by American Society for Reproductive Medicine. C1 [Royster, Greene Donald; Csokmay, John M.; Yauger, Belinda J.; Chason, Rebecca J.; Hill, Micah J.] Walter Reed Natl Mil Med Ctr, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, Bethesda, MD USA. [Royster, Greene Donald; DeCherney, Alan H.; Wolff, Erin F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Krishnamoorthy, Kavitha] Univ Miami Jackson Hlth Syst, Dept Obstet & Gynecol, Miami, FL USA. RP Royster, GD (reprint author), 10 CRC,Room 1E-3140,10 Ctr Dr MSC 1109, Bethesda, MD 20892 USA. EM DonRoysterMD@gmail.com FU Intramural research program of the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported, in part, by Intramural research program of the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 28 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD AUG PY 2016 VL 106 IS 2 BP 363 EP U181 DI 10.1016/j.fertnstert.2016.04.023 PG 11 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DS4PQ UT WOS:000380763400026 PM 27172401 ER PT J AU Marsh, EE Bernardi, LA Steinberg, ML de Chavez, PJ Visser, JA Carnethon, MR Baird, DD AF Marsh, Erica E. Bernardi, Lia A. Steinberg, Marissa L. de Chavez, Peter J. Visser, Jenny A. Carnethon, Mercedes R. Baird, Donna D. TI Novel correlates between antimullerian hormone and menstrual cycle characteristics in African-American women (23-35 years-old) SO FERTILITY AND STERILITY LA English DT Article DE AMH; ovarian reserve; African-American women ID ANTI-MULLERIAN HORMONE; POLYCYSTIC-OVARY-SYNDROME; REPRODUCTIVE-AGE WOMEN; ANTRAL FOLLICLE COUNT; THYROID AUTOIMMUNITY; CAUCASIAN WOMEN; RESERVE; MENOPAUSE; CONTRACEPTIVES; RECRUITMENT AB Objective: To characterize normative antimullerian hormone (AMH) levels and ascertain which factors are associated with AMH in a large cohort of reproductive-age women. Design: Cross-sectional study. Setting: Not applicable. Patient(s): A total of 1,654 African-American women (AAW) ages 23-34 at recruitment. Intervention(s): Not applicable. Main Outcome Measure(s): Serum AMH measured using an ultrasensitive ELISA. Result(s): The median AMH was 3.18 ng/mL, and there was a significant, but nonlinear, relationship between age and AMH, with levels peaking at age 25. As AMH was not normally distributed, log transformation was performed and used for all analyses. In a multivariable age-adjusted model, body mass index, current use of hormonal contraception, and history of a thyroid condition were inversely associated with AMH, while history of abnormal menstrual bleeding and menstrual cycles longer than 35 days were positively associated with AMH. Conclusion(s): While age is correlated with AMH, it accounts for only a portion of the variation seen. This study adds valuable information to the existing literature on normative AMH levels in young reproductive-age women. While our findings fill a critical data gap for ovarian reserve in AAW, the insights gained will be of benefit for all women. (C) 2016 by American Society for Reproductive Medicine. C1 [Marsh, Erica E.; Bernardi, Lia A.; Steinberg, Marissa L.] Northwestern Univ, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Feinberg Sch Med, Chicago, IL 60611 USA. [de Chavez, Peter J.; Carnethon, Mercedes R.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Visser, Jenny A.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Baird, Donna D.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Marsh, EE (reprint author), Northwestern Univ, Div Reprod Endocrinol & Infertil, 676 North St Clair St,Suite 1845, Chicago, IL 60611 USA. EM erica-marsh@northwestern.edu RI Visser, Jenny /F-8156-2011; Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU National Institutes of Health (NIH) [P01HD57877, R21 HD077479-01]; Women's Reproductive Health Research Scholar Program at Northwestern [NIH K12HD050121]; RWJ Harold Amos Medical Faculty Development Award; Friends of Prentice Women's Health Research Award; Evergreen Invitational Women's Health Grants Initiative; Woman's Board of Northwestern Memorial Hospital Grant; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX Supported by the National Institutes of Health (NIH; grant nos. P01HD57877 and R21 HD077479-01 to E.E.M.), the Women's Reproductive Health Research Scholar Program at Northwestern (grant no. NIH K12HD050121 to E.E.M.), the RWJ Harold Amos Medical Faculty Development Award (to E.E.M.), the Friends of Prentice Women's Health Research Award (to E.E.M.), the Evergreen Invitational Women's Health Grants Initiative (to E.E.M.), and the Woman's Board of Northwestern Memorial Hospital Grant (to L.A.B.). In addition, this research was supported in part (ongoing salary for D.D.B.) by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 48 TC 2 Z9 2 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD AUG PY 2016 VL 106 IS 2 BP 443 EP U271 DI 10.1016/j.fertnstert.2016.04.008 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DS4PQ UT WOS:000380763400037 PM 27114331 ER PT J AU Doran, AG Wong, K Flint, J Adams, DJ Hunter, KW Keane, TM AF Doran, Anthony G. Wong, Kim Flint, Jonathan Adams, David J. Hunter, Kent W. Keane, Thomas M. TI Deep genome sequencing and variation analysis of 13 inbred mouse strains defines candidate phenotypic alleles, private variation and homozygous truncating mutations SO GENOME BIOLOGY LA English DT Article DE Sequencing; Mouse genomes; Laboratory mouse; Genomic variation; Disease; Cancer; arthritis; Biological pathways ID PHOSPHATIDYLCHOLINE TRANSFER PROTEIN; DNA MISMATCH-REPAIR; PHOSPHORYLASE-KINASE DEFICIENCY; COLLAGEN-INDUCED ARTHRITIS; RHEUMATOID-ARTHRITIS; PROMOTER POLYMORPHISMS; EXTRACELLULAR-MATRIX; STRUCTURAL VARIATION; PROSTATE-CANCER; GASTRIC-CANCER AB Background: The Mouse Genomes Project is an ongoing collaborative effort to sequence the genomes of the common laboratory mouse strains. In 2011, the initial analysis of sequence variation across 17 strains found 56.7 M unique single nucleotide polymorphisms (SNPs) and 8.8 M indels. We carry out deep sequencing of 13 additional inbred strains (BUB/BnJ, C57BL/10J, C57BR/cdJ, C58/J, DBA/1J, I/LnJ, KK/HiJ, MOLF/EiJ, NZB/B1NJ, NZW/LacJ, RF/J, SEA/GnJ and ST/bJ), cataloguing molecular variation within and across the strains. These strains include important models for immune response, leukaemia, age-related hearing loss and rheumatoid arthritis. We now have several examples of fully sequenced closely related strains that are divergent for several disease phenotypes. Results: Approximately 27.4 M unique SNPs and 5 M indels are identified across these strains compared to the C57BL/6 J reference genome (GRCm38). The amount of variation found in the inbred laboratory mouse genome has increased to 71 M SNPs and 12 M indels. We investigate the genetic basis of highly penetrant cancer susceptibility in RF/J finding private novel missense mutations in DNA damage repair and highly cancer associated genes. We use two highly related strains (DBA/1J and DBA/2J) to investigate the genetic basis of collagen-induced arthritis susceptibility. Conclusions: This paper significantly expands the catalogue of fully sequenced laboratory mouse strains and now contains several examples of highly genetically similar strains with divergent phenotypes. We show how studying private missense mutations can lead to insights into the genetic mechanism for a highly penetrant phenotype. C1 [Hunter, Kent W.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Doran, Anthony G.; Wong, Kim; Adams, David J.; Keane, Thomas M.] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England. [Flint, Jonathan] Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England. RP Hunter, KW (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA.; Keane, TM (reprint author), Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England. EM hunterk@mail.nih.gov; tk2@sanger.ac.uk OI Doran, Anthony/0000-0003-3061-4102; Keane, Thomas/0000-0001-7532-6898 FU Medical Research Council [MR/L007428/1]; BBSRC [BB/M000281/1]; Wellcome Trust; Cancer Research UK; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by the Medical Research Council (MR/L007428/1), BBSRC (BB/M000281/1) and the Wellcome Trust. DJA is supported by Cancer Research UK and the Wellcome Trust. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 100 TC 1 Z9 1 U1 5 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD AUG 1 PY 2016 VL 17 AR 167 DI 10.1186/s13059-016-1024-y PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DS5XB UT WOS:000380855200001 PM 27480531 ER PT J AU Hohenadel, MG Baier, LJ Piaggi, P Muller, YL Hanson, RL Krakoff, J Thearle, MS AF Hohenadel, M. G. Baier, L. J. Piaggi, P. Muller, Y. L. Hanson, R. L. Krakoff, J. Thearle, M. S. TI The impact of genetic variants on BMI increase during childhood versus adulthood SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article ID BODY-MASS INDEX; MELANOCORTIN-4 RECEPTOR GENE; PIMA-INDIANS; AMERICAN-INDIANS; ENERGY-EXPENDITURE; OBESITY; WEIGHT; RISK; ASSOCIATION; ADIPOSITY AB BACKGROUND: Genetic variants that predispose individuals to obesity may have differing influences during childhood versus adulthood, and additive effects of such variants are likely to occur. Our ongoing studies to identify genetic determinants of obesity in American Indians have identified 67 single-nucleotide polymorphisms (SNPs) that reproducibly associate with maximum lifetime non-diabetic body mass index (BMI). This study aimed to identify when, during the lifetime, these variants have their greatest impact on BMI increase. SUBJECTS/METHODS: A total of 5906 Native Americans of predominantly Pima Indian heritage with repeated measures of BMI between the ages of 5 and 45 years were included in this study. The association between each SNP with the rates of BMI increase during childhood (5-19 years) and adulthood (20-45 years) were assessed separately. The significant SNPs were used to calculate a cumulative allelic risk score (ARS) for childhood and adulthood, respectively, to assess the additive effect of these variants within each period of life. RESULTS: The majority of these SNPs (36 of 67) were associated with rate of BMI increase during childhood (P-value range: 0.00004-0.05), whereas only nine SNPs were associated with rate of BMI change during adulthood (P-value range: 0.002-0.02). These 36 SNPs associated with childhood BMI gain likely had a cumulative effect as a higher childhood-ARS associated with rate of BMI change (beta=0.032 kg m(-2) per year per risk allele, 95% confidence interval: 0.027-0.036, P<0.0001), such that at age 19 years, individuals with the highest number of risk alleles had a BMI of 10.2 kg m(-2) greater than subjects with the lowest number of risk alleles. CONCLUSIONS: Overall, our data indicates that genetic polymorphisms associated with lifetime BMI may influence the rate of BMI increase during different periods in the life course. The majority of these polymorphisms have a larger impact on BMI during childhood, providing further evidence that prevention of obesity will need to begin early in life. C1 [Hohenadel, M. G.; Baier, L. J.; Piaggi, P.; Muller, Y. L.; Hanson, R. L.; Krakoff, J.; Thearle, M. S.] NIDDKD, Phoenix Epidemiol & Clin Res Branch, 4212N 16th St, Phoenix, AZ 85016 USA. RP Hohenadel, MG (reprint author), NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, 4212N 16th St, Phoenix, AZ 85016 USA. EM maximilian.hohenadel@nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX We gratefully acknowledge the help of the nursing staff, physician assistants, laboratory technicians and dietary staffs of all three branches of the National Institute of Diabetes, Digestive and Kidney Disease in Phoenix, AZ, USA. Most of all, we thank the volunteers for their participation in the studies. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Study protocols are registered under ClinicalTrials.gov: NCT00339482 and NCT00340132. NR 49 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD AUG PY 2016 VL 40 IS 8 BP 1301 EP 1309 DI 10.1038/ijo.2016.53 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA DS4KG UT WOS:000380749400014 PM 27076275 ER PT J AU Coakley, M Hurt, DE AF Coakley, Meghan Hurt, Darrell E. TI 3D Printing in the Laboratory: Maximize Time and Funds with Customized and Open-Source Labware SO JALA LA English DT Article DE 3D printing; computer-assisted design; prototyping; equipment AB 3D printing, also known as additive manufacturing, is the computer-guided process of fabricating physical objects by depositing successive layers of material. It has transformed manufacturing across virtually every industry, bringing about incredible advances in research and medicine. The rapidly growing consumer market now includes convenient and affordable desktop 3D printers. These are being used in the laboratory to create custom 3D-printed equipment, and a growing community of designers are contributing open-source, cost-effective innovations that can be used by both professionals and enthusiasts. User stories from investigators at the National Institutes of Health and the biomedical research community demonstrate the power of 3D printing to save valuable time and funding. While adoption of 3D printing has been slow in the biosciences to date, the potential is vast. The market predicts that within several years, 3D printers could be commonplace within the home; with so many practical uses for 3D printing, we anticipate that the technology will also play an increasingly important role in the laboratory. ?? ?????????????3D?????????????????????????????????????????????????3D printing????????????????????????????????????????????????????????????????????????????????????????3D?????????????????????????????3D?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????3D????????????????????????????3D??????????????????????????????????????????3D????????????????????????????????3D?????????????????????????????????????????????????????????? ?? ?? ????? ??? 3D ???? ??? ???? ?? ???? ?? ??? ???? ??? ?? ??? ???????. ? ??? ?? ?? ??? ?? ?? ??? ??? ???? ??? ?? ??? ??? ??? ??? ????. ??? ???? ??? ??? ?? ???? ??? ???? 3D ???? ???????. ??? ??? 3D ?? ??? ??? ?? ????? ???? ???, ???? ???? ????? ??? ? ??? ??? ??? ? ?? ?? ??? ?????? ??? ???? ????. ?? ???(National Institutes of Health)? ????? ?? ?????? ??? ?? ???, 3D ??? ??? ?? ??? ??? ??? ??? ? ??? ?????. ???? 3D ???? ?????? ??? ?????? ???? ?????. ??? ? ? ??? 3D ???? ?? ??? ???? ??? ?????. ??? ?? 3D ??? ?? ??? ??, ? ??? ?????? ?? ? ??? ??? ? ??? ?????. ?? 3D ??,???????,??????????????????????????????????????????????,?????????????????,???????3D ??????????????????????,????????? 3D ????,???????????????????????,???????????????,??????????????????(National Institutes of Health)??????????????????????,3D ?????????????????????,?? 3D ????????????????,?????????????????,?????,3D ??????????????? 3D ??????,????,??,????,?????????????????? ?? 3D ?????????,???????????????????????????????????????????,?????????????????,?????????3D ??????????????????????,????????? 3D ????,??????????????????????????,???????????????,?????????????????? (National Institutes of Health) ???????????????????????,3D ?????????????????????,?? 3D ????????????????,????????????,?????,3D ???????????????? 3D ??????,????,??,????,??????????????????? C1 [Coakley, Meghan] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, 5601 Fishers Lane 4A33, Bethesda, MD 20852 USA. [Hurt, Darrell E.] Bioinformat & Computat Biosci Branch, Bethesda, MD USA. RP Coakley, M (reprint author), NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, 5601 Fishers Lane 4A33, Bethesda, MD 20852 USA.; Hurt, DE (reprint author), NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, 5601 Fishers Lane,4A50, Bethesda, MD 20852 USA. EM meghan.coakley@nih.gov; darrellh@niaid.nih.gov FU HHS Ignite initiative from the US Department of Health and Human Services; HHS Ventures initiative from the US Department of Health and Human Services FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors are founders and project leads for the NIH 3D Print Exchange. The Exchange is owned and managed by the Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The site was created in collaboration with the Eunice Kennedy Shriver National Institute for Child Health and Human Development and the National Library of Medicine. Initial funding and support for the Exchange were provided in part by HHS Ignite and HHS Ventures, initiatives from the US Department of Health and Human Services. NR 18 TC 2 Z9 2 U1 4 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2211-0682 EI 1540-2452 J9 JALA-J LAB AUTOM JI JALA PD AUG PY 2016 VL 21 IS 4 BP 489 EP 495 DI 10.1177/2211068216649578 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DS7KS UT WOS:000380963000002 PM 27197798 ER PT J AU Zhu, HZ Zhou, P Alcauter, S Chen, YY Cao, HB Tian, M Ming, D Qi, HZ Wang, XM Zhao, X He, F Ni, HY Gao, W AF Zhu, Haoze Zhou, Peng Alcauter, Sarael Chen, Yuanyuan Cao, Hongbao Tian, Miao Ming, Dong Qi, Hongzhi Wang, Xuemin Zhao, Xin He, Feng Ni, Hongyan Gao, Wei TI Changes of intranetwork and internetwork functional connectivity in Alzheimer's disease and mild cognitive impairment SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE Alzheimer's disease; resting state functional magnetic resonance imaging; amnestic mild cognitive impairment; networks ID DEFAULT-MODE NETWORK; RESTING-STATE FMRI; WORKING-MEMORY; EXECUTIVE DYSFUNCTION; SALIENCE NETWORK; BRAIN; TASK; ATTENTION; DEMENTIA; CORTEX AB Objective. Alzheimer's disease (AD) is a serious neurodegenerative disorder characterized by deficits of working memory, attention, language and many other cognitive functions. Although different stages of the disease are relatively well characterized by clinical criteria, stage-specific pathological changes in the brain remain relatively poorly understood, especially at the level of large-scale functional networks. In this study, we aimed to characterize the potential disruptions of large-scale functional brain networks based on a sample including amnestic mild cognition impairment (aMCI) and AD patients to help delineate the underlying stage-dependent AD pathology. Approach. We sought to identify the neural connectivity mechanisms of aMCI and AD through examination of both intranetwork and internetwork interactions among four of the brain's key networks, namely dorsal attention network (DAN), default mode network (DMN), executive control network (ECN) and salience network (SAL). We analyzed functional connectivity based on resting-state functional magnetic resonance imaging (rs-fMRI) data from 25 Alzheimer's disease patients, 20 aMCI patients and 35 elderly normal controls (NC). Main results. Intranetwork functional disruptions within the DAN and ECN were detected in both aMCI and AD patients. Disrupted intranetwork connectivity of DMN and anti-correlation between DAN and DMN were observed in AD patients. Moreover, aMCI-specific alterations in the internetwork functional connectivity of SAL were observed. Significance. Our results confirmed previous findings that AD pathology was related to dysconnectivity both within and between resting-state networks but revealed more spatial details. Moreover, the SAL network, reportedly flexibly coupling either with the DAN or DMN networks during different brain states, demonstrated interesting alterations specifically in the early stage of the disease. C1 [Ni, Hongyan] Tianjin First Ctr Hosp, Radiol Dept, Tianjin, Peoples R China. [Zhu, Haoze; Zhou, Peng; Chen, Yuanyuan; Tian, Miao; Ming, Dong; Qi, Hongzhi; Wang, Xuemin; Zhao, Xin; He, Feng] Tianjin Univ, Sch Precis Instrument & Optoelectr Engn, Tianjin, Peoples R China. [Alcauter, Sarael] Univ Nacl Autonoma Mexico, Inst Neurobiol, Mexico City 04510, DF, Mexico. [Cao, Hongbao] NIH, Dept Mental Hlth, Bldg 10, Bethesda, MD 20892 USA. [Gao, Wei] Cedars Sinai Med Ctr, Biomed Imaging Res Inst, Dept Biomed Sci & Acad Imaging, Los Angeles, CA 90048 USA. RP Ni, HY (reprint author), Tianjin First Ctr Hosp, Radiol Dept, Tianjin, Peoples R China.; Zhou, P (reprint author), Tianjin Univ, Sch Precis Instrument & Optoelectr Engn, Tianjin, Peoples R China.; Gao, W (reprint author), Cedars Sinai Med Ctr, Biomed Imaging Res Inst, Dept Biomed Sci & Acad Imaging, Los Angeles, CA 90048 USA. EM zpzp@tju.edu.cn; nihyan@sina.com; gaow@cshs.org FU National Natural Science Foundation of China [31271062, 81222021, 810171423, 61172008, 51377120, 51007063]; Natural Science Foundation of Tianjin [13JCQNJC13900]; Ministry of Science and Technology of China [2012BAI34B02]; Ministry of Education of China [NCET-10-0618] FX National Natural Science Foundation of China: 31271062, 81222021, 810171423, 61172008, 51377120, 51007063 Natural Science Foundation of Tianjin: 13JCQNJC13900; National Key Technology R&D Program of the Ministry of Science and Technology of China: 2012BAI34B02; Program for New Century Excellent Talents in University of the Ministry of Education of China: NCET-10-0618 NR 0 TC 2 Z9 2 U1 5 U2 11 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 EI 1741-2552 J9 J NEURAL ENG JI J. Neural Eng. PD AUG PY 2016 VL 13 IS 4 AR 046008 DI 10.1088/174-2560/13/4/046008 PG 12 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA DS3FQ UT WOS:000380668900011 PM 27247279 ER PT J AU Pretegiani, E Mari, F Renieri, A Penco, S Dotti, MT AF Pretegiani, Elena Mari, Francesca Renieri, Alessandra Penco, Silvana Dotti, Maria Teresa TI Nicolaides-Baraitser syndrome: defining a phenotype SO JOURNAL OF NEUROLOGY LA English DT Letter ID INTELLECTUAL DISABILITY C1 [Pretegiani, Elena] NEI, Sensorimotor Res Lab, IRP, NIH, 49 Convent Dr,Room 2A50, Bethesda, MD 20892 USA. [Pretegiani, Elena; Dotti, Maria Teresa] Univ Siena, Dept Med Surg & Neurol Sci, Neurodegenerat Dis Unit, Siena, Italy. [Mari, Francesca; Renieri, Alessandra] Univ Siena, Med Genet, Siena, Italy. [Mari, Francesca; Renieri, Alessandra] Azienda Osped Univ Senese, Genet Med, Siena, Italy. [Penco, Silvana] AO Niguarda Ca Granda, Med Genet, Milan, Italy. RP Pretegiani, E (reprint author), NEI, Sensorimotor Res Lab, IRP, NIH, 49 Convent Dr,Room 2A50, Bethesda, MD 20892 USA.; Pretegiani, E (reprint author), Univ Siena, Dept Med Surg & Neurol Sci, Neurodegenerat Dis Unit, Siena, Italy. EM elena.pretegiani@nih.gov NR 10 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5354 EI 1432-1459 J9 J NEUROL JI J. Neurol. PD AUG PY 2016 VL 263 IS 8 BP 1659 EP 1660 DI 10.1007/s00415-016-8194-0 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DS3OH UT WOS:000380691900022 PM 27286846 ER PT J AU Baeksted, C Nissen, A Pappot, H Bidstrup, PE Mitchell, SA Basch, E Dalton, SO Johansen, C AF Baeksted, Christina Nissen, Aase Pappot, Helle Bidstrup, Pernille Envold Mitchell, Sandra A. Basch, Ethan Dalton, Susanne Oksbjerg Johansen, Christoffer TI Danish Translation and Linguistic Validation of the US National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Patient-reported outcomes; PRO-CTCAE; linguistic validation; symptomatic toxicity; treatment adverse events; cancer clinical trials ID SYMPTOMS AB Context. The Common Terminology Criteria for Adverse Events (CTCAE) is the basis for standardized clinician-based grading and reporting of adverse events in cancer clinical trials. The U.S. National Cancer Institute has developed the PatientReported Outcomes version of the CTCAE (PRO-CTCAE) to incorporate patient self-reporting of symptomatic adverse events. Objectives. The aim of the study was to translate and linguistically validate a Danish language version of PRO-CTCAE. Methods. The U.S. English language PRO-CTCAE was translated into Danish using forward and backward procedures with reconciliation. The linguistic validity of the PRO-CTCAE Danish was examined in two successive rounds of semistructured cognitive interviews in a sample of 56 patients equally distributed by gender and cancer type (prostate, head and neck, lung, breast, gynecological, gastrointestinal, and hematological cancer), and who were currently undergoing cancer treatment. Results. In the first round of linguistic validation (n = 42), the phrasing of five symptomatic toxicities was adjusted, and the refined phrasing was retested in a second round of interviews (n = 14). Agreement about phrasing that was both culturally acceptable and semantically comprehensible was achieved in the second round. Statements from participants describing the meaning of the PRO-CTCAE symptomatic toxicities support conceptual equivalence to the U.S. English language version. Conclusion. Availability of the NCI PRO-CTCAE in languages beyond English will support international congruence in selfreporting of side effects of cancer treatment. A rigorous methodology was used to develop the Danish language version of PRO-CTCAE. Results provide preliminary support for the use of PRO-CTCAE in cancer clinical trials that include Danish speakers. (C) 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Baeksted, Christina; Nissen, Aase] Danish Canc Soc, Unit Documentat & Qual, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. [Bidstrup, Pernille Envold; Dalton, Susanne Oksbjerg; Johansen, Christoffer] Danish Canc Soc, Unit Survivorship, Copenhagen, Denmark. [Baeksted, Christina; Pappot, Helle; Johansen, Christoffer] Rigshosp, Finsen Ctr, Dept Oncol, Copenhagen, Denmark. [Mitchell, Sandra A.] NCI, Div Canc Control & Populat Sci, Outcomes Res Branch, Rockville, MD USA. [Basch, Ethan] Univ N Carolina, Lineberger Comprehens Canc Ctr, Canc Outcomes Res Program, Chapel Hill, NC USA. RP Baeksted, C (reprint author), Danish Canc Soc, Unit Documentat & Qual, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. EM baeksted@cancer.dk FU Danish Cancer Society [127 12 004-9102]; Department of Oncology, Rigshospitalet, Copenhagen University Hospital FX This study was supported by grants from the Danish Cancer Society (127 12 004-9102) and Department of Oncology, Rigshospitalet, Copenhagen University Hospital. The authors declare that they have no conflicts of interest. NR 15 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD AUG PY 2016 VL 52 IS 2 BP 292 EP 297 DI 10.1016/j.jpainsymman.2016.02.008 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA DT7RD UT WOS:000381683000020 ER PT J AU Toprani, VM Joshi, SB Kueltzo, LA Schwartz, RM Middaugh, CR Volkin, DB AF Toprani, Vishal M. Joshi, Sangeeta B. Kueltzo, Lisa A. Schwartz, Richard M. Middaugh, C. Russell Volkin, David B. TI A Micro-Polyethylene Glycol Precipitation Assay as a Relative Solubility Screening Tool for Monoclonal Antibody Design and Formulation Development SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE solubility; monoclonal antibody; VRC01; HIV; polyethylene glycol; formulation; candidate selection; comparability; stability ID PROTEIN CONCENTRATION FORMULATIONS; BROADLY NEUTRALIZING ANTIBODIES; COMPARABILITY ASSESSMENTS; HIV-1 NEUTRALIZATION; EXCLUDED-VOLUME; SERUM-ALBUMIN; MECHANISM; VACCINE AB Adequate protein solubility is an important prerequisite for development, manufacture, and administration of biotherapeutic drug candidates, especially for high-concentration protein formulations. A previously established method for determining the relative apparent solubility (thermodynamic activity) of proteins using polyethylene glycol (PEG) precipitation is adapted for screening and comparing monoclonal antibody (mAb) candidates where only limited quantities (<= 1 mg) are available. This micro-PEG assay is used to evaluate various broadly neutralizing mAb candidates to HIV-1 viral spike (gp120 and gp41 glycoproteins). Using similar to 1 mg of VRC01-WT mAb per assay, the precision of the micro-PEG assay was established. A series of 7 different broadly neutralizing mAbs to the HIV-1 viral spike proteins were compared by curve shape (%PEG vs. protein concentration), %PEG(midpoint) determinations, and extrapolated apparent solubility values. Numerous formulation conditions were then evaluated for their relative effects on the VRC01-WT mAb. The PEG(midpt) and apparent solubility values of VRC01-WT mAb decreased as the solution pH increased and increased as NaCl and arginine were added. A final optimization of the micro-PEG assay established that amounts as low as 0.1-0.2 mg can be used. Thus, the micro-PEG assay has significant potential as a relative solubility screening tool during candidate selection and early formulation development. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Toprani, Vishal M.; Joshi, Sangeeta B.; Middaugh, C. Russell; Volkin, David B.] Univ Kansas, Macromol & Vaccine Stabilizat Ctr, Dept Pharmaceut Chem, 2030 Becker Dr, Lawrence, KS 66047 USA. [Kueltzo, Lisa A.; Schwartz, Richard M.] NIAID, Vaccine Prod Program, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Volkin, DB (reprint author), Univ Kansas, Macromol & Vaccine Stabilizat Ctr, Dept Pharmaceut Chem, 2030 Becker Dr, Lawrence, KS 66047 USA. EM volkin@ku.edu FU Vaccine Research Center (NIAID/NIH); Gilead Sciences, Inc. FX The University of Kansas authors wish to thank and acknowledge Vaccine Research Center (NIAID/NIH) for providing the mAbs and financial support of this study. Additional financial support for V. M. Toprani was also provided by a graduate student fellowship from Gilead Sciences, Inc. NR 40 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD AUG PY 2016 VL 105 IS 8 BP 2319 EP 2327 DI 10.1016/j.xphs.2016.05.021 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DT8UE UT WOS:000381770400010 PM 27368120 ER PT J AU Torain, MJ Maragh-Bass, AC Dankwa-Mullen, I Hisam, B Kodadek, LM Lilley, EJ Najjar, P Changoor, NR Rose, JA Zogg, CK Maddox, YT Britt, LD Haider, AH AF Torain, Maya J. Maragh-Bass, Allysha C. Dankwa-Mullen, Irene Hisam, Butool Kodadek, Lisa M. Lilley, Elizabeth J. Najjar, Peter Changoor, Navin R. Rose, John A., Jr. Zogg, Cheryl K. Maddox, Yvonne T. Britt, L. D. Haider, Adil H. TI Surgical Disparities: A Comprehensive Review and New Conceptual Framework SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Review ID TRAUMATIC BRAIN-INJURY; MINIMALLY INVASIVE SURGERY; HIGH-VOLUME HOSPITALS; SOCIAL-CLASS BIAS; RACIAL DISPARITIES; SOCIOECONOMIC-STATUS; UNITED-STATES; RACIAL/ETHNIC DISPARITIES; UNCONSCIOUS RACE; CANCER-SURGERY C1 [Torain, Maya J.; Maragh-Bass, Allysha C.; Hisam, Butool; Lilley, Elizabeth J.; Najjar, Peter; Changoor, Navin R.; Rose, John A., Jr.; Zogg, Cheryl K.; Haider, Adil H.] Harvard Med Sch, Brigham & Womens Hosp, Dept Surg, Ctr Surg & Publ Hlth, Boston, MA USA. [Torain, Maya J.; Maragh-Bass, Allysha C.; Hisam, Butool; Lilley, Elizabeth J.; Najjar, Peter; Changoor, Navin R.; Rose, John A., Jr.; Zogg, Cheryl K.; Haider, Adil H.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Dankwa-Mullen, Irene] Natl Inst Minor Hlth & Hlth Dispar, Bethesda, MD USA. [Maddox, Yvonne T.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Hisam, Butool] Dow Univ Hlth Sci, Coll Med, Karachi, Pakistan. [Kodadek, Lisa M.] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. [Britt, L. D.] Eastern Virginia Med Sch, Dept Surg, Norfolk, VA 23501 USA. RP Haider, AH (reprint author), Ctr Surg & Publ Hlth, 1620 Tremont St,Suite 4-020, Boston, MA 02120 USA. EM ahhaider@partners.org FU National Institutes of Health (NIH); American College of Surgeons (ACS) Summit on Surgical Disparities Research FX The research was supported in its completion by the planning committee of the 2015 National Institutes of Health (NIH) and American College of Surgeons (ACS) Summit on Surgical Disparities Research. The ACS was represented by Drs LD Britt, Adil H Haider, and Beth Sutton; the NIH was represented by Drs Yvonne Maddox, Irene Dankwa-Mullen, Claudette Brooks, and Salina Waddy. The NIH guided the creation of the theoretical framework for the present research; the ACS has provided a searchable database that now contains the results of our literature review (available at: https://www.facs.org/health-care-disparities/search). We would also like to thank Anju Ranjit, MD, MPH, from the Center for Surgery and Public Health in Boston, MA, for her assistance with developing the PROSPERO listing of the review methodology. NR 86 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD AUG PY 2016 VL 223 IS 2 BP 408 EP 418 DI 10.1016/j.jamcollsurg.2016.04.047 PG 11 WC Surgery SC Surgery GA DS4KY UT WOS:000380751200027 PM 27296524 ER PT J AU Chang, LW Grabowski, MK Ssekubugu, R Nalugoda, F Kigozi, G Nantume, B Lessler, J Moore, SM Quinn, TC Reynolds, SJ Gray, RH Serwadda, D Wawer, MJ AF Chang, Larry W. Grabowski, Mary K. Ssekubugu, Robert Nalugoda, Fred Kigozi, Godfrey Nantume, Betty Lessler, Justin Moore, Sean M. Quinn, Thomas C. Reynolds, Steven J. Gray, Ronald H. Serwadda, David Wawer, Maria J. TI Heterogeneity of the HIV epidemic in agrarian, trading, and fishing communities in Rakai, Uganda: an observational epidemiological study SO LANCET HIV LA English DT Article ID LAKE VICTORIA; RISK-FACTORS; PREVALENCE; DISEASE; PRIORITIZATION; PREVENTION; INFECTION; DISTRICT; SPREAD; MODEL AB Background Understanding the extent to which HIV burden differs across communities and the drivers of local disparities is crucial for an effective and targeted HIV response. We assessed community-level variations in HIV prevalence, risk factors, and treatment and prevention service uptake in Rakai, Uganda. Methods The Rakai Community Cohort Study (RCCS) is an open, population-based cohort of people aged 15-49 years in 40 communities. Participants are HIV tested and interviewed to obtain sociodemographic, behavioural, and health information. RCCS data from Aug 10, 2011, to May 30, 2013, were used to classify communities as agrarian (n=27), trading (n=9), or lakeside fishing sites (n=4). We mapped HIV prevalence with Bayesian methods, and characterised variability across and within community classifications. We also assessed differences in HIV risk factors and uptake of antiretroviral therapy and male circumcision between community types. Findings 17119 individuals were included, 9215 (54%) of whom were female. 9931 participants resided in agrarian, 3318 in trading, and 3870 in fishing communities. Median HIV prevalence was higher in fishing communities (42%, range 38-43) than in trading (17%, 11-21) and agrarian communities (14%, 9-26). Antiretroviral therapy use was significantly lower in both men and women in fishing communities than in trading (age-adjusted prevalence risk ratio in men 0.64, 95% CI 0.44-0.97; women 0.53, 0.42-0.66) and agrarian communities (men 0.55, 0. 42-0.72; women 0.65, 0.54-0.79), as was circumcision coverage among men (vs trading 0.48, 0.42-0.55; vs agrarian 0.64, 0.56-0.72). Self-reported risk behaviours were significantly higher in men than in women and in fishing communities than in other community types. Interpretation Substantial heterogeneity in HIV prevalence, risk factors, and service uptake in Rakai, Uganda, emphasises the need for local surveillance and the design of targeted HIV responses. High HIV burden, risk behaviours, and low use of combination HIV prevention in fishing communities make these populations a priority for intervention. C1 [Chang, Larry W.; Quinn, Thomas C.; Reynolds, Steven J.] Johns Hopkins Sch Med, Div Infect Dis, Dept Med, Baltimore, MD USA. [Chang, Larry W.; Grabowski, Mary K.; Ssekubugu, Robert; Nalugoda, Fred; Kigozi, Godfrey; Nantume, Betty; Gray, Ronald H.; Serwadda, David; Wawer, Maria J.] Rakai Hlth Sci Program, Entebbe, Uganda. [Chang, Larry W.; Grabowski, Mary K.; Lessler, Justin; Moore, Sean M.; Gray, Ronald H.; Wawer, Maria J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Chang, Larry W.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Social & Behav Intervent Program, Baltimore, MD USA. [Quinn, Thomas C.; Reynolds, Steven J.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. RP Chang, LW (reprint author), Johns Hopkins Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. EM lchang8@jhmi.edu FU National Institute of Mental Health [K23MH086338, R01MH107275]; National Institute of Allergy and Infectious Diseases [U01AI100031, R01AI110324, R01AI102939]; National Institute of Child Health and Development [RO1HD070769, R01HD050180]; National Institute for Allergy and Infectious Diseases Division of Intramural Research, National Institutes of Health; Bill & Melinda Gates Foundation [22006.02]; Johns Hopkins University Center for AIDS Research [P30AI094189] FX We thank the participants of the RH SP RCCS. This study was supported by the National Institute of Mental Health (K23MH086338, R01MH107275), the National Institute of Allergy and Infectious Diseases (R01AI110324, U01AI100031, R01AI110324, R01AI102939), the National Institute of Child Health and Development (RO1HD070769, R01HD050180), and the National Institute for Allergy and Infectious Diseases Division of Intramural Research, National Institutes of Health; the Bill & Melinda Gates Foundation (22006.02); and the Johns Hopkins University Center for AIDS Research (P30AI094189). NR 28 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 2352-3018 J9 LANCET HIV JI Lancet HIV PD AUG PY 2016 VL 3 IS 8 BP E388 EP E396 DI 10.1016/S2352-3018(16)30034-0 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DS5SK UT WOS:000380842400011 PM 27470029 ER PT J AU Wang, HD Wolock, TM Carter, A Nguyen, G Kyu, HH Gakidou, E Hay, SI Mills, EJ Trickey, A Msemburi, W Coates, MM Mooney, MD Fraser, MS Sligar, A Salomon, J Larson, HJ Friedman, J Abajobir, AA Abate, KH Abbas, KM Abd El Razek, MM Abd-Allah, F Abdulle, AM Abera, SF Abubakar, I Abu-Raddad, LJ Abu-Rmeileh, NME Abyu, GY Adebiyi, AO Adedeji, IA Adelekan, AL Adofo, K Adou, AK Ajala, ON Akinyemiju, TF Akseer, N Al Lami, FH Al-Aly, Z Alam, K Alam, NKM Alasfoor, D Aldhahri, SFS Aldridge, RW Alegretti, MA Aleman, AV Alemu, ZA Alfonso-Cristancho, R Ali, R Alkerwi, A Alla, F Al-Raddadi, RMS Alsharif, U Alvarez, E Alvis-Guzman, N Amare, AT Amberbir, A Amegah, AK Ammar, W Amrock, SM Antonio, CAT Anwari, P Auml;rnlov, J Al Artaman, Asayesh, H Asghar, RJ Assadi, R Atique, S Atkins, LS Avokpaho, EFGA Awasthi, A Quintanilla, BPA Bacha, U Badawi, A Barac, A Barnighausen, T Basu, A Bayou, TA Bayou, YT Bazargan-Hejazi, S Beardsley, J Bedi, N Bennett, DA Bensenor, IM Betsu, BD Beyene, AS Bhatia, E Bhutta, ZA Biadgilign, S Bikbov, B Birlik, SM Bisanzio, D Brainin, M Brazinova, A Breitborde, NJK Brown, A Burch, M Butt, ZA Campuzano, JC Cardenas, R Carrero, JJ Castaneda-Orjuela, CA Rivas, JC Catala-Lopez, F Chang, HY Chang, JC Chavan, L Chen, WQ Chiang, PPC Chibalabala, M Chisumpa, VH Choi, JYJ Christopher, DJ Ciobanu, LG Cooper, C Dahiru, T Damtew, SA Dandona, L Dandona, R das Neves, J de Jager, P De Leo, D Degenhardt, L Dellavalle, RP Deribe, K Deribew, A Jarlais, DCD Dharmaratne, SD Ding, EL Doshi, PP Driscoll, TR Dubey, M Elshrek, YM Elyazar, I Endries, AY Ermakov, SP Eshrati, B Esteghamati, A Faghmous, IDA Sofia e Sa Farinha, C Faro, A Farvid, MS Farzadfar, F Fereshtehnejad, SM Fernandes, JC Fischer, F Fitchett, JRA Foigt, N Fullman, N Furst, T Gankpe, FG Gebre, T Gebremedhin, AT Gebru, AA Geleijnse, JM Gessner, BD Gething, PW Ghiwot, TT Giroud, M Gishu, MD Glaser, E Goenka, S Goodridge, A Gopalani, SV Goto, A Gugnani, HC Guimaraes, MDC Gupta, R Gupta, R Gupta, V Haagsma, J Hafezi-Nejad, N Hagan, H Hailu, GB Hamadeh, RR Hamidi, S Hammami, M Hankey, GJ Hao, YT Harb, HL Harikrishnan, S Haro, JM Harun, KM Havmoeller, R Hedayati, MT Heredia-Pi, IB Hoek, HW Horino, M Horita, N Hosgood, HD Hoy, DG Hsairi, M Hu, GQ Huang, H Huang, JJ Iburg, KM Idrisov, BT Innos, K Iyer, VJ Jacobsen, KH Jahanmehr, N Jakovljevic, MB Javanbakht, M Jayatilleke, AU Jeemon, P Jha, V Jiang, GH Jiang, Y Jibat, T Jonas, JB Kabir, Z Kamal, R Kan, HD Karch, A Karema, CK Karletsos, D Kasaeian, A Kaul, A Kawakami, N Kayibanda, JF Keiyoro, PN Kemp, AH Kengne, AP Kesavachandran, CN Khader, YS Khalil, I Khan, AR Khan, EA Khang, YH Khubchandani, J Kim, YJ Kinfu, Y Kivipelto, M Kokubo, Y Kosen, S Koul, PA Koyanagi, A Defo, BK Bicer, BK Kulkarni, VS Kumar, GA Lal, DK Lam, H Lam, JO Langan, SM Lansingh, VC Larsson, A Leigh, J Leung, R Li, YM Lim, SS Lipshultz, SE Liu, SW Lloyd, BK Logroscino, G Lotufo, PA Lunevicius, R Abd El Razek, HM Mahdavi, M Majdan, M Majeed, A Makhlouf, C Malekzadeh, R Mapoma, CC Marcenes, W Martinez-Raga, J Marzan, MB Masiye, F Mason-Jones, AJ Mayosi, BM Mckee, M Meaney, PA Mehndiratta, MM Mekonnen, AB Melaku, YA Memiah, P Memish, ZA Mendoza, W Meretoja, A Meretoja, TJ Mhimbira, FA Miller, TR Mikesell, J Mirarefin, M Mohammad, KA Mohammed, S Mokdad, AH Monasta, L Moradi-Lakeh, M Mori, R Mueller, UO Murimira, B Murthy, GVS Naheed, A Naldi, L Nangia, V Nash, D Nawaz, H Nejjari, C Ngalesoni, FN Ngirabega, JDD Le Nguyen, Q Nisar, MI Norheim, OF Norman, RE Nyakarahuka, L Ogbo, FA Oh, IH Ojelabi, FA Olusanya, BO Olusanya, JO Opio, JN Oren, E Ota, E Padukudru, MA Park, HY Park, JH Patil, ST Patten, SB Paul, VK Pearson, K Peprah, EK Pereira, CC Perico, N Pesudovs, K Petzold, M Phillips, MR Pillay, JD Plass, D Polinder, S Pourmalek, F Prokop, DM Qorbani, M Rafay, A Rahimi, K Rahimi-Movaghar, V Rahman, M Rahman, MHU Rahman, SU Rai, RK Rajsic, S Ram, U Rana, SM Rao, PV Remuzzi, G Rojas-Rueda, D Ronfani, L Roshandel, G Roy, A Ruhago, GM Saeedi, MY Sagar, R Saleh, MM Sanabria, JR Santos, IS Sarmiento-Suarez, R Sartorius, B Sawhney, M Schutte, AE Schwebel, DC Seedat, S Sepanlou, SG Servan-Mori, EE Shaikh, MA Sharma, R She, J Sheikhbahaei, S Shen, JB Shibuya, K Shin, HH Sigfusdottir, ID Silpakit, N Silva, DAS Silveira, DGA Simard, EP Sindi, S Singh, JA Singh, OP Singh, PK Skirbekk, V Sliwa, K Soneji, S Sorensen, RJD Soriano, JB Soti, DO Sreeramareddy, CT Stathopoulou, V Steel, N Sunguya, BF Swaminathan, S Sykes, BL Tabares-Seisdedos, R Talongwa, RT Tavakkoli, M Taye, B Tedla, BA Tekle, T Shifa, GT Temesgen, AM Terkawi, AS Tesfay, FH Tessema, GA Thapa, K Thomson, AJ Thorne-Lyman, AL Tobe-Gai, R Topor-Madry, R Towbin, JA Tran, BX Dimbuene, ZT Tsilimparis, N Tura, AK Ukwaja, KN Uneke, CJ Uthman, OA Venketasubramanian, N Vladimirov, SK Vlassov, VV Vollset, SE Wang, LH Weiderpass, E Weintraub, RG Werdecker, A Westerman, R Wijeratne, T Wilkinson, JD Wiysonge, CS Wolfe, CDA Won, SH Wong, JQ Xu, GL Yadav, AK Yakob, B Yalew, AZ Yano, YC Yaseri, M Yebyo, HG Yip, P Yonemoto, N Yoon, SJ Younis, MZ Yu, CH Yu, SC Zaidi, Z Zaki, ME Zeeb, H Zhang, H Zhao, Y Zodpey, S Zoeckler, L Zuhlke, LJ Lopez, AD Murray, CJL AF Wang, Haidong Wolock, Tim M. Carter, Austin Nguyen, Grant Kyu, Hmwe Hmwe Gakidou, Emmanuela Hay, Simon I. Mills, Edward J. Trickey, Adam Msemburi, William Coates, Matthew M. Mooney, Meghan D. Fraser, Maya S. Sligar, Amber Salomon, Joshua Larson, Heidi J. Friedman, Joseph Abajobir, Amanuel Alemu Abate, Kalkidan Hassen Abbas, Kaja M. Abd El Razek, Mohamed Magdy Abd-Allah, Foad Abdulle, Abdishakur M. Abera, Semaw Ferede Abubakar, Ibrahim Abu-Raddad, Laith J. Abu-Rmeileh, Niveen M. E. Abyu, Gebre Yitayih Adebiyi, Akindele Olupelumi Adedeji, Isaac Akinkunmi Adelekan, Ademola Lukman Adofo, Koranteng Adou, Arsene Kouablan Ajala, Oluremi N. Akinyemiju, Tomi F. Akseer, Nadia Al Lami, Faris Hasan Al-Aly, Ziyad Alam, Khurshid Alam, Noore K. M. Alasfoor, Deena Aldhahri, Saleh Fahed S. Aldridge, Robert William Alegretti, Miguel Angel Aleman, Alicia V. Alemu, Zewdie Aderaw Alfonso-Cristancho, Rafael Ali, Raghib Alkerwi, Ala'a Alla, Francois Al-Raddadi, Rajaa Mohammad Salem Alsharif, Ubai Alvarez, Elena Alvis-Guzman, Nelson Amare, Azmeraw T. Amberbir, Alemayehu Amegah, Adeladza Kofi Ammar, Walid Amrock, Stephen Marc Antonio, Carl Abelardo T. Anwari, Palwasha Arnlov, Johan Al Artaman Asayesh, Hamid Asghar, Rana Jawad Assadi, Reza Atique, Suleman Atkins, Lydia S. Avokpaho, Euripide Frinel G. Arthur Awasthi, Ashish Quintanilla, Beatriz Paulina Ayala Bacha, Umar Badawi, Alaa Barac, Aleksandra Barnighausen, Till Basu, Arindam Bayou, Tigist Assefa Bayou, Yibeltal Tebekaw Bazargan-Hejazi, Shahrzad Beardsley, Justin Bedi, Neeraj Bennett, Derrick A. Bensenor, Isabela M. Betsu, Balem Demtsu Beyene, Addisu Shunu Bhatia, Eesh Bhutta, Zulfiqar A. Biadgilign, Sibhatu Bikbov, Boris Birlik, Sait Mentes Bisanzio, Donal Brainin, Michael Brazinova, Alexandra Breitborde, Nicholas J. K. Brown, Alexandria Burch, Michael Butt, Zahid A. Campuzano, Julio Cesar Cardenas, Rosario Carrero, Juan Jesus Castaneda-Orjuela, Carlos A. Rivas, Jacqueline Castillo Catala-Lopez, Ferran Chang, Hsing-Yi Chang, Jung-chen Chavan, Laxmikant Chen, Wanqing Chiang, Peggy Pei-Chia Chibalabala, Mirriam Chisumpa, Vesper Hichilombwe Choi, Jee-Young Jasmine Christopher, Devasahayam Jesudas Ciobanu, Liliana G. Cooper, Cyrus Dahiru, Tukur Damtew, Solomon Abreha Dandona, Lalit Dandona, Rakhi das Neves, Jose de Jager, Pieter De Leo, Diego Degenhardt, Louisa Dellavalle, Robert P. Deribe, Kebede Deribew, Amare Jarlais, Don C. Des Dharmaratne, Samath D. Ding, Eric L. Doshi, Pratik Pinal Driscoll, Tim R. Dubey, Manisha Elshrek, Yousef Mohamed Elyazar, Iqbal Endries, Aman Yesuf Ermakov, Sergey Petrovich Eshrati, Babak Esteghamati, Alireza Faghmous, Imad D. A. Sofia e Sa Farinha, Carla Faro, Andre Farvid, Maryam S. Farzadfar, Farshad Fereshtehnejad, Seyed-Mohammad Fernandes, Joao C. Fischer, Florian Fitchett, Joseph Robert Ander Foigt, Nataliya Fullman, Nancy Furst, Thomas Gankpe, Fortune Gbetoho Gebre, Teshome Gebremedhin, Amanuel Tesfay Gebru, Alemseged Aregay Geleijnse, Johanna M. Gessner, Bradford D. Gething, Peter W. Ghiwot, Tsegaye Tewelde Giroud, Maurice Gishu, Melkamu Dedefo Glaser, Elizabeth Goenka, Shifalika Goodridge, Amador Gopalani, Sameer Vali Goto, Atsushi Gugnani, Harish Chander Guimaraes, Mark D. C. Gupta, Rahul Gupta, Rajeev Gupta, Vipin Haagsma, Juanita Hafezi-Nejad, Nima Hagan, Holly Hailu, Gessessew Bugssa Hamadeh, Randah Ribhi Hamidi, Samer Hammami, Mouhanad Hankey, Graeme J. Hao, Yuantao Harb, Hilda L. Harikrishnan, Sivadasanpillai Haro, Josep Maria Harun, Kimani M. Havmoeller, Rasmus Hedayati, Mohammad T. Heredia-Pi, Ileana Beatriz Hoek, Hans W. Horino, Masako Horita, Nobuyuki Hosgood, H. Dean Hoy, Damian G. Hsairi, Mohamed Hu, Guoqing Huang, Hsiang Huang, John J. Iburg, Kim Moesgaard Idrisov, Bulat T. Innos, Kaire Iyer, Veena J. Jacobsen, Kathryn H. Jahanmehr, Nader Jakovljevic, Mihajlo B. Javanbakht, Mehdi Jayatilleke, Achala Upendra Jeemon, Panniyammakal Jha, Vivekanand Jiang, Guohong Jiang, Ying Jibat, Tariku Jonas, Jost B. Kabir, Zubair Kamal, Ritul Kan, Haidong Karch, Andre Karema, Corine Kakizi Karletsos, Dimitris Kasaeian, Amir Kaul, Anil Kawakami, Norito Kayibanda, Jeanne Francoise Keiyoro, Peter Njenga Kemp, Andrew Haddon Kengne, Andre Pascal Kesavachandran, Chandrasekharan Nair Khader, Yousef Saleh Khalil, Ibrahim Khan, Abdur Rahman Khan, Ejaz Ahmad Khang, Young-Ho Khubchandani, Jagdish Kim, Yun Jin Kinfu, Yohannes Kivipelto, Miia Kokubo, Yoshihiro Kosen, Soewarta Koul, Parvaiz A. Koyanagi, Ai Defo, Barthelemy Kuate Bicer, Burcu Kucuk Kulkarni, Veena S. Kumar, G. Anil Lal, Dharmesh Kumar Lam, Hilton Lam, Jennifer O. Langan, Sinead M. Lansingh, Van C. Larsson, Anders Leigh, James Leung, Ricky Li, Yongmei Lim, Stephen S. Lipshultz, Steven E. Liu, Shiwei Lloyd, Belinda K. Logroscino, Giancarlo Lotufo, Paulo A. Lunevicius, Raimundas Abd El Razek, Hassan Magdy Mahdavi, Mahdi Majdan, Marek Majeed, Azeem Makhlouf, Carla Malekzadeh, Reza Mapoma, Chabila C. Marcenes, Wagner Martinez-Raga, Jose Marzan, Melvin Barrientos Masiye, Felix Mason-Jones, Amanda J. Mayosi, Bongani M. Mckee, Martin Meaney, Peter A. Mehndiratta, Man Mohan Mekonnen, Alemayehu B. Melaku, Yohannes Adama Memiah, Peter Memish, Ziad A. Mendoza, Walter Meretoja, Atte Meretoja, Tuomo J. Mhimbira, Francis Apolinary Miller, Ted R. Mikesell, Joseph Mirarefin, Mojde Mohammad, Karzan Abdulmuhsin Mohammed, Shafiu Mokdad, Ali H. Monasta, Lorenzo Moradi-Lakeh, Maziar Mori, Rintaro Mueller, Ulrich O. Murimira, Brighton Murthy, Gudlavalleti Venkata Satyanarayana Naheed, Aliya Naldi, Luigi Nangia, Vinay Nash, Denis Nawaz, Haseeb Nejjari, Chakib Ngalesoni, Frida Namnyak Ngirabega, Jean De Dieu Quyen Le Nguyen Nisar, Muhammad Imran Norheim, Ole F. Norman, Rosana E. 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CA GBD 2015 HIV Collaborators TI Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015: the Global Burden of Disease Study 2015 SO LANCET HIV LA English DT Article ID PROJECTION PACKAGE; SYSTEMATIC ANALYSIS; UNAIDS ESTIMATION; MALE CIRCUMCISION; 188 COUNTRIES; INFECTION; PREVENTION; EPIDEMIC; MODEL; TRIAL AB Background Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015. Methods For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification. Findings Global HIV incidence reached its peak in 1997, at 3.3 million new infections (95% uncertainty interval [UI] 3.1-3.4 million). Annual incidence has stayed relatively constant at about 2.6 million per year (range 2.5-2.8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38.8 million (95% UI 37.6-40.4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1.8 million deaths (95% UI 1.7-1.9 million) in 2005, to 1.2 million deaths (1.1-1.3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections. Interpretation Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030. Copyright (C) The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license C1 [Wang, Haidong; Wolock, Tim M.; Carter, Austin; Nguyen, Grant; Kyu, Hmwe Hmwe; Gakidou, Emmanuela; Hay, Simon I.; Msemburi, William; Coates, Matthew M.; Mooney, Meghan D.; Fraser, Maya S.; Sligar, Amber; Larson, Heidi J.; Friedman, Joseph; Brown, Alexandria; Dandona, Lalit; Fullman, Nancy; Haagsma, Juanita; Khalil, Ibrahim; Lim, Stephen S.; Mikesell, Joseph; Mokdad, Ali H.; Moradi-Lakeh, Maziar; Pearson, Katherine; Silpakit, Naris; Sorensen, Reed J. D.; Temesgen, Awoke Misganaw; Vollset, Stein Emil; Zoeckler, Leo; Murray, Christopher J. L.] Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. 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[Gessner, Bradford D.] Agence Medecine Prevent, Paris, France. [Giroud, Maurice] Univ Hosp Dijon, Dijon, France. [Gishu, Melkamu Dedefo; Tura, Abera Kenay] Haramaya Univ, Dire Dawa, Ethiopia. [Gishu, Melkamu Dedefo] Kersa Hlth & Demog Surveillance Syst, Harar, Ethiopia. [Glaser, Elizabeth] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA USA. [Goodridge, Amador] INDICASAT AIP, Inst Invest Cientif, City Of Knowledge, Panama. [Goodridge, Amador] INDICASAT AIP, Serv Alta Tecnol, City Of Knowledge, Panama. [Gopalani, Sameer Vali] Govt Federated States Micronesia, Dept Hlth & Social Aff airs, Palikir, Micronesia. [Goto, Atsushi] Tokyo Womens Med Univ, Dept Publ Hlth, Tokyo, Japan. [Gugnani, Harish Chander] St James Sch Med, Dept Microbiol, The Quarter, Anguilla. [Gugnani, Harish Chander] St James Sch Med, Dept Epidemiol & Biostat, The Quarter, Anguilla. [Guimaraes, Mark D. C.] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. West Virginia Bur Publ Hlth, Charleston, WV USA. Eternal Heart Care Ctr, Jaipur, Rajasthan, India. Res Inst, Jaipur, Rajasthan, India. [Gupta, Vipin] Univ Delhi, Delhi, India. [Hagan, Holly] NYU, New York, NY USA. [Hamadeh, Randah Ribhi] Arabian Gulf Univ, Manama, Bahrain. [Hamidi, Samer] Hamdan Bin Mohammed Smart Univ, Dubai, U Arab Emirates. [Hammami, Mouhanad] Wayne Cty Dept Hlth & Human Serv, Detroit, MI USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia. [Hankey, Graeme J.] Harry Perkins Inst Med Res, Nedlands, WA, Australia. [Hankey, Graeme J.] Western Australian Neurosci Res Inst, Nedlands, WA, Australia. [Hao, Yuantao] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China. [Harikrishnan, Sivadasanpillai] Sree Chitra Tirunal Inst Med Sci & Technol, Trivandrum, Kerala, India. [Koyanagi, Ai] Res & Dev Unit, Barcelona, Spain. [Haro, Josep Maria] Parc Sanitari Sant Joan de Deu CIBERSAM, Barcelona, Spain. [Haro, Josep Maria] Univ Barcelona, Barcelona, Spain. [Harun, Kimani M.] Kenyatta Univ, Nairobi, Kenya. [Hedayati, Mohammad T.] Mazandaran Univ Med Sci, Sari, Iran. [Hoek, Hans W.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Skirbekk, Vegard] Columbia Univ, New York, NY USA. [Horino, Masako] Nevada Div Behav & Publ Hlth, Carson City, NV USA. [Horino, Masako] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Horita, Nobuyuki] Yokohama City Univ, Sch Med, Yokohama, Kanagawa, Japan. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hoy, Damian G.] Secretariat Pacific Commun, Publ Hlth Div, Noumea, New Caledonia. [Hsairi, Mohamed] Natl Inst Publ Hlth, Tunis, Tunisia. [Hu, Guoqing] Cent S Univ, Dept Epidemiol & Hlth Stat, Sch Publ Hlth, Changsha, Hunan, Peoples R China. [Huang, Hsiang] Cambridge Hlth Alliance, Cambridge, MA USA. [Huang, John J.] Yale Univ, New Haven, CT USA. [Iburg, Kim Moesgaard] Aarhus Univ, Aarhus, Denmark. [Idrisov, Bulat T.] Bashkir State Med Univ, Ufa, Russia. [Idrisov, Bulat T.] Boston Univ, Boston Med Ctr, Boston, MA 02215 USA. Boston Univ, Boston Med Ctr, Boston, MA 02215 USA. [Innos, Kaire] Natl Inst Hlth Dev, Tallinn, Estonia. [Iyer, Veena J.] Indian Inst Publ Hlth Gandhinagar, Ahmadabad, Gujarat, India. [Jacobsen, Kathryn H.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA 22030 USA. [Jahanmehr, Nader] Shahid Beheshti Med Univ, Tehran, Iran. [Jakovljevic, Mihajlo B.] Univ Kragujevac, Fac Med Sci, Kragujevac, Serbia. [Javanbakht, Mehdi] Univ Aberdeen, Aberdeen, Scotland. [Jayatilleke, Achala Upendra] Postgrad Inst Med, Colombo, Sri Lanka. [Jayatilleke, Achala Upendra] Inst Violence & Injury Prevent, Colombo, Sri Lanka. [Jha, Vivekanand] Postgrad Inst Med Educ & Res, Chandigarh, India. [Jiang, Guohong] Tianjin Ctr Dis Control & Prevent, Tianjin, Peoples R China. [Jiang, Ying] Univ Occupat & Environm Hlth, Dept Hlth Dev, Inst Ind Ecol Sci, Dept Environm Epidemiol, Kitakyushu, Fukuoka, Japan. [Deribe, Kebede] Univ Addis Ababa, Sch Publ Hlth, Debre Zeit, Ethiopia. [Jibat, Tariku] Univ Addis Ababa, Debre Zeit, Ethiopia. [Jonas, Jost B.] Heidelberg Univ, Dept Ophthalmol, Med Fac Mannheim, Mannheim, Germany. [Kabir, Zubair] Univ Coll Cork, Cork, Ireland. [Kamal, Ritul; Kesavachandran, Chandrasekharan Nair] CSIR, Indian Inst Toxicol Res, Lucknow, Uttar Pradesh, India. [She, Jun] Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China. [Zhang, Hao] Fudan Univ, Zhongshan Hosp, Dept Nephrol, Shanghai, Peoples R China. [Kan, Haidong] Fudan Univ, Shanghai, Peoples R China. [Karch, Andre] Helmholtz Ctr Infect Res, Epidemiol & Stat Methods Res Grp, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res, Hannover Braunschweig Site, Braunschweig, Germany. [Karletsos, Dimitris] Clinton Hlth Access Initiat, Boston, MA USA. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Kawakami, Norito] Univ Tokyo, Sch Publ Hlth, Tokyo, Japan. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Kayibanda, Jeanne Francoise] Ottawa Hlth Res Inst, Ottawa, ON, Canada. [Keiyoro, Peter Njenga] Inst Trop & Infect Dis, Nairobi, Kenya. [Keiyoro, Peter Njenga] Sch Continuing & Distance Educ, Nairobi, Kenya. [Kengne, Andre Pascal] South African Med Res Council, Cape Town, South Africa. [Sliwa, Karen] Univ Cape Town, Fac Hlth Sci, Hatter Inst Cardiovascular Res Africa, Cape Town, South Africa. [Kengne, Andre Pascal; Mayosi, Bongani M.] Univ Cape Town, Cape Town, South Africa. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Irbid, Jordan. [Khan, Abdur Rahman] Univ Louisville, Louisville, KY 40292 USA. [Khan, Ejaz Ahmad] Hlth Serv Acad, Islamabad, Pakistan. [Khan, Ejaz Ahmad] Expanded Programme Immunizat, Islamabad, Pakistan. [Khubchandani, Jagdish] Ball State Univ, Muncie, IN 47306 USA. [Kim, Yun Jin] SouthernUniv Coll, Skudai, Malaysia. [Kinfu, Yohannes] Univ Canberra, Canberra, ACT, Australia. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan. [Kosen, Soewarta] NIHRD, Ctr Community Empowerment Hlth Policy & Humanitie, Jakarta, Indonesia. [Koul, Parvaiz A.] Sherikashmir Inst Med Sci, Srinagar, Jammu & Kashmir, India. [Defo, Barthelemy Kuate] Univ Montreal, Dept Demog, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Publ Hlth Res Inst, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Dept Social & Prevent Med, Sch Publ Hlth, Montreal, PQ, Canada. [Bicer, Burcu Kucuk] Hacettepe Univ, Inst Publ Hlth, Ankara, Turkey. [Kulkarni, Veena S.] Univ Arkansas, State Univ, Fayetteville, AR 72701 USA. [Lam, Hilton] Natl Inst Hlth, Inst Hlth Policy & Dev Studies, Manila, Philippines. [Lam, Jennifer O.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Bach Xuan Tran] Johns Hopkins Univ, Baltimore, MD USA. [Lansingh, Van C.] Help Me See Inc, New York, NY USA. [Lansingh, Van C.] Inst Mexicano Oftalmol, Queretaro, Mexico. [Leung, Ricky] SUNY Albany, Rensselaer, NY USA. [Li, Yongmei] San Francisco VA Med Ctr, San Francisco, CA USA. Wayne State Univ, Sch Med, Miami, FL USA. [Lipshultz, Steven E.; Wilkinson, James D.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Liu, Shiwei; Wang, Linhong] Natl Ctr Chron & Noncommunicable Dis Control & Pr, Beijing, Peoples R China. [Yu, Shicheng] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. [Lloyd, Belinda K.] Monash Univ, Eastern Hlth Clin Sch, Fitzroy, Vic, Australia. [Lloyd, Belinda K.] Eastern Hlth, Turning Point, Melbourne, Vic, Australia. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. [Lunevicius, Raimundas] Aintree Univ Hosp Natl Hlth Serv Fdn Trust, Liverpool, Merseyside, England. [Lunevicius, Raimundas] Univ Liverpool, Sch Med, Liverpool, Merseyside, England. [Abd El Razek, Hassan Magdy; Zaki, Maysaa El Sayed] Mansoura Fac Med, Mansoura, Egypt. [Polinder, Suzanne] Erasmus Univ, Dept Publ Hlth, Univ Med Ctr, Rotterdam, Netherlands. [Mahdavi, Mahdi] Erasmus Univ, Rotterdam, Netherlands. [Mahdavi, Mahdi] Iranian Minist Hlth, Tehran, Iran. [Marcenes, Wagner] Queen Mary Univ London, London, England. [Martinez-Raga, Jose] Hosp Univ Doctor Peset, Valencia, Spain. [Martinez-Raga, Jose] Univ CEU UCH, Moncada, Spain. [Marzan, Melvin Barrientos] Univ East Ramon Magsaysay, Mem Med Ctr, Quezon City, Philippines. [Mason-Jones, Amanda J.] Univ York, Dept Hlth Sci, York, N Yorkshire, England. [Meaney, Peter A.] Univ Penn, Pereleman Sch Med, Philadelphia, PA 19104 USA. [Meaney, Peter A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Mehndiratta, Man Mohan] Janakpuri Superspecialty Hosp, New Delhi, India. [Mekonnen, Alemayehu B.; Tedla, Bemnet Amare; Tessema, Gizachew Assefa] Univ Gondar, Gondar, Ethiopia. [Memish, Ziad A.] Univ West Florida, Pensacola, FL 32514 USA. [Memish, Ziad A.] Saudi Minist Hlth, Riyadh, Saudi Arabia. [Memish, Ziad A.] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia. [Mendoza, Walter] United Nations Populat Fund, Lima, Peru. [Meretoja, Atte] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. [Meretoja, Tuomo J.] Helsinki Univ Hosp, Ctr Comprehens Canc, Breast Surg Unit, Helsinki, Finland. [Meretoja, Tuomo J.] Univ Helsinki, Helsinki, Finland. [Mhimbira, Francis Apolinary] Ifakara Hlth Inst, Bagamoyo, Tanzania. [Miller, Ted R.] Pacific Inst Res & Evaluat, Calverton, MD USA. [Miller, Ted R.] Curtin Univ, Ctr Populat Hlth, Perth, WA, Australia. [Mirarefin, Mojde] Hunger Act Los Angeles, Los Angeles, CA USA. [Mohammad, Karzan Abdulmuhsin] Univ Salahaddin, Erbil, Iraq. [Mohammed, Shafiu] Heidelberg Univ, Inst Publ Hlth, Heidelberg, Germany. [Monasta, Lorenzo; Ronfani, Luca] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Moradi-Lakeh, Maziar] Iran Univ Med Sci, Dept Community Med, Gastrointestinal & Liver Dis Res Ctr, Tehran, Iran. [Mori, Rintaro] Natl Ctr Child Hlth & Dev, Tokyo, Japan. [Werdecker, Andrea] Fed Inst Populat Res, Competence Ctr Mortal Follow Up German Natl Cohor, Wiesbaden, Germany. [Mueller, Ulrich O.; Westerman, Ronny] Fed Inst Populat Res, Wiesbaden, Germany. [Murimira, Brighton] Minist Hlth & Child Care, AIDS & TB Unit, Bindura, Zimbabwe. [Murimira, Brighton] Zimbabwe Natl Family Planning Council, Harare, Zimbabwe. [Naheed, Aliya] Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh. [Naldi, Luigi] Azienda Osped Papa Giovanni XXIII, Bergamo, Italy. [Nangia, Vinay] Suraj Eye Inst, Nagpur, Maharashtra, India. [Nash, Denis] CUNY, Sch Publ Hlth, New York, NY 10021 USA. [Nawaz, Haseeb] Southern Illinois Univ, Springfield, IL USA. [Nejjari, Chakib] Fac Med, Fes, Morocco. [Ngalesoni, Frida Namnyak] Minist Hlth & Social Welf, Dar Es Salaam, Tanzania. [Ngirabega, Jean De Dieu] East African Community Hlth Res Commiss, Kigali, Rwanda. [Quyen Le Nguyen] Duy Tan Univ, Inst Global Hlth Innovat, Da Nang, Vietnam. [Vollset, Stein Emil] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Norheim, Ole F.] Univ Bergen, Bergen, Norway. [Norman, Rosana E.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Nyakarahuka, Luke] Makerere Univ, Kampala, Uganda. Amer Univ Beirut, Ctr Res Populat & Hlth, Fac Hlth Sci, Beirut, Lebanon. [Ogbo, Felix Akpojene] Univ Western Sydney, Sydney, NSW, Australia. [Oh, In-Hwan] Kyung Hee Univ, Dept Prevent Med, Sch Med, Seoul, South Korea. [Olusanya, Bolajoko Olubukunola] Ctr Healthy Start Initiat, Ikoyi, Nigeria. [Olusanya, Jacob Olusegun] Ctr Healthy Start Initiat, Lagos, Nigeria. [Opio, John Nelson] Lira Dist Local Govt, Lira Municipal Council, Lira, Uganda. [Ota, Erika] Natl Res Inst Child Hlth & Dev, Tokyo, Japan. [Padukudru, Mahesh Anand] JSS Univ, JSS Med Coll, Mysore, Karnataka, India. [Park, Hye-Youn] Calif Air Resources Board, Sacramento, CA USA. [Park, Jae-Hyun] Sungkyunkwan Univ, Dept Social & Prevent Med, Samsung Biomed Res Inst, Sch Med, Suwon, South Korea. Univ Calgary, Calgary, AB, Canada. [Patil, Snehal T.] Sch Dent Sci, Karad, India. [Patten, Scott B.] Univ Calgary, Dept Community Hlth Sci, Calgary, AB, Canada. [Paul, Vinod K.; Roy, Ambuj; Sagar, Rajesh] All India Inst Med Sci, New Delhi, India. [Peprah, Emmanuel Kwame] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Pereira, Claudia C.] Fiocruz MS, Rio De Janeiro, Brazil. [Perico, Norberto; Remuzzi, Giuseppe] IRCCS Mario Negri Inst Pharmacol Res, Ctr Anna Maria Astori, Bergamo, Italy. [Pesudovs, Konrad; Tesfay, Fisaha Haile] Flinders Univ S Australia, Adelaide, SA, Australia. [Petzold, Max] Hlth Metr Unit, Gothenburg, Sweden. [Phillips, Michael Robert] Shanghai Jiao Tong Univ, Sch Med, Shanghai, Peoples R China. [Simard, Edgar P.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Phillips, Michael Robert] Emory Univ, Atlanta, GA 30322 USA. [Pillay, Julian David] Durban Univ Technol, Durban, South Africa. [Plass, Dietrich] Sect Exposure Assessment & Environm Hlth Indicato, Berlin, Germany. [Pourmalek, Farshad] Univ British Columbia, Vancouver, BC, Canada. [Qorbani, Mostafa] Alborz Univ Med Sci, Dept Community Med, Sch Med, Karaj, Iran. [Rafay, Anwar; Rana, Saleem M.] Contech Int Hlth Consultants, Lahore, Pakistan. [Rafay, Anwar; Rana, Saleem M.] Contech Sch Publ Hlth, Lahore, Pakistan. [Rahman, Mahfuzar] BRAC, Res & Evaluat Div, Dhaka, Bangladesh. [Rahman, Sajjad Ur] Hamad Med Corp, Doha, Qatar. [Rai, Rajesh Kumar] Soc Hlth & Demog Surveillance, Suri, India. [Rajsic, Sasa] UMIT, ERAWEB Program, Hall In Tirol, Austria. [Rao, Paturi Vishnupriya] Diabet Res Soc, Hyderabad, Andhra Pradesh, India. [Rao, Paturi Vishnupriya] Diabet Res Ctr, Hyderabad, Andhra Pradesh, India. 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[Sharma, Rajesh] Indian Inst Technol Ropar, Roopnagar, India. [Shen, Jiabin] Res Inst Nationwide Childrens Hosp, Columbus, OH USA. [Shen, Jiabin] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Shin, Hwashin Hyun] Hlth Canada, Ottawa, ON, Canada. [Sigfusdottir, Inga Dora] Reykjavik Univ, Reykjavik, Iceland. [Santos Silva, Diego Augusto] Univ Fed Santa Catarina, Florianopolis, SC, Brazil. [Alves Silveira, Dayane Gabriele] Univ Brasilia, Brasilia, DF, Brazil. [Singh, Om Prakash] Banaras Hindu Univ, Dept Med, Inst Med Sci, Varanasi, Uttar Pradesh, India. [Singh, Prashant Kumar] Inst Human Dev, New Delhi, India. [Skirbekk, Vegard] Norwegian Inst Publ Hlth, Oslo, Norway. [Soneji, Samir] Dartmouth Coll, 1 Med Ctr Dr, Lebanon, NH 03756 USA. [Soriano, Joan B.] Univ Autonoma Madrid, Inst Invest Hosp Univ Princesa, Catedra UAM Linde, Palma de Mallorca, Spain. [Karema, Corine Kakizi] Minist Hlth, Malaria & Other Parasit Dis Div, Nairobi, Kenya. [Soti, David O.] Minist Hlth, Nairobi, Kenya. [Sreeramareddy, Chandrashekhar T.] Int Med Univ, Dept Community Med, Kuala Lumpur, Malaysia. [Stathopoulou, Vasiliki] Attikon Univ Hosp, Athens, Greece. [Steel, Nicholas] Univ East Anglia, Norwich, Norfolk, England. [Steel, Nicholas] Publ Hlth England, London, England. [Swaminathan, Soumya] Natl Inst Res TB, Madras, Tamil Nadu, India. [Sykes, Bryan L.] Univ Calif Irvine, Dept Criminol, Irvine, CA USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Law & Soc, Irvine, CA USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Sociol, Irvine, CA USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Publ Hlth, Irvine, CA USA. [Talongwa, Roberto Tchio] MINSANTE, Minist Hlth, Yaounde, Cameroon. [Tavakkoli, Mohammad] Westchester Med Ctr, Valhalla, NY USA. [Taye, Bineyam] Univ Addis Ababa, Addis Ababa, Ethiopia. [Tedla, Bemnet Amare] James Cook Univ, Cairns, Qld, Australia. [Terkawi, Abdullah Sulieman] Univ Virginia, Dept Anesthesiol, Charlottesville, VA USA. 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[Wijeratne, Tissa] Western Hlth Footscray, Footscray, Vic, Australia. [Wilkinson, James D.] Wayne State Univ, Sch Med, Detroit, MI USA. [Wolfe, Charles D. A.] Kings Coll London, Div Hlth & Social Care Res, London, England. [Wolfe, Charles D. A.] Guys & St Thomas NHS Fdn Trust, Natl Inst Hlth Res, Comprehens Biomed Res Ctr, London, England. [Wolfe, Charles D. A.] Kings Coll London, London, England. [Wong, John Q.] Manila Univ, Ateneo Sch Med & Publ Hlth, Pasig, Philippines. [Xu, Gelin] Nanjing Univ, Sch Med, Dept Neurol, Jinling Hosp, Nanjing, Jiangsu, Peoples R China. [Yano, Yuichiro] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Yaseri, Mehdi] Ophthalm Res Ctr, Tehran, Iran. [Yebyo, Henock Gebremedhin] Univ Zurich, Zurich, Switzerland. [Yip, Paul] Univ Hong Kong, Social Work & Social Adm Dept, Hong Kong, Hong Kong, Peoples R China. [Yip, Paul] Univ Hong Kong, Hong Kong Jockey Club Ctr Suicide Res & Prevent, Hong Kong, Hong Kong, Peoples R China. [Yonemoto, Naohiro] Kyoto Univ, Dept Biostat, Sch Publ Hlth, Kyoto, Japan. [Yoon, Seok-Jun] Korea Univ, Dept Prevent Med, Coll Med, Seoul, South Korea. [Younis, Mustafa Z.] Jackson State Univ, Jackson, MS USA. [Yu, Chuanhua] Wuhan Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Wuhan, Peoples R China. [Yu, Chuanhua] Wuhan Univ, Global Hlth Inst, Wuhan, Peoples R China. [Zaidi, Zoubida] Univ Hosp, Setif, Algeria. [Zeeb, Hajo] Leibniz Inst Prevent Res & Epidemiol, Bremen, Germany. [Zhang, Hao] Shanghai Inst Kidney Dis & Dialysis, Shanghai, Peoples R China. [Zhao, Yong] Chongqing Med Univ, Chongqing, Peoples R China. [Zuhlke, Liesl Joanna] Red Cross War Mem Childrens Hosp, Cape Town, South Africa. RP Wang, HD (reprint author), Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA.; Wang, HD (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. EM haidong@uw.edu RI Roshandel, gholamreza/N-2260-2016; Beyene, Tariku Jibat/A-6875-2017; Martinez-Raga, Jose/B-6251-2017; Weiderpass, Elisabete/M-4029-2016; das Neves, Jose/J-8369-2013; Jacobsen, Kathryn/B-5857-2008; Hankey, Graeme /H-4968-2014; Degenhardt, Louisa/D-4515-2012; Ronfani, Luca/B-6668-2013; NORMAN, ROSANA/F-2774-2010; Salomon, Joshua/D-3898-2009; Monasta, Lorenzo/B-1388-2012; Majdan, Marek/K-5017-2012; Gishu, Melkamu Dedefo/C-3747-2017; Alsharif, Ubai/C-6527-2017; Lotufo, Paulo/A-9843-2008; Karch, Andre/D-6973-2017; Hedayati, Mohammad T./E-2304-2017; Patten, Scott/B-4434-2011; Abbas, Kaja/E-6590-2017; Pereira, David/M-9286-2013; OI Olusanya, Bolajoko/0000-0002-3826-0583; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Heredia-Pi, Ileana Beatriz/0000-0002-9998-9239; Goenka, Shifalika/0000-0001-6993-2883; Miller, Ted/0000-0002-0958-2639; Xu, Gelin/0000-0002-6194-0341; GEBREMDHIN, AMANUEL TESFAY/0000-0003-2459-1805; Al-Aly, Ziyad/0000-0002-2600-0434; assadi, reza/0000-0002-5016-2994; Vlassov, Vasiliy/0000-0001-5203-549X; Roshandel, gholamreza/0000-0002-5494-0722; Beyene, Tariku Jibat/0000-0002-7474-1966; Martinez-Raga, Jose/0000-0002-2856-6562; Weiderpass, Elisabete/0000-0003-2237-0128; das Neves, Jose/0000-0002-2317-2759; Jacobsen, Kathryn/0000-0002-4198-6246; Hankey, Graeme /0000-0002-6044-7328; Degenhardt, Louisa/0000-0002-8513-2218; Ronfani, Luca/0000-0001-5710-3914; NORMAN, ROSANA/0000-0002-9742-1957; Salomon, Joshua/0000-0003-3929-5515; Monasta, Lorenzo/0000-0001-7774-548X; Majdan, Marek/0000-0001-8037-742X; Gishu, Melkamu Dedefo/0000-0002-3466-1232; Alsharif, Ubai/0000-0002-4024-3950; Lotufo, Paulo/0000-0002-4856-8450; Karch, Andre/0000-0003-3014-8543; Hedayati, Mohammad T./0000-0001-6415-4648; Patten, Scott/0000-0001-9871-4041; Abbas, Kaja/0000-0003-0563-1576; Pereira, David/0000-0003-0384-7592; Wiysonge, Charles/0000-0002-1273-4779; Birlik, Sait Mentes/0000-0002-9889-8837; Santos, Itamar/0000-0003-3212-8466; Alkerwi, Ala'a/0000-0002-7448-3936; Schutte, Aletta/0000-0001-9217-4937; Sindi, Shireen/0000-0002-3786-0552; Leung, Ricky/0000-0002-2852-6771; Pesudovs, Konrad/0000-0002-6322-9369; Aldridge, Robert/0000-0003-0542-0816; Catala-Lopez, Ferran/0000-0002-3833-9312; Javanbakht, Mehdi/0000-0002-8661-8439; Gething, Peter/0000-0001-6759-5449; Langan, Sinead/0000-0002-7022-7441; Deribe, Kebede/0000-0002-8526-6996; Uthman, Olalekan/0000-0002-8567-3081; Khang, Young-Ho/0000-0002-9585-8266; Kemp, Andrew/0000-0003-1146-3791; Kamal, Ritul/0000-0001-9741-1698; Glaser, Elizabeth/0000-0002-1918-057X; Awasthi, Ashish/0000-0002-9308-9782; Amegah, A Kofi/0000-0001-5868-6402; Atique, Suleman/0000-0002-5149-0703; Norheim, Ole F./0000-0002-5748-5956; Hoek, Hans/0000-0001-6353-5465; Hay, Simon/0000-0002-0611-7272; Moradi-Lakeh, Maziar/0000-0001-7381-5305; Castaneda-Orjuela, Carlos/0000-0002-8735-6223 FU Bill AMP; Melinda Gates Foundation; National Institute of Mental Health, National Institutes of Health (NIH) [R01MH110163]; National Institute on Aging, NIH [P30AG047845]; Qatar National Research Fund (NPRP) [04-924-3-251]; Bill AMP; Melinda Gates Foundation [OPP1068048]; Fundacao para a Ciencia e a Tecnologia, Portugal [SFRH/BPD/92934/2013]; Wellcome Trust Fellowship in Public Health and Tropical Medicine [099876]; Swiss National Science Foundation (SNSF) [P300P3-154634]; Sistema Nacional de Investigadores de Panama-SNI; Wellcome Trust-DBT India Alliance Clinical and Public Health Intermediate Fellowship; Academy of Finland; Swedish Research Council; Alzheimerfonden; Alzheimer's Research AMP; Prevention Foundation; Center for Innovative Medicine (CIMED) at Karolinska Institutet South Campus; AXA Research Fund; Wallenberg Clinical Scholars Award from the Knut och Alice Wallenbergs Foundation; Sheika Salama Bint Hamdan Al Nahyan Foundation; ISCIII (General Branch Evaluation and Promotion of Health Research); European Regional Development Fund (ERDF-FEDER); National Institute for Health Research (NIHR) Clinician Scientist Fellowship [NIHR/CS/010/014]; NIHR; EU Innovative Medicines Initiative; Centre for Strategic AMP; International Studies; WHO; German National Cohort Consortium [O1ER1511D]; NIHR Oxford Biomedical Research Centre; NIHR Career Development Fellowship; Oxford Martin School; International Society of Nephrology (ISN); FAPESP (Brazilian public agency); Fonds de la recherche en sante du Quebec (FRSQ); Generalitat Valenciana [PROMETEOII/2015/021]; ISCIII-FEDER [PI14/00894]; Strategic Public Policy Research [HKU7003-SPPR-12]; [CP13/00150]; [PI15/00862] FX We thank the countless individuals who have contributed to the Global Burden of Disease (GBD) Study 2015 in various capacities. We specifically thank Jeffrey Eaton and John Stover. HW and CJLM received funding for this study from the Bill & Melinda Gates Foundation; the National Institute of Mental Health, National Institutes of Health (NIH; R01MH110163); and the National Institute on Aging, NIH (P30AG047845). LJAR acknowledges the support of Qatar National Research Fund (NPRP 04-924-3-251) who provided the main funding for generating the data provided to the GBD-Institute for Health Metrics and Evaluation effort. BPAQ acknowledges institutional support from PRONABEC (National Program of Scholarship and Educational Loan), provided by the Peruvian government. DB is supported by the Bill & Melinda Gates Foundation (grant number OPP1068048). JDN was supported in his contribution to this work by a Fellowship from Fundacao para a Ciencia e a Tecnologia, Portugal (SFRH/BPD/92934/2013). KD is supported by a Wellcome Trust Fellowship in Public Health and Tropical Medicine (grant number 099876). TF received financial support from the Swiss National Science Foundation (SNSF; project number P300P3-154634). AG acknowledges funding from Sistema Nacional de Investigadores de Panama-SNI. PJ is supported by Wellcome Trust-DBT India Alliance Clinical and Public Health Intermediate Fellowship. MK receives research support from the Academy of Finland, the Swedish Research Council, Alzheimerfonden, Alzheimer's Research & Prevention Foundation, Center for Innovative Medicine (CIMED) at Karolinska Institutet South Campus, AXA Research Fund, Wallenberg Clinical Scholars Award from the Knut och Alice Wallenbergs Foundation, and the Sheika Salama Bint Hamdan Al Nahyan Foundation. AK's work was supported by the Miguel Servet contract financed by the CP13/00150 and PI15/00862 projects, integrated into the National R&D&I and funded by the ISCIII (General Branch Evaluation and Promotion of Health Research), and the European Regional Development Fund (ERDF-FEDER). SML is funded by a National Institute for Health Research (NIHR) Clinician Scientist Fellowship (grant number NIHR/CS/010/014). HJL reports grants from the NIHR, EU Innovative Medicines Initiative, Centre for Strategic & International Studies, and WHO. WM is Program analyst, Population and Development, in the Peru Country Office of the United Nations Population Fund, which does not necessarily endorse this study. For UOM, funding from the German National Cohort Consortium (O1ER1511D) is gratefully acknowledged. KR reports grants from NIHR Oxford Biomedical Research Centre, NIHR Career Development Fellowship, and Oxford Martin School during the conduct of the study. GR acknowledges that work related to this paper has been done on the behalf of the GBD Genitourinary Disease Expert Group supported by the International Society of Nephrology (ISN). ISS reports grants from FAPESP (Brazilian public agency). RSS receives institutional support from Universidad de Ciencias Aplicadas y Ambientales, UDCA, Bogota Colombia. SS receives postdoctoral funding from the Fonds de la recherche en sante du Quebec (FRSQ), including its renewal. RTS was supported in part by grant number PROMETEOII/2015/021 from Generalitat Valenciana and the national grant PI14/00894 from ISCIII-FEDER. PY acknowledges support from Strategic Public Policy Research (HKU7003-SPPR-12). NR 54 TC 13 Z9 14 U1 54 U2 68 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 2352-3018 J9 LANCET HIV JI Lancet HIV PD AUG PY 2016 VL 3 IS 8 BP E361 EP E387 DI 10.1016/S2352-3018(16)30087-X PG 27 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DS5SK UT WOS:000380842400010 ER PT J AU Muller, TA Grundler, R Istvanffy, R Rudelius, M Hennighausen, L Illert, AL Duyster, J AF Mueller, T. A. Grundler, R. Istvanffy, R. Rudelius, M. Hennighausen, L. Illert, A. L. Duyster, J. TI Lineage-specific STAT5 target gene activation in hematopoietic progenitor cells predicts the FLT3(+)-mediated leukemic phenotype SO LEUKEMIA LA English DT Article ID ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; ONCOSTATIN-M; BONE-MARROW; STEM-CELLS; C-MYC; MYELOPROLIFERATIVE DISEASE; MULTIPOTENT PROGENITORS; TRANSPLANTATION MODEL; ITD MUTATIONS AB Mutations that activate FMS-like tyrosine kinase 3 (FLT3) are frequent occurrences in acute myeloid leukemia. Two distinct types of mutations have been described: internal duplication of the juxtamembranous domain (ITD) and point mutations of the tyrosine kinase domain (TKD). Although both mutations lead to constitutive FLT3 signaling, only FLT3-ITD strongly activates signal transducer and activator of transcription 5 (STAT5). In a murine transplantation model, FLT3-ITD induces a myeloproliferative neoplasm, whereas FLT3-TKD leads to a lymphoid malignancy with significantly longer latency. Here we report that the presence of STAT5 is critical for the development of a myeloproliferative disease by FLT3-ITD in mice. Deletion of Stat5 in FLT3-ITD-induced leukemogenesis leads not only to a significantly longer survival (82 vs 27 days) of the diseased mice, but also to an immunophenotype switch with expansion of the lymphoid cell compartment. Interestingly, we were able to show differential STAT5 activation in FLT3-ITD+ myeloid and lymphoid murine progenitors. STAT5 target genes such as Oncostatin M were highly expressed in FLT3-ITD+ myeloid but not in FLT3-ITD+ lymphoid progenitor cells. Strikingly, FLT3-TKD expression in combination with Oncostatin M is sufficient to reverse the phenotype to a myeloproliferative disease in FLT3-TKD mice. Thus, lineage-specific STAT5 activation in hematopoietic progenitor cells predicts the FLT3(+)-mediated leukemic phenotype in mice. C1 [Mueller, T. A.; Illert, A. L.; Duyster, J.] Univ Med Ctr Freiburg, Dept Hematol Oncol & Stem Cell Transplantat, Hugstetterstr 55, D-79106 Freiburg, Germany. [Grundler, R.; Istvanffy, R.] Tech Univ Munich, Klinikum Rechts Isar, Dept Internal Med 3, Munich, Germany. [Rudelius, M.] Tech Univ Munich, Klinikum Rechts Isar, Dept Pathol, Munich, Germany. [Rudelius, M.] Univ Wurzburg, Inst Pathol, Wurzburg, Germany. [Rudelius, M.] Comprehens Canc Ctr Mainfranken, Wurzburg, Germany. [Hennighausen, L.] NIDDK, NIH, Bethesda, MD 20892 USA. [Illert, A. L.; Duyster, J.] German Canc Consortium DKTK, Heidelberg, Germany. [Illert, A. L.; Duyster, J.] German Canc Res Ctr, Heidelberg, Germany. RP Illert, AL; Duyster, J (reprint author), Univ Med Ctr Freiburg, Dept Hematol Oncol & Stem Cell Transplantat, Hugstetterstr 55, D-79106 Freiburg, Germany. EM Lena.Illert@uniklinik-freiburg.de; Justus.Duyster@uniklinik-freiburg.de FU DFG [FOR 2033]; Intramural Research Program (IRP) of the National Institutes of Diabetes, Digestive and Kidney Disease, NIH (Bethesda, MD, USA); University Clinic Freiburg; government Baden-Wurttemberg (BSL) FX We thank M Follo for help with FACS sorting and G Schafer for technical assistance. This work was supported by a DFG grant (FOR 2033 to JD and TAM). LH was supported by the Intramural Research Program (IRP) of the National Institutes of Diabetes, Digestive and Kidney Disease, NIH (Bethesda, MD, USA). ALI was supported by a Research grant from University Clinic Freiburg and from the government Baden-Wurttemberg (BSL). NR 49 TC 1 Z9 1 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD AUG PY 2016 VL 30 IS 8 BP 1725 EP 1733 DI 10.1038/leu.2016.72 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA DS5MN UT WOS:000380826400011 PM 27046463 ER PT J AU Abulaban, KM Song, H Zhang, X Kimmel, PL Kusek, JW Nelson, RG Feldman, HI Vasan, RS Ying, J Mauer, M Nelsestuen, GL Bennett, M Brunner, HI Rovin, BH AF Abulaban, K. M. Song, H. Zhang, X. Kimmel, P. L. Kusek, J. W. Nelson, R. G. Feldman, H. I. Vasan, R. S. Ying, J. Mauer, M. Nelsestuen, G. L. Bennett, M. Brunner, H. I. Rovin, B. H. TI Predicting decline of kidney function in lupus nephritis using urine biomarkers SO LUPUS LA English DT Article DE SLE; lupus nephritis; kidney injury; biomarker; renal function decline ID GELATINASE-ASSOCIATED LIPOCALIN; STAGE RENAL-DISEASE; ERYTHEMATOSUS; CLASSIFICATION; CHILDREN; CRITERIA; MARKER; US AB Objective To evaluate candidate biomarkers to predict future renal function decline (RFD) in children and adults with lupus nephritis (LN). Methods At the time of enrollment into prospective observational LN cohort studies liver-type fatty acid binding protein (LFABP), albumin, monocyte chemoattractant protein-1 (MCP-1), uromodulin, transferrin, and hepcidin were measured in urine samples of two cohorts of patients with LN, one followed at a pediatric (cohort-1; n=28) and one at an adult institution (cohort-2; n=69). The primary outcome was RFD, defined in cohort-1 as a decrease in estimated glomerular filtration rate (eGFR) of 20% and in cohort-2 as a sustained increase of 25% in serum creatinine concentration (SCr), both from baseline. Results All patients (n=97) had normal eGFR or SCr at the time of urine collection at baseline. RFD occurred in 29% (8/28) of patients in cohort-1 during a mean follow-up of 6.1 months, and in 30% (21/69) of those in cohort-2 during a mean follow-up of 60 months. Individually, in cohort-1, levels of MCP-1, transferrin, LFABP, and albumin were higher in the RFD group than those who maintained renal function, with statistical significance for LFABP and albumin. In cohort-2 the RFD group also had higher levels of urine MCP-1 and albumin than others. The combination of LFABP, MCP-1, albumin, and transferrin had good predictive accuracy for RFD in both cohorts (area under the ROC curve=0.77-0.82). Conclusion The combinatorial urine biomarker LFABP, MCP-1, albumin, and transferrin shows promise as a predictor of renal functional decline in LN, and warrants further investigation. C1 [Abulaban, K. M.; Bennett, M.; Brunner, H. I.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. [Song, H.; Zhang, X.; Rovin, B. H.] Ohio State Univ, Dept Internal Med, Wexner Med Ctr, Columbus, OH 43210 USA. [Kimmel, P. L.; Kusek, J. W.] NIDDK, Bethesda, MD 20892 USA. [Nelson, R. G.] NIDDK, Phoenix, AZ USA. [Feldman, H. I.] Univ Penn, Dept Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Vasan, R. S.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [Vasan, R. S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, R. S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Ying, J.] Univ Cincinnati, Dept Environm Hlth, Cincinnati, OH USA. [Mauer, M.; Nelsestuen, G. L.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Abulaban, K. M.] Michigan State Univ, Helen DeVos Childrens Hosp, Dept Pediat, Grand Rapids, MI USA. RP Rovin, BH (reprint author), Ohio State Univ, Wexner Med Ctr, Div Nephrol, 395 West 12th Ave, Columbus, OH 43210 USA. EM Brad.Rovin@osumc.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Institute of Diabetes and Digestive and Kidney Diseases as part of the CKD Biomarker Consortium [U01 DK085673] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a cooperative agreement (U01 DK085673) from the National Institute of Diabetes and Digestive and Kidney Diseases as part of the CKD Biomarker Consortium. NR 19 TC 1 Z9 1 U1 2 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0961-2033 EI 1477-0962 J9 LUPUS JI Lupus PD AUG PY 2016 VL 25 IS 9 BP 1012 EP 1018 DI 10.1177/0961203316631629 PG 7 WC Rheumatology SC Rheumatology GA DS7RV UT WOS:000380981500009 PM 26873651 ER PT J AU Warren, JL Mariotto, A Melbert, D Schrag, D Doria-Rose, P Penson, D Yabroff, KR AF Warren, Joan L. Mariotto, Angela Melbert, Danielle Schrag, Deborah Doria-Rose, Paul Penson, David Yabroff, K. Robin TI Sensitivity of Medicare Claims to Identify Cancer Recurrence in Elderly Colorectal and Breast Cancer Patients SO MEDICAL CARE LA English DT Article DE Medicare; SEER; health claims; recurrence; outcomes; disease-free progression ID PROSTATE-CANCER; UNITED-STATES; SURVIVAL; DEATH; SURVEILLANCE; POPULATION; UTILITY AB Background: Researchers are increasingly interested in using observational data to evaluate cancer outcomes following treatment, including cancer recurrence and disease-free survival. Because population-based cancer registries do not collect recurrence data, recurrence is often imputed from health claims, primarily by identifying later cancer treatments after initial treatment. The validity of this approach has not been established. Research Design: We used the linked Surveillance, Epidemiology, and End Results-Medicare data to assess the sensitivity of Medicare claims for cancer recurrence in patients very likely to have had a recurrence. We selected newly diagnosed stage II/III colorectal (n = 6910) and female breast cancer (n = 3826) patients during 1994-2003 who received initial cancer surgery, had a treatment break, and then died from cancer in 1994-2008. We reviewed all claims from the treatment break until death for indicators of recurrence. We focused on additional cancer treatment (surgery, chemotherapy, radiation therapy) as the primary indicator, and used multivariate logistic regression analysis to evaluate patient factors associated with additional treatment. We also assessed metastasis diagnoses and end-of-life care as recurrence indicators. Results: Additional treatment was the first indicator of recurrence for 38.8% of colorectal patients and 35.2% of breast cancer patients. Patients aged 70 and older were less likely to have additional treatment (P < 0.05), in adjusted analyses. Over 20% of patients either had no recurrence indicator before death or had end-of-life care as their first indicator. Conclusions: Identifying recurrence through additional cancer treatment in Medicare claims will miss a large percentage of patients with recurrences; particularly those who are older. C1 [Warren, Joan L.; Mariotto, Angela; Doria-Rose, Paul; Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E428, Bethesda, MD 20892 USA. [Melbert, Danielle] Informat Management Serv Inc, Beltsville, MD USA. [Schrag, Deborah] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Penson, David] Vanderbilt Ingram Canc Ctr, Ctr Surg Qual & Outcomes Res, Nashville, TN USA. RP Warren, JL (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E428, Bethesda, MD 20892 USA. EM joan_warren@nih.gov OI Doria-Rose, Vincent/0000-0002-8802-5143 FU Intramural NIH HHS [Z99 CA999999] NR 24 TC 2 Z9 2 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD AUG PY 2016 VL 54 IS 8 BP E47 EP E54 DI 10.1097/MLR.0000000000000058 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DS1ZM UT WOS:000380502800001 PM 24374419 ER PT J AU Singh, AP Foley, JF Rubino, M Boyle, MC Tandon, A Shah, R Archer, TK AF Singh, Ajeet P. Foley, Julie F. Rubino, Mark Boyle, Michael C. Tandon, Arpit Shah, Ruchir Archer, Trevor K. TI Brg1 Enables Rapid Growth of the Early Embryo by Suppressing Genes That Regulate Apoptosis and Cell Growth Arrest SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CHROMATIN-REMODELING COMPLEX; MAMMALIAN SWI/SNF COMPLEXES; DNA-DAMAGE; CARCINOMA-CELLS; P53 PATHWAY; STEM-CELLS; ACTIVATION; MOUSE; DIFFERENTIATION; EXPRESSION AB SWI/SNF (switching/sucrose nonfermenting)-dependent chromatin remodeling establishes coordinated gene expression programs during development, yet important functional details remain to be elucidated. We show that the Brg1 (Brahma-related gene 1; Smarca4) ATPase is globally expressed at high levels during postimplantation development and its conditional ablation, beginning at gastrulation, results in increased apoptosis, growth retardation, and, ultimately, embryonic death. Global gene expression analysis revealed that genes upregulated in Rosa26CreERT2; Brg1(flox/flox) embryos (here referred to as Brg1(d/d) embryos to describe embryos with deletion of the Brg1(flox/flox) alleles) negatively regulate cell cycle progression and cell growth. In addition, the p53 (Trp53) protein, which is virtually undetectable in early wild-type embryos, accumulated in the Brg1(d/d) embryos and activated the p53-dependent pathways. Using P19 cells, we show that Brg1 and CHD4 (chromodomain helicase DNA binding protein 4) coordinate to control target gene expression. Both proteins physically interact and show a substantial overlap of binding sites at chromatin-accessible regions adjacent to genes differentially expressed in the Brg1(d/d) embryos. Specifically, Brg1 deficiency results in reduced levels of the repressive histone H3 lysine K27 trimethylation (H3K27me3) histone mark and an increase in the amount of open chromatin at the regulatory region of the p53 and p21 (Cdkn1a) genes. These results provide insights into the mechanisms by which Brg1 functions, which is in part via the p53 program, to constrain gene expression and facilitate rapid embryonic growth. C1 [Singh, Ajeet P.; Rubino, Mark; Boyle, Michael C.; Archer, Trevor K.] NIEHS, Chromatin & Gene Express Sect, Epigenet & Stem Cell Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Foley, Julie F.] NIEHS, Special Tech Grp, Cellular & Mol Pathol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Tandon, Arpit; Shah, Ruchir] Sciome LLC, Res Triangle Pk, NC USA. [Boyle, Michael C.] Amgen Inc, Comparat Biol & Safety Sci, Thousand Oaks, CA USA. RP Archer, TK (reprint author), NIEHS, Chromatin & Gene Express Sect, Epigenet & Stem Cell Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov FU HHS | NIH | National Institute of Environmental Health Sciences (NIEHS) [Z01ES071006-15] FX This work, including the efforts of Trevor K. Archer, was funded by HHS | NIH | National Institute of Environmental Health Sciences (NIEHS) (Z01ES071006-15). NR 49 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2016 VL 36 IS 15 BP 1990 EP 2010 DI 10.1128/MCB.01101-15 PG 21 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS1QL UT WOS:000380371200001 PM 27185875 ER PT J AU Yoo, KH Oh, S Kang, K Wang, CC Robinson, GW Ge, K Hennighausen, L AF Yoo, Kyung Hyun Oh, Sumin Kang, Keunsoo Wang, Chaochen Robinson, Gertraud W. Ge, Kai Hennighausen, Lothar TI Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme-Independent Mechanisms SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; LYSINE 27 DEMETHYLASES; STEM-CELLS; GLAND DEVELOPMENT; PROGENITOR CELLS; BREAST-CANCER; UTX; DIFFERENTIATION; PREGNANCY; EZH2 AB Establishment of the mammary luminal cell lineage is controlled primarily by hormones and through specific transcription factors (TFs). Previous studies have linked histone methyltransferases to the differentiation of mammary epithelium, thus opening the possibility of biological significance of counteracting demethylases. We have now demonstrated an essential role for the H3K27me3 demethylase KDM6A in generating a balanced alveolar compartment. Deletion of Kdm6a in the mammary luminal cell lineage led to a paucity of luminal cells and an excessive expansion of basal cells, both in vivo and in vitro. The inability to form structurally normal ducts and alveoli during pregnancy resulted in lactation failure. Mutant luminal cells did not exhibit their distinctive transcription factor pattern and displayed basal characteristics. The genomic H3K27me3 landscape was unaltered in mutant tissue, and support for a demethylase-independent mechanism came from mice expressing a catalytically inactive KDM6A. Mammary tissue developed normally in these mice. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments demonstrated KDM6A binding to putative enhancers enriched for key mammary TFs and H3K27ac. This study demonstrated for the first time that the mammary luminal lineage relies on KDM6A to ensure a transcription program leading to differentiated alveoli. Failure to fully implement this program results in structurally and functionally impaired mammary tissue. C1 [Yoo, Kyung Hyun; Oh, Sumin; Wang, Chaochen; Robinson, Gertraud W.; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Oh, Sumin] Dankook Univ, Dept Nanobiomed Sci, Cheonan, Chungnam, South Korea. [Oh, Sumin] Dankook Univ, PLUS NBM Global Res Ctr Regenerat Med BK21, Cheonan, Chungnam, South Korea. [Kang, Keunsoo] Dankook Univ, Dept Microbiol, Cheonan, Chungnam, South Korea. [Wang, Chaochen; Ge, Kai] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD USA. RP Hennighausen, L (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. EM lotharh@mail.nih.gov FU Intramural Research Program (IRP) of the National Institutes of Health FX This work, including the efforts of Kyung Hyun Yoo, Sumin Oh, Keunsoo Kang, Chaochen Wang, Gertraud Wasner Robinson, Kai Ge, and Lothar Hennighausen, was funded by the Intramural Research Program (IRP) of the National Institutes of Health. NR 57 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2016 VL 36 IS 16 BP 2108 EP 2120 DI 10.1128/MCB.00089-16 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS5JI UT WOS:000380817600001 PM 27215382 ER PT J AU Li, FM Bullough, KZ Vashisht, AA Wohlschlegel, JA Philpott, CC AF Li, Fengmin Bullough, Kimberly Z. Vashisht, Ajay A. Wohlschlegel, James A. Philpott, Caroline C. TI Poly(rC)-Binding Protein 2 Regulates Hippo Signaling To Control Growth in Breast Epithelial Cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID IRON CHAPERONES PCBP1; MESENCHYMAL TRANSITION; UBIQUITIN LIGASE; CANCER CELLS; PATHWAY; TAZ; IDENTIFICATION; KINASES; GENE; HYDROXYLASE AB Poly(rC)-binding proteins (PCBPs) are multifunctional adapters that mediate interactions between nucleic acids, iron cofactors, and other proteins, affecting the fates and activities of the components of these interactions. Here, we show that PCBP2 forms a complex with the Hippo pathway components Salvador (Sav1), Mst1, Mst2, and Lats1 in human cells and mouse tissues. Hippo is a kinase cascade that functions to phosphorylate and inactivate the transcriptional coactivators YAP and TAZ, which control cell growth and proliferation. PCBP2 specifically interacts with the scaffold protein Sav1 and prevents proteolytic cleavage of the Mst1 kinase, resulting in increased signaling through Hippo and suppressed activity of YAP and TAZ. Human breast epithelial cells lacking PCBP2 exhibit impaired proteasomal degradation of TAZ. They accumulate TAZ in both the nucleus and the cytosol, increase expression of YAP and TAZ connective tissue growth factor (CTGF) and Cyr61 target genes, and exhibit anchorage-independent growth. Thus, PCBP2 can function as a component of the Hippo complex, enhancing signaling, suppressing activity of YAP and TAZ, and altering the growth characteristics of cells. C1 [Li, Fengmin; Bullough, Kimberly Z.; Philpott, Caroline C.] NIDDK, Genet & Metab Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Vashisht, Ajay A.; Wohlschlegel, James A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA. RP Philpott, CC (reprint author), NIDDK, Genet & Metab Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM carolinep@mail.nih.gov FU NIDDK (Intramural Research program); NIH [GM089778] FX This work, including the efforts of Fengmin Li, Kimberly B. Zumbrennen-Bullough, and Caroline C. Philpott, was funded by NIDDK (Intramural Research program). This work, including the efforts of Ajay A. Vashisht and James A. Wohlschlegel, was funded by NIH (GM089778). NR 38 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2016 VL 36 IS 16 BP 2121 EP 2131 DI 10.1128/MCB.00104-16 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS5JI UT WOS:000380817600002 PM 27215387 ER PT J AU Hasegawa, A Kaneko, H Ishihara, D Nakamura, M Watanabe, A Yamamoto, M Trainor, CD Shimizu, R AF Hasegawa, Atsushi Kaneko, Hiroshi Ishihara, Daishi Nakamura, Masahiro Watanabe, Akira Yamamoto, Masayuki Trainor, Cecelia D. Shimizu, Ritsuko TI GATA1 Binding Kinetics on Conformation-Specific Binding Sites Elicit Differential Transcriptional Regulation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CHROMATIN OCCUPANCY ANALYSIS; X-LINKED THROMBOCYTOPENIA; DNA-BINDING; SELF-ASSOCIATION; IN-VIVO; ERYTHROID-DIFFERENTIATION; GENE ACTIVATION; ZINC FINGERS; PROTEIN; REPRESSION AB GATA1 organizes erythroid and megakaryocytic differentiation by orchestrating the expression of multiple genes that show diversified expression profiles. Here, we demonstrate that GATA1 monovalently binds to a single GATA motif (Single-GATA) while a monomeric GATA1 and a homodimeric GATA1 bivalently bind to two GATA motifs in palindromic (Pal-GATA) and direct-repeat (Tandem-GATA) arrangements, respectively, and form higher stoichiometric complexes on respective elements. The amino-terminal zinc (N) finger of GATA1 critically contributes to high occupancy of GATA1 on Pal-GATA. GATA1 lacking the N finger-DNA association fails to trigger a rate of target gene expression comparable to that seen with the wild-type GATA1, especially when expressed at low level. This study revealed that Pal-GATA and Tandem-GATA generate transcriptional responses from GATA1 target genes distinct from the response of Single-GATA. Our results support the notion that the distinct alignments in binding motifs are part of a critical regulatory strategy that diversifies and modulates transcriptional regulation by GATA1. C1 [Hasegawa, Atsushi; Kaneko, Hiroshi; Ishihara, Daishi; Shimizu, Ritsuko] Tohoku Univ, Grad Sch Med, Dept Mol Hematol, Sendai, Miyagi, Japan. [Hasegawa, Atsushi; Ishihara, Daishi; Yamamoto, Masayuki] Tohoku Univ, Grad Sch Med, Dept Med Biochem, Sendai, Miyagi, Japan. [Kaneko, Hiroshi; Yamamoto, Masayuki; Shimizu, Ritsuko] Tohoku Univ, Tohoku Med Mega Bank Org, Sendai, Miyagi, Japan. [Nakamura, Masahiro; Watanabe, Akira] Kyoto Univ, Ctr iPS Cell Res & Applicat, Kyoto, Japan. [Trainor, Cecelia D.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Shimizu, R (reprint author), Tohoku Univ, Grad Sch Med, Dept Mol Hematol, Sendai, Miyagi, Japan.; Shimizu, R (reprint author), Tohoku Univ, Tohoku Med Mega Bank Org, Sendai, Miyagi, Japan.; Trainor, CD (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM ceceliat@mail.nih.gov; rshimizu@med.tohoku.ac.jp RI Yamamoto, Masayuki/A-4873-2010 FU Ministry of Education, Culture, Sports, Science, and Technology (MEXT) [22118002]; HHS \ NIH \ National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Japan Society for the Promotion of Science (JSPS) [24659142, 15H04759]; Naito Foundation; Japan Agency for Medical Research and Development (AMED); Takeda Medical Research Foundation FX This work, including the efforts of Masayuki Yamamoto, was funded by Ministry of Education, Culture, Sports, Science, and Technology (MEXT) (22118002). This work, including the efforts of Cecelia Trainor, was funded by HHS vertical bar NIH vertical bar National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). This work, including the efforts of Ritsuko Shimizu, was funded by Japan Society for the Promotion of Science (JSPS) (24659142 and 15H04759). This work, including the efforts of Atsushi Hasegawa, was funded by Japan Society for the Promotion of Science (JSPS). This work, including the efforts of Masayuki Yamamoto, was funded by Naito Foundation. This work, including the efforts of Masayuki Yamamoto, was funded by Japan Agency for Medical Research and Development (AMED). This work, including the efforts of Ritsuko Shimizu, was funded by Japan Agency for Medical Research and Development (AMED). This work, including the efforts of Masayuki Yamamoto, was funded by Takeda Medical Research Foundation. NR 48 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2016 VL 36 IS 16 BP 2151 EP 2167 DI 10.1128/MCB.00017-16 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS5JI UT WOS:000380817600005 PM 27215385 ER PT J AU Trexler, AJ Sochacki, KA Taraska, JW AF Trexler, Adam J. Sochacki, Kem A. Taraska, Justin W. TI Imaging the recruitment and loss of proteins and lipids at single sites of calcium-triggered exocytosis SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ADRENAL CHROMAFFIN CELLS; FUSION PORE EXPANSION; CLATHRIN-MEDIATED ENDOCYTOSIS; GREEN FLUORESCENT PROTEIN; SYNAPTIC VESICLE FUSION; SECRETORY GRANULES; PLASMA-MEMBRANE; NEUROTRANSMITTER RELEASE; REGULATED EXOCYTOSIS; INSULIN-SECRETION AB How and when the dozens of molecules that control exocytosis assemble in living cells to regulate the fusion of a vesicle with the plasma membrane is unknown. Here we image with two-color total internal reflection fluorescence microscopy the local changes of 27 proteins at single dense-core vesicles undergoing calcium-triggered fusion. We identify two broad dynamic behaviors of exocytic molecules. First, proteins enriched at exocytic sites are associated with DCVs long before exocytosis, and near the time of membrane fusion, they diffuse away. These proteins include Rab3 and Rab27, rabphilin3a, munc18a, tomosyn, and CAPS. Second, we observe a group of classical endocytic proteins and lipids, including dynamins, amphiphysin, syndapin, endophilin, and PIP2, which are rapidly and transiently recruited to the exocytic site near the time of membrane fusion. Dynamin mutants unable to bind amphiphysin were not recruited, indicating that amphiphysin is involved in localizing dynamin to the fusion site. Expression of mutant dynamins and knockdown of endogenous dynamin altered the rate of cargo release from single vesicles. Our data reveal the dynamics of many key proteins involved in exocytosis and identify a rapidly recruited dynamin/PIP2/BAR assembly that regulates the exocytic fusion pore of dense-core vesicles in cultured endocrine beta cells. C1 [Trexler, Adam J.; Sochacki, Kem A.; Taraska, Justin W.] NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Taraska, JW (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM justin.taraska@nih.gov FU Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health FX We thank J. Silver, J. Hammer, and all members of the Taraska lab for critical reading of the manuscript and S. L. Shyng (Oregon Health & Science University, Portland, OR) for INS-1/832-13 cells. We also thank Patricia Connelly of the National Heart, Lung, and Blood Institute Electron Microscopy Core for help with thin-section TEM. J.W.T. is supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 83 TC 2 Z9 2 U1 5 U2 6 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 AUG 1 PY 2016 VL 27 IS 15 BP 2423 EP 2434 DI 10.1091/mbc.E16-01-0057 PG 12 WC Cell Biology SC Cell Biology GA DS5MH UT WOS:000380825800008 PM 27307587 ER PT J AU Iordanova, MD Deroche, MLD Esber, GR Schoenbaum, G AF Iordanova, Mihaela D. Deroche, Mickael L. D. Esber, Guillem R. Schoenbaum, Geoffrey TI Neural correlates of two different types of extinction learning in the amygdala central nucleus SO NATURE COMMUNICATIONS LA English DT Article ID SURPRISE-INDUCED ENHANCEMENT; ORBITOFRONTAL CORTEX; CONDITIONED FEAR; BASOLATERAL AMYGDALA; INHIBITORY CIRCUITS; IMAGINED OUTCOMES; ATTENTION; BEHAVIOR; OVEREXPECTATION; LESIONS AB Extinction is a fundamental form of memory updating in which one learns to stop expecting an event that no longer occurs. This learning ensues when one experiences a change in environmental contingencies, that is, when an expected outcome fails to occur (simple extinction), or when a novel inflated expectation of a double outcome (overexpectation) is in conflict with the real outcome, and is a process that has been linked to amygdala function. Here, we show that in rats, the same neuronal population in the amygdala central nucleus updates reward expectancies and behaviour in both types of extinction, and neural changes in one paradigm are reflected in the other. This work may have implications for the management of addiction and anxiety disorders that require treatments based on the outcome omission, and disorders such as obesity that could use overexpectation, but not omission strategies. C1 [Iordanova, Mihaela D.; Esber, Guillem R.; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Cellular Neurobiol Res Branch, Behav Neurophysiol Res Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Iordanova, Mihaela D.; Schoenbaum, Geoffrey] Univ Maryland, Dept Anat & Neurobiol, Sch Med, 20 Penn St, Baltimore, MD 21201 USA. [Iordanova, Mihaela D.] Concordia Univ, Dept Psychol, 7141 Sherbrooke West, Montreal, PQ H4B 1R6, Canada. [Iordanova, Mihaela D.] Concordia Univ, Ctr Studies Behav Neurobiol, 7141 Sherbrooke West, Montreal, PQ H4B 1R6, Canada. [Deroche, Mickael L. D.] McGill Univ, Ctr Res Brain Language & Mus, 3640 Rue Montagne, Montreal, PQ H3G 2A8, Canada. [Schoenbaum, Geoffrey] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21287 USA. RP Iordanova, MD; Schoenbaum, G (reprint author), NIDA, Intramural Res Program, Cellular Neurobiol Res Branch, Behav Neurophysiol Res Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA.; Iordanova, MD; Schoenbaum, G (reprint author), Univ Maryland, Dept Anat & Neurobiol, Sch Med, 20 Penn St, Baltimore, MD 21201 USA.; Iordanova, MD (reprint author), Concordia Univ, Dept Psychol, 7141 Sherbrooke West, Montreal, PQ H4B 1R6, Canada.; Iordanova, MD (reprint author), Concordia Univ, Ctr Studies Behav Neurobiol, 7141 Sherbrooke West, Montreal, PQ H4B 1R6, Canada.; Schoenbaum, G (reprint author), Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21287 USA. EM mihaela.iordanova@concordia.ca; geoffrey.schoenbaum@nih.gov OI Schoenbaum, Geoffrey/0000-0001-8180-0701; Deroche, Mickael/0000-0002-8698-2249 FU Intramural Research Program at the Institute of Drug Abuse and a Pathways to Independence Award [1K99DA032649] FX This study was supported by the Intramural Research Program at the Institute of Drug Abuse and a Pathways to Independence Award (1K99DA032649) to M.D.I. Gratitude is extended to Drs Jason Trageser and Brain Sadacca for providing help during the beginning stages of this work, and to Dr Thomas Stalnaker for his insightful and thoughtful criticisms of this manuscript. The opinions expressed in this article are the authors' own and do not reflect the view of the NIH/DHHS. NR 43 TC 0 Z9 0 U1 2 U2 3 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 AUG PY 2016 VL 7 AR 12330 DI 10.1038/ncomms12330 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT8UJ UT WOS:000381770900001 PM 27531638 ER PT J AU Liu, Y Ge, QL Chan, B Liu, HH Singh, SR Manley, J Lee, J Weideman, AM Hou, G Hou, SX AF Liu, Ying Ge, Qinglan Chan, Brian Liu, Hanhan Singh, Shree Ram Manley, Jacob Lee, Jae Weideman, Ann Marie Hou, Gerald Hou, Steven X. TI Whole-animal genome-wide RNAi screen identifies networks regulating male germline stem cells in Drosophila SO NATURE COMMUNICATIONS LA English DT Article ID SELF-RENEWAL; TRANSGENIC RNAI; SIGNALING PATHWAY; TUMOR-SUPPRESSOR; JAK/STAT PATHWAY; GENE-EXPRESSION; DISCS-LARGE; TESTIS; NICHE; MAINTENANCE AB Stem cells are regulated both intrinsically and externally, including by signals from the local environment and distant organs. To identify genes and pathways that regulate stem-cell fates in the whole organism, we perform a genome-wide transgenic RNAi screen through ubiquitous gene knockdowns, focusing on regulators of adult Drosophila testis germline stem cells (GSCs). Here we identify 530 genes that regulate GSC maintenance and differentiation. Of these, we further knock down 113 selected genes using cell-type-specific Gal4s and find that more than half were external regulators, that is, from the local microenvironment or more distal sources. Some genes, for example, versatile (vers), encoding a heterochromatin protein, regulates GSC fates differentially in different cell types and through multiple pathways. We also find that mitosis/cytokinesis proteins are especially important for male GSC maintenance. Our findings provide valuable insights and resources for studying stem cell regulation at the organismal level. C1 [Liu, Ying; Ge, Qinglan; Chan, Brian; Liu, Hanhan; Singh, Shree Ram; Manley, Jacob; Lee, Jae; Weideman, Ann Marie; Hou, Gerald; Hou, Steven X.] NCI, Basic Res Lab, NIH, 1050 Boyles St,Bldg 560,Room 12-70, Frederick, MD 21702 USA. RP Hou, SX (reprint author), NCI, Basic Res Lab, NIH, 1050 Boyles St,Bldg 560,Room 12-70, Frederick, MD 21702 USA. EM hous@mail.nih.gov RI Singh, Shree Ram/B-7614-2008 OI Singh, Shree Ram/0000-0001-6545-583X FU Intramural Research Program of National Institutes of Health, National Cancer Institute FX We thank Ting Xie, Kwang-Wook Choi, Xin Chen, VDRC, Kyoto, National Institute of Genetics (NIG) and the BDSC for fly stocks; Ruth Lehmann, James B. Skeath, Iswar Hariharan and the DSHB for antibodies; Dong Yan and Yanhui Hu for help analysing genes; and Dr Stephen Lockett and Kimberly Peifley of Optical Microscopy and Analysis Laboratory (OMAL) for help with the confocal microscopy. This research was supported by the Intramural Research Program of National Institutes of Health, National Cancer Institute. NR 69 TC 1 Z9 1 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2016 VL 7 AR 12149 DI 10.1038/ncomms12149 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS5YB UT WOS:000380857800001 PM 27484291 ER PT J AU Bernstein, MB Krishnan, S Hodge, JW Chang, JY AF Bernstein, Michael B. Krishnan, Sunil Hodge, James W. Chang, Joe Y. TI Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; INDUCED IMMUNOGENIC MODULATION; TISSUE MICROARRAY EVALUATION; MELANOMA BRAIN METASTASES; BODY RADIATION-THERAPY; CD8(+) T-CELLS; PROSTATE-CANCER; LOCAL RADIATION; TUMOR-CELLS; POTENTIAL INDICATIONS AB Conventional radiotherapy, in addition to its well-established tumoricidal effects, can also activate the host immune system. Radiation therapy modulates tumour phenotypes, enhances antigen presentation and tumour immunogenicity, increases production of cytokines and alters the tumour microenvironment, enabling destruction of the tumour by the immune system. Investigating the combination of radiotherapy with immunotherapeutic agents, which also promote the host antitumour immune response is, therefore, a logical progression. As the spectrum of clinical use of stereotactic radiotherapy continues to broaden, the question arose as to whether the ablative radiation doses used can also stimulate immune responses and, if so, whether we can amplify these effects by combining immunotherapy and stereotactic ablative radiotherapy (SABR). In this Perspectives article, we explore the preclinical and clinical evidence supporting activation of the immune system following SABR. We then examine studies that provide data on the effectiveness of combining these two techniques-immunotherapy and SABR-in an approach that we have termed 'ISABR'. Lastly, we provide general guiding principles for the development of future clinical trials to investigate the efficacy of ISABR in the hope of generating further interest in these exciting developments. C1 [Bernstein, Michael B.; Krishnan, Sunil; Chang, Joe Y.] Univ Texas MD Anderson Canc Ctr, Div Radiat Oncol, Unit 97, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Hodge, James W.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, Bldg 10,Room 8B13, Bethesda, MD 20892 USA. RP Chang, JY (reprint author), Univ Texas MD Anderson Canc Ctr, Div Radiat Oncol, Unit 97, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM jychang@mdanderson.org RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU NCI NIH HHS [P30 CA016672] NR 66 TC 11 Z9 12 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD AUG PY 2016 VL 13 IS 8 BP 516 EP 524 DI 10.1038/nrclinonc.2016.30 PG 9 WC Oncology SC Oncology GA DS4MU UT WOS:000380756000008 PM 26951040 ER PT J AU Schindler, CW Redhi, GH Vemuri, K Makriyannis, A Le Foll, B Bergman, J Goldberg, SR Justinova, Z AF Schindler, Charles W. Redhi, Godfrey H. Vemuri, Kiran Makriyannis, Alexandros Le Foll, Bernard Bergman, Jack Goldberg, Steven R. Justinova, Zuzana TI Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID CB1 RECEPTOR ANTAGONIST; CONDITIONED PLACE PREFERENCES; SEEKING BEHAVIOR; NUCLEUS-ACCUMBENS; RISK-FACTORS; FOOD-INTAKE; RATS; COCAINE; ADDICTION; SR141716A AB Nicotine, the main psychoactive component of tobacco, and (-) -Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior. Drugs that act as inverse agonists of cannabinoid CBI receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC, but their clinical use is hindered by potentially serious side effects. The recently developed CBI-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence. Here we compare attenuation of nicotine and THC reinforcement and reinstatement in squirrel monkeys by the CBI-receptor inverse agonist rimonabant and by the recently developed CB1-receptor neutral antagonist AM4113. Both rimonabant and AM4113 reduced two effects of nicotine and THC that play major roles in tobacco and marijuana dependence: (1) maintenance of high rates of drug-taking behavior, and (2) priming-or cue-induced reinstatement of drug-seeking behavior in abstinent subjects (models of relapse). In contrast, neither rimonabant nor AM4113 modified cocaine-reinforced or food-reinforced operant behavior under similar experimental conditions. However, both rimonabant and AM4113 reduced cue-induced reinstatement in monkeys trained to self-administer cocaine, suggesting the involvement of a common cannabinoid-mediated mechanism in the cue-induced reinstatement for different drugs of abuse. These findings point to CBI-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence. C1 [Schindler, Charles W.; Redhi, Godfrey H.; Goldberg, Steven R.; Justinova, Zuzana] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD USA. [Vemuri, Kiran; Makriyannis, Alexandros] Northeastern Univ, Dept Pharmaceut Sci, Ctr Drug Discovery, Boston, MA 02115 USA. [Vemuri, Kiran; Makriyannis, Alexandros] Northeastern Univ, Ctr Drug Discovery, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Le Foll, Bernard] Univ Toronto, Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON, Canada. [Le Foll, Bernard] Ctr Addict & Mental Hlth, Alcohol Res & Treatment Clin, Addict Med Serv, Ambulatory Care & Structured Treatments, Toronto, ON, Canada. [Le Foll, Bernard] Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Toronto, ON, Canada. [Le Foll, Bernard] Univ Toronto, Dept Family & Community Med, Toronto, ON, Canada. [Le Foll, Bernard] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada. [Le Foll, Bernard] Univ Toronto, Div Brain & Therapeut, Dept Psychiat, Toronto, ON, Canada. [Le Foll, Bernard] Univ Toronto, Inst Med Sci, Toronto, ON, Canada. [Bergman, Jack] Harvard Med Sch, McLean Hosp, Preclin Pharmacol Program, Boston, MA USA. RP Justinova, Z (reprint author), NIDA, Preclin Pharmacol Sect, Intramural Res Program, NIH,US Dept HHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM zjustino@intra.nida.nih.gov RI Justinova, Zuzana/A-9109-2011 OI Justinova, Zuzana/0000-0001-5793-7484 FU NIDA [R01DA19205, R01DA31020, P01DA009158, R01DA007215, R37DA023142, R37DA003801]; Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX This study is dedicated to the memory of Dr Steven R Goldberg (died on 25 November 2014). AM4113 was provided by Dr Alexandros Makriyannis. Rimonabant was provided by NIDA Drug Supply Program (Bethesda, MD). We thank Dr Ira Baum and Philip White for their excellent veterinary assistance during the study. This work was supported in part by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, by NIDA grants R01DA19205, R01DA31020 (to Jack Bergman), and P01DA009158, R01DA007215, R37DA023142, and R37DA003801 (to Alexandros Makriyannis). NR 57 TC 3 Z9 3 U1 6 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2016 VL 41 IS 9 BP 2283 EP 2293 DI 10.1038/npp.2016.27 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DS1SC UT WOS:000380377300011 PM 26888056 ER PT J AU Eisenberg, DP Kohn, PD Hegarty, CE Ianni, AM Kolachana, B Gregory, MD Masdeu, JC Berman, KF AF Eisenberg, Daniel P. Kohn, Philip D. Hegarty, Catherine E. Ianni, Angela M. Kolachana, Bhaskar Gregory, Michael D. Masdeu, Joseph C. Berman, Karen F. TI Common Variation in the DOPA Decarboxylase (DDC) Gene and Human Striatal DDC Activity In Vivo SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID AMINO-ACID DECARBOXYLASE; GENOME-WIDE ASSOCIATION; LIVING HUMAN BRAIN; SCHIZOPHRENIA; ATTENTION; DISORDER; DYSFUNCTION; PET; POPULATION; PSYCHOSIS AB The synthesis of multiple amine neurotransmitters, such as dopamine, norepinephrine, serotonin, and trace amines, relies in part on DOPA decarboxylase (DDC, AADC), an enzyme that is required for normative neural operations. Because rare, loss-of-function mutations in the DDC gene result in severe enzymatic deficiency and devastating autonomic, motor, and cognitive impairment, DDC common genetic polymorphisms have been proposed as a source of more moderate, but clinically important, alterations in DDC function that may contribute to risk, course, or treatment response in complex, heritable neuropsychiatric illnesses. However, a direct link between common genetic variation in DDC and DDC activity in the living human brain has never been established. We therefore tested for this association by conducting extensive genotyping across the DDC gene in a large cohort of 120 healthy individuals, for whom DDC activity was then quantified with [F-18]-FDOPA positron emission tomography (PET). The specific uptake constant, K-i, a measure of DDC activity, was estimated for striatal regions of interest and found to be predicted by one of five tested haplotypes, particularly in the ventral striatum. These data provide evidence for cis-acting, functional common polymorphisms in the DDC gene and support future work to determine whether such variation might meaningfully contribute to DDC-mediated neural processes relevant to neuropsychiatric illness and treatment. C1 [Eisenberg, Daniel P.; Kohn, Philip D.; Hegarty, Catherine E.; Ianni, Angela M.; Kolachana, Bhaskar; Gregory, Michael D.; Masdeu, Joseph C.; Berman, Karen F.] NIMH, Sect Integrat Neuroimaging, Clin & Translat Neurosci Branch, Intramural Res Program,NIH,DHHS, Bethesda, MD USA. RP Berman, KF (reprint author), NIMH, Sect Integrat Neuroimaging, NIH, Intramural Res Program, 9000 Rockville Pike,Bldg 10,Room 3C103A, Bethesda, MD 20892 USA. EM Karen.Berman@nih.gov RI Eisenberg, Daniel/S-4342-2016 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (Bethesda, MD) [MH002717 (NCT00024622)] FX This work was funded by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (Bethesda, MD) under project MH002717 (NCT00024622). The authors declare no conflict of interest with respect to this work. NR 37 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2016 VL 41 IS 9 BP 2303 EP 2308 DI 10.1038/npp.2016.31 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DS1SC UT WOS:000380377300013 PM 26924680 ER PT J AU Inoue-Choi, M Virk-Baker, MK Aschebrook-Kilfoy, B Cross, AJ Subar, AF Thompson, FE Sinha, R Ward, MH AF Inoue-Choi, Maki Virk-Baker, Mandeep K. Aschebrook-Kilfoy, Briseis Cross, Amanda J. Subar, Amy F. Thompson, Frances E. Sinha, Rashmi Ward, Mary H. TI Development and calibration of a dietary nitrate and nitrite database in the NIH-AARP Diet and Health Study SO PUBLIC HEALTH NUTRITION LA English DT Article DE Nitrate; Nitrite; Dietary database; FFQ ID N-NITROSO COMPOUNDS; FOOD FREQUENCY QUESTIONNAIRES; RETIRED-PERSONS DIET; CURED MEAT-PRODUCTS; GASTRIC-CANCER; AMERICAN-ASSOCIATION; NATIONAL-INSTITUTES; NETHERLANDS COHORT; COLORECTAL ADENOMA; OVARIAN-CANCER AB Objective: Nitrate and nitrite are probable human carcinogens when ingested under conditions that increase the formation of N-nitroso compounds. There have been limited efforts to develop US databases of dietary nitrate and nitrite for standard FFQ. Here we describe the development of a dietary nitrate and nitrite database and its calibration. Design: We analysed data from a calibration study of 1942 members of the NIH-AARP (NIH-AARP, National Institutes of Health-AARP) Diet and Health Study who reported all foods and beverages consumed on the preceding day in two non-consecutive 24 h dietary recalls (24HR) and completed an FFQ. Based on a literature review, we developed a database of nitrate and nitrite contents for foods reported on these 24HR and for food category line items on the FFQ. We calculated daily nitrate and nitrite intakes for both instruments, and used a measurement error model to compute correlation coefficients and attenuation factors for the FFQ-based intake estimates using 24HR-based values as reference data. Results: FFQ-based median nitrate intake was 68.9 and 74.1 mg/d,and nitrite intake was 1.3 and 1.0 mg/d, in men and women, respectively. These values were similar to 24HR-based intake estimates. Energy-adjusted correlation coefficients between FFQ-and 24HR-based values for men and women respectively were 0.59 and 0.57 for nitrate and 0.59 and 0.58 for nitrite; energy-adjusted attenuation factors were 0.59 and 0.57 for nitrate and 0.47 and 0.38 for nitrite. Conclusions: The performance of the FFQ in assessing dietary nitrate and nitrite intakes is comparable to that for many other macro-and micronutrients. C1 [Inoue-Choi, Maki; Aschebrook-Kilfoy, Briseis; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 9609 Med Ctr Dr,6E314, Rockville, MD 20850 USA. [Inoue-Choi, Maki] Natl Inst Minor Hlth & Hlth Dispar, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Virk-Baker, Mandeep K.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Rockville, MD USA. [Aschebrook-Kilfoy, Briseis] Univ Chicago, Dept Publ Hlth Sci, Div Biol Sci, Chicago, IL USA. [Cross, Amanda J.] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Subar, Amy F.; Thompson, Frances E.] NCI, Epidemiol & Genom Res Program, Risk Factor Assessment Branch, Div Canc Control & Populat Sci, Rockville, MD USA. [Sinha, Rashmi] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. RP Ward, MH (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 9609 Med Ctr Dr,6E314, Rockville, MD 20850 USA. EM wardm@exchange.nih.gov FU Intramural Research Program of the NCI, NIH, Department of Health and Human Services; Division of Intramural Research of the National Institute on Minority Health and Health Disparities, NIH; Cancer Prevention Fellowship at the NCI, NIH; NIH training grant [TU2CA105666] FX This research was partially supported by the Intramural Research Program of the NCI, NIH, Department of Health and Human Services. M.I.-C. was partly supported by the Division of Intramural Research of the National Institute on Minority Health and Health Disparities, NIH. M.K.V.-B. was supported by the Cancer Prevention Fellowship at the NCI, NIH. B.A.-K. was supported by an NIH training grant (number TU2CA105666). NR 70 TC 0 Z9 0 U1 1 U2 2 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 EI 1475-2727 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD AUG PY 2016 VL 19 IS 11 BP 1934 EP 1943 DI 10.1017/S1368980015003407 PG 10 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA DS6MY UT WOS:000380897300003 PM 26626817 ER PT J AU Salazar, A Tolivaisa, S Allard, D Bishop, TS Bousleiman, S Clark, K Dalton, W Harris, S Hale, K Hill, K Johnson, F Mallett, G Moseley, L Ortiz, F Wilson, C Thom, EA AF Salazar, Ashley Tolivaisa, Susan Allard, Donna Bishop, Tammy S. Bousleiman, Sabine Clark, Kelly Dalton, Wendy Harris, Stacy Hale, Kathy Hill, Kim Johnson, Francee Mallett, Gail Moseley, Lisa Ortiz, Felecia Wilson, Cynthia Thom, Elizabeth A. CA Eunice Kennedy Shriver Natl Inst C TI What we have learned about best practices for recruitment and retention in multicenter pregnancy studies SO SEMINARS IN PERINATOLOGY LA English DT Review DE pregnancy research; subject recruitment; subject retention; multi-center research ID RANDOMIZED-TRIAL AB For 30 years, the Eunice Kennedy Shriuer National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network has had significant impact on clinical practice in obstetrics. The MFMU Network has conducted 50 randomized clinical trials and observational studies designed to improve pregnancy outcomes for mothers and children. Each center has a designated clinical research nurse coordinator who coordinates the day-to-day operations of each trial and leads a research team that is responsible for recruitment and retention of participants. Some of the lessons learned by the nurse coordinators over the past 30 years are described with examples from recent studies. Best practices that we have amassed from our experience are also described. (C) 2016 Elsevier Inc. All rights reserved. C1 [Salazar, Ashley] Univ Texas Med Branch, 301 Univ Blvd, Galveston, TX 77555 USA. [Tolivaisa, Susan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Allard, Donna] Brown Univ, Women & Infants Hosp Rhode Isl, Providence, RI 02912 USA. [Bishop, Tammy S.] Duke Univ, Durham, NC USA. [Bousleiman, Sabine] Columbia Univ, Med Ctr, New York, NY USA. [Clark, Kelly] Univ N Carolina, Chapel Hill, NC USA. [Dalton, Wendy] Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Harris, Stacy] Univ Alabama Birmingham, Birmingham, AL USA. [Hale, Kathy] Univ Colorado, Anschutz Med Campus, Aurora, CO USA. [Hill, Kim] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Johnson, Francee] Ohio State Univ, Columbus, OH 43210 USA. [Mallett, Gail] Northwestern Univ, Chicago, IL 60611 USA. [Moseley, Lisa] Univ Texas Southwestern Med Ctr, Houston, TX USA. [Ortiz, Felecia] Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Houston, TX 77030 USA. [Wilson, Cynthia] Stanford Univ, Stanford, CA 94305 USA. [Thom, Elizabeth A.] George Washington Univ, Washington, DC USA. RP Salazar, A (reprint author), Univ Texas Med Branch, 301 Univ Blvd, Galveston, TX 77555 USA. EM assalaza@utmb.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), United States; National Heart, Lung, and Blood Institute (NHLBI), United States; National Center for Research Resources (NCRR), United States, and General Clinical Research Centers (GCRC) [HD21410, HD27860, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, HD53097, HD53118, HD68282, HD68268, HD36801, UL1RR000005, UL1-RR024153, UL1-RR024989, UL1RR-025764, M01-RR00034, M01-RR00080, C06-RR11234] FX This work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), United States, the National Heart, Lung, and Blood Institute (NHLBI), United States, the National Center for Research Resources (NCRR), United States, and General Clinical Research Centers (GCRC) [HD21410, HD27860, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, HD53097, HD53118, HD68282, HD68268, HD36801, UL1RR000005, UL1-RR024153, UL1-RR024989, UL1RR-025764, M01-RR00034, M01-RR00080, and C06-RR11234]. Comments and views of the authors do not necessarily represent views of the NIH. NR 8 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0146-0005 EI 1558-075X J9 SEMIN PERINATOL JI Semin. Perinatol. PD AUG PY 2016 VL 40 IS 5 BP 321 EP 327 DI 10.1053/j.semperi.2016.03.010 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DT8WU UT WOS:000381777200010 PM 27174555 ER PT J AU Thom, EA Rice, MM Saade, GR Reddy, UM AF Thom, Elizabeth A. Rice, Madeline Murguia Saade, George R. Reddy, Uma M. CA Eunice Kennedy Shriver Natl Inst C TI What we have learned about the design of randomized trials in pregnancy SO SEMINARS IN PERINATOLOGY LA English DT Review DE randomized trial; study design; bias; primary outcome ID PRETERM BIRTH; ANTENATAL CORTICOSTEROIDS; PREVENTION; OUTCOMES; CAPROATE; COURSES; SINGLE AB For nearly 30 years the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network has been conducting randomized trials in pregnant women, many of which have changed clinical practice. Since 1986, the MFMU Network has conducted 29 randomized trials, of which the 17. trials started or completed since 2003 are described here. Study design choices are described including decisions regarding the fundamental questions to be answered and the rationale behind choices of primary and secondary outcomes. Some of the potential pitfalls, particularly relating to bias, that can affect the interpretation of trial results are described along with the mechanisms that the Network has used to avoid or minimize them. (C) 2016 Elsevier Inc. All rights reserved. C1 [Thom, Elizabeth A.; Rice, Madeline Murguia] George Washington Univ, Ctr Biostat, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. [Saade, George R.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Thom, EA (reprint author), George Washington Univ, Ctr Biostat, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM e_thom@bsc.gwu.edu FU NICHD NIH HHS [U01 HD036801, U10 HD036801] NR 26 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0146-0005 EI 1558-075X J9 SEMIN PERINATOL JI Semin. Perinatol. PD AUG PY 2016 VL 40 IS 5 BP 328 EP 334 DI 10.1053/j.semperi.2016.03.011 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DT8WU UT WOS:000381777200011 PM 27344190 ER PT J AU Shaw, ND McHill, AW Schiavon, M Kangarloo, T Mankowski, PW Cobelli, C Klerman, EB Hall, JE AF Shaw, Natalie D. McHill, Andrew W. Schiavon, Michele Kangarloo, Tairmae Mankowski, Piotr W. Cobelli, Claudio Klerman, Elizabeth B. Hall, Janet E. TI Effect of Slow Wave Sleep Disruption on Metabolic Parameters in Adolescents SO SLEEP LA English DT Article DE glucose; insulin; puberty; slow wave sleep ID BETA-CELL FUNCTION; EYE-MOVEMENT SLEEP; INSULIN-RESISTANCE; GLUCOSE-TOLERANCE; OBESE ADOLESCENTS; APNEA SYNDROME; CHILDREN; DURATION; ARCHITECTURE; ASSOCIATION AB Study Objectives: Cross-sectional studies report a correlation between slow wave sleep (SWS) duration and insulin sensitivity (SI) in children and adults. Suppression of SWS causes insulin resistance in adults but effects in children are unknown. This study was designed to determine the effect of SWS fragmentation on SI in children. Methods: Fourteen pubertal children (11.3-14.1 y, body mass index 29th to 97th percentile) were randomized to sleep studies and mixed meal (MM) tolerance tests with and without SWS disruption. Beta-cell responsiveness (F) and SI were determined using oral minimal modeling. Results: During the disruption night, auditory stimuli (68.1 +/- 10.7/night; mean +/- standard error) decreased SWS by 40.0 +/- 8.0%. SWS fragmentation did not affect fasting glucose (non-disrupted 76.9 +/- 2.3 versus disrupted 80.6 +/- 2.1 mg/dL), insulin (9.2 +/- 1.6 versus 10.4 +/- 2.0 mu IU/mL), or C-peptide (1.9 +/- 0.2 versus 1.9 +/- 0.1 ng/mL) levels and did not impair SI (12.9 +/- 2.3 versus 10.1 +/- 1.6 10(-4) dL/kg/min per mu IU/mL) or Phi (73.4 +/- 7.8 versus 74.4 +/- 8.4 10(-9) min(-1)) to a MM challenge. Only the subjects in the most insulin-sensitive tertile demonstrated a consistent decrease in SI after SWS disruption. Conclusion: Pubertal children across a range of body mass indices may be resistant to the adverse metabolic effects of acute SWS disruption. Only those subjects with high SI (i.e., having the greatest "metabolic reserve") demonstrated a consistent decrease in SI. These results suggest that adolescents may have a unique ability to adapt to metabolic stressors, such as acute SWS disruption, to maintain euglycemia. Additional studies are necessary to confirm that this resiliency is maintained in settings of chronic SWS disruption. C1 [Shaw, Natalie D.; Kangarloo, Tairmae; Hall, Janet E.] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, Boston, MA 02114 USA. [Shaw, Natalie D.; Hall, Janet E.] NIEHS, Clin Res Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [McHill, Andrew W.; Mankowski, Piotr W.; Klerman, Elizabeth B.] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, 75 Francis St, Boston, MA 02115 USA. [McHill, Andrew W.; Mankowski, Piotr W.; Klerman, Elizabeth B.] Harvard Med Sch, Div Sleep Med, Boston, MA USA. [Schiavon, Michele; Cobelli, Claudio] Univ Padua, Dept Informat Engn, Padua, Italy. RP Shaw, ND (reprint author), NIEHS, Bldg 101,A349,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM natalie.shaw@nih.gov OI Shaw, Natalie/0000-0002-0847-9170; Hall, Janet/0000-0003-4644-3061 FU NIH [K23HD073304-02, T32HL007901, K24HL105664, R01HL114088, R01GM105018, P01AG009975, R21HD086392, NSBRI HFP02802, HFP04201, R01 DK-78646, R01 DK-82396]; NIH (National Institute of Diabetes and Digestive Diseases [NIDDK]-Boston Area Diabetes Endocrinology Research Center Pilot Research Grant Award); Pediatric Endocrine Society; Harvard Catalyst (The Harvard Clinical and Translational Science Center) [1UL1TR001102-01]; Harvard University; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [NIEHS] (Lasker Clinical Research Scholar Award) [1SI2ES025429-01]; Marathon Pharmaceuticals FX This was not an industry supported study. Dr. Shaw received support from the NIH (K23HD073304-02 and the National Institute of Diabetes and Digestive Diseases [NIDDK]-sponsored Boston Area Diabetes Endocrinology Research Center Pilot Research Grant Award), the Pediatric Endocrine Society, and Harvard Catalyst (The Harvard Clinical and Translational Science Center [Award #1UL1TR001102-01] and financial contributions from Harvard University and its affiliated academic health care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources or the National Institutes of Health). Drs. McHill, Klerman, and Cobelli are funded by the NIH (T32HL007901; K24HL105664, R01HL114088, R01GM105018, P01AG009975, R21HD086392, NSBRI HFP02802, HFP04201; and R01 DK-78646 and R01 DK-82396, respectively). This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [NIEHS] (1SI2ES025429-01, Lasker Clinical Research Scholar Award to Dr. Shaw). Dr. Hall has received research support from Marathon Pharmaceuticals. Dr. Vienne has consulted for Celgene International Sarl. The other authors have indicated no financial conflicts of interest. Clinical studies were conducted in the Clinical Research Unit at Massachusetts General Hospital, Boston, MA. Analyses were performed at NIEHS, Brigham and Women's Hospital, and the University of Padova. This study does not meet the FDAAA 801 definition of an "applicable clinical trial" and as such was not registered at clinicaltrials.gov. NR 51 TC 2 Z9 2 U1 3 U2 3 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD AUG 1 PY 2016 VL 39 IS 8 BP 1591 EP 1599 DI 10.5665/sleep.6028 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT8NF UT WOS:000381746800015 PM 27166229 ER PT J AU Nieto-Estevez, V Oueslati-Morales, CO Li, L Pickel, J Morales, AV Vicario-Abejon, C AF Nieto-Estevez, Vanesa Oueslati-Morales, Carlos O. Li, Lingling Pickel, James Morales, Aixa V. Vicario-Abejon, Carlos TI Brain Insulin-Like Growth Factor-I Directs the Transition from Stem Cells to Mature Neurons During Postnatal/Adult Hippocampal Neurogenesis SO STEM CELLS LA English DT Article DE Brain IGF-I; Neural stem cells; Neurogenesis; Hippocampus; Conditional knockout ID CENTRAL-NERVOUS-SYSTEM; ADULT-RAT BRAIN; IGF-I; DENTATE GYRUS; OLFACTORY-BULB; TRANSCRIPTIONAL CONTROL; RECEPTOR EXPRESSION; MOUSE HIPPOCAMPUS; PROGENITOR CELLS; ANALYSIS REVEALS AB The specific actions of insulin-like growth factor-I (IGF-I) and the role of brain-derived IGF-I during hippocampal neurogenesis have not been fully defined. To address the influence of IGF-I on the stages of hippocampal neurogenesis, we studied a postnatal/adult global Igf-I knockout (KO) mice (Igf-I-/-) and a nervous system Igf-I conditional KO (Igf-I-Delta/Delta). In both KO mice we found an accumulation of Tbr2(+)-intermediate neuronal progenitors, some of which were displaced in the outer granule cell layer (GCL) and the molecular layer (ML) of the dentate gyrus (DG). Similarly, more ectopic Ki67(+)-cycling cells were detected. Thus, the GCL was disorganized with significant numbers of Prox1(+)-granule neurons outside this layer and altered morphology of radial glial cells (RGCs). Dividing progenitors were also generated in greater numbers in clonal hippocampal stem cell (HPSC) cultures from the KO mice. Indeed, higher levels of Hes5 and Ngn2, transcription factors that maintain the stem and progenitor cell state, were expressed in both HPSCs and the GCL-ML from the Igf-ID/D mice. To determine the impact of Igf-I deletion on neuronal generation in vivo, progenitors in Igf-I-/- and Igf-I+/+ mice were labeled with a GFP-expressing vector. This revealed that in the Igf-I-/- mice more GFP(+)-immature neurons were formed and they had less complex dendritic trees. These findings indicate that local IGF-I plays critical roles during postnatal/adult hippocampal neurogenesis, regulating the transition from HPSCs and progenitors to mature granule neurons in a cell stage-dependent manner. C1 [Nieto-Estevez, Vanesa; Oueslati-Morales, Carlos O.; Li, Lingling; Morales, Aixa V.; Vicario-Abejon, Carlos] CSIC, Inst Cajal, Ave Doctor Arce 37, E-28002 Madrid, Spain. [Nieto-Estevez, Vanesa; Oueslati-Morales, Carlos O.; Vicario-Abejon, Carlos] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain. [Pickel, James] NIMH, Transgen Core, NIH, Bethesda, MD 20892 USA. RP Vicario-Abejon, C (reprint author), CSIC, Inst Cajal, Ave Doctor Arce 37, E-28002 Madrid, Spain. EM cvicario@cajal.csic.es RI Morales, Aixa V./M-2135-2016 OI Morales, Aixa V./0000-0001-6295-5142 FU Spanish Ministerio de Ciencia e Innovacion (MICINN) [BFU2007-61230, BFU2010-1963, SAF2013-4759R]; Spanish Ministerio de Economia y Competitividad (MINECO) [BFU2007-61230, BFU2010-1963, SAF2013-4759R]; Instituto de Salud Carlos III (ISCIII) [CIBERNED CB06/05/0065]; Comunidad de Madrid [S2011/BMD-2336]; MICINN; MINECO; [BFU2014-57494-R] FX We wish to thank Dr. A. Lepier (Institute of Physiological Genomics, Muenchen) for sharing with us the 1F8 cells and protocols, Drs. D. LeRoith and S. Yakar (Mount Sinai School of Medicine, New York) for providing us with the Igf-l loxP mice, Drs. G. Provenzano and Y. Bozzi (University of Trento, Italy) for input on Igf-I in situ hybridization, and M.J. Roman (Institute Cajal, Madrid) for her technical support. This work was funded by grants from the Spanish Ministerio de Ciencia e Innovacion and Ministerio de Economia y Competitividad (MICINN and MINECO; BFU2007-61230, BFU2010-1963 and SAF2013-4759R, the Instituto de Salud Carlos III (ISCIII; CIBERNED CB06/05/0065), and the Comunidad de Madrid (S2011/BMD-2336) to C.V.-A; and BFU2014-57494-R to A.V.M. V.N.-E was supported by a FPI Fellowship from the MICINN and MINECO. NR 79 TC 2 Z9 2 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD AUG PY 2016 VL 34 IS 8 BP 2194 EP 2209 DI 10.1002/stem.2397 PG 16 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA DS4RD UT WOS:000380767600017 PM 27144663 ER PT J AU Lima, FO Silva, GS Furie, KL Frankel, MR Lev, MH Camargo, ECS Haussen, DC Singhal, AB Koroshetz, WJ Smith, WS Nogueira, RG AF Lima, Fabricio O. Silva, Gisele S. Furie, Karen L. Frankel, Michael R. Lev, Michael H. Camargo, Erica C. S. Haussen, Diogo C. Singhal, Aneesh B. Koroshetz, Walter J. Smith, Wade S. Nogueira, Raul G. TI Field Assessment Stroke Triage for Emergency Destination A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes SO STROKE LA English DT Article DE cerebrovascular occlusion; scale; stroke, acute, prehospital emergency care; triage ID ACUTE ISCHEMIC-STROKE; SEVERITY SCALE; THROMBECTOMY; ANGIOGRAPHY; VALIDATION; DESIGN; SCORE; TIME AB Background and Purpose-Patients with large vessel occlusion strokes (LVOS) may be better served by direct transfer to endovascular capable centers avoiding hazardous delays between primary and comprehensive stroke centers. However, accurate stroke field triage remains challenging. We aimed to develop a simple field scale to identify LVOS. Methods-The Field Assessment Stroke Triage for Emergency Destination (FAST-ED) scale was based on items of the National Institutes of Health Stroke Scale (NIHSS) with higher predictive value for LVOS and tested in the Screening Technology and Outcomes Project in Stroke (STOPStroke) cohort, in which patients underwent computed tomographic angiography within the first 24 hours of stroke onset. LVOS were defined by total occlusions involving the intracranial internal carotid artery, middle cerebral artery-M1, middle cerebral artery-2, or basilar arteries. Patients with partial, bihemispheric, and anterior+posterior circulation occlusions were excluded. Receiver operating characteristic curve, sensitivity, specificity, positive predictive value, and negative predictive value of FAST-ED were compared with the NIHSS, Rapid Arterial Occlusion Evaluation (RACE) scale, and Cincinnati Prehospital Stroke Severity (CPSS) scale. Results-LVO was detected in 240 of the 727 qualifying patients (33%). FAST-ED had comparable accuracy to predict LVO to the NIHSS and higher accuracy than RACE and CPSS (area under the receiver operating characteristic curve: FAST-ED=0.81 as reference; NIHSS=0.80, P=0.28; RACE=0.77, P=0.02; and CPSS=0.75, P=0.002). A FAST-ED >= 4 had sensitivity of 0.60, specificity of 0.89, positive predictive value of 0.72, and negative predictive value of 0.82 versus RACE >= 5 of 0.55, 0.87, 0.68, and 0.79, and CPSS >= 2 of 0.56, 0.85, 0.65, and 0.78, respectively. Conclusions-FAST-ED is a simple scale that if successfully validated in the field, it may be used by medical emergency professionals to identify LVOS in the prehospital setting enabling rapid triage of patients. C1 [Lima, Fabricio O.] Univ Fortaleza, Ctr Ciencias Saude, Curso Med, Fortaleza, CE, Brazil. [Silva, Gisele S.] Univ Fed Sao Paulo, Dept Neurol, Neurovasc Serv, Sao Paulo, SP, Brazil. [Furie, Karen L.] Brown Univ, Dept Neurol, Providence, RI USA. [Frankel, Michael R.; Haussen, Diogo C.; Nogueira, Raul G.] Emory Univ, Sch Med, Grady Mem Hosp, Marcus Stroke & Neurosci Ctr,Neuroendovasc & Neur, Atlanta, GA USA. [Lev, Michael H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Camargo, Erica C. S.; Singhal, Aneesh B.] Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Boston, MA USA. [Koroshetz, Walter J.] NINDS, NIH, Bethesda, MD USA. [Smith, Wade S.] Univ Calif San Francisco, Dept Neurol, Neurovasc Serv, San Francisco, CA USA. RP Nogueira, RG (reprint author), 49 Jesse Hill Dr,SE Room 333, Atlanta, GA 30303 USA. EM raul.g.nogueira@emory.edu FU NIH [R01NS051412, P50NS051343, R21NS077442, R21-NS085574, U10NS086729]; Biogen; Boehringer Ingelheim; Stryker Neurovascular-modest FX Dr Lev reports working as consultant for GE Healthcare, MLNM Pharm, MedyMatch, and D-Pharm. He also reports receiving institution research support from GE Healthcare. Dr Singhal is a deputy PI of the New England Regional Coordinating Center for the National Institutes of Health (NIH) StrokeNet. He reports receiving partial support from the following NIH grants during the conduct of the study: R01NS051412, P50NS051343, R21NS077442, R21-NS085574, and U10NS086729. He is on ACTION (A Multicenter, Double-Blind, Placebo-Controlled, Randomized, Parallel-Group Study to Evaluate the Safety and Efficacy of Intravenous Natalizumab on Reducing Infarct Volume in Acute Ischemic Stroke) trial Advisory Board sponsored by Biogen. He is the site PI of stroke clinical trial sponsored by Boehringer Ingelheim. Dr Smith is a consultant for Stryker Neurovascular, DSMB board. Dr Nogueira is the PI for Trevo-2 Trial (sponsored by Stryker Neurovascular-modest) and the DAWN (Diffusion Weighted Imaging [DWI] or Computerized Tomography Perfusion [CTP] Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention) trial (no compensation). He is on the Steering Committee of SWIFT Trial (modest) and SWIFT Prime (no compensation). He receives compensation from the STAR (Solitaire FR Thrombectomy for Acute Revascularisation) trial (Angiographic Core Lab-significant). He is also part of the Executive Committee for the Penumbra 3D separator Trial (no compensation). He is also an Editor-In-Chief of the Interventional Neurology Journal (no compensation). The other authors report no conflicts. NR 19 TC 6 Z9 6 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD AUG PY 2016 VL 47 IS 8 BP 1997 EP 2002 DI 10.1161/STROKEAHA.116.013301 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DS5GC UT WOS:000380808400017 PM 27364531 ER PT J AU Kochmann, M Locatis, C AF Kochmann, Matthias Locatis, Craig TI Direct to Consumer Mobile Teledermatology Apps: An Exploratory Study SO TELEMEDICINE AND E-HEALTH LA English DT Article DE teledermatology; telemedicine; technology; m-health; dermatology AB Background: Since 2012, "Direct to Consumer'' mobile teledermatology apps have become more available, relinquishing many data collection tasks normally done by healthcare professionals directly to patients. Introduction: To determine user friendliness, diagnostic quality, and service of commercially available mobile teledermatology apps. Materials and Methods: All mobile teledermatology apps available at the Apple App Store were reviewed. The two most popular mobile teledermatology apps were identified and tested together with three apps having similar functionality using a single case of a patient who was also examined by a dermatologist in-person. Results: Apps varied in diagnostic scope, data gathering methods, services, rendered results, and in geographic coverage and cost. Discussion: None of the apps take a history as thoroughly as recommended by textbooks. Key medical questions like current medications and allergies are not asked often. Most apps rendered concordant results, except for the one having the least thorough history taking. Conclusions: Mobile teledermatology application interfaces, services, and cost vary, with some risking medical errors and possible distribution of continuity of care. The American Telemedicine Association's guidelines for teledermatology need to address the use of direct to consumer apps. To protect consumers, app regulation, certification, or guidelines suggesting appropriate development and use might be considered. C1 [Kochmann, Matthias] Suny Downstate Med Ctr, Dept Pediat, 450 Clarkson Ave,Box 49, Brooklyn, NY 11203 USA. [Locatis, Craig] NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RP Kochmann, M (reprint author), Suny Downstate Med Ctr, Dept Pediat, 450 Clarkson Ave,Box 49, Brooklyn, NY 11203 USA. EM matthias.kochmann@downstate.edu FU National Institutes of Health; National Library of Medicine FX This research was supported by the intramural research program at the National Institutes of Health and the National Library of Medicine. NR 10 TC 0 Z9 0 U1 9 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 EI 1556-3669 J9 TELEMED E-HEALTH JI Telemed. e-Health PD AUG PY 2016 VL 22 IS 8 BP 689 EP 693 DI 10.1089/tmj.2015.0189 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DS5EZ UT WOS:000380805400009 PM 26960113 ER PT J AU Nelson, EA Barnes, AB Wiehle, RD Fontenot, GK Hoenen, T White, JM AF Nelson, Elizabeth A. Barnes, Alyson B. Wiehle, Ronald D. Fontenot, Gregory K. Hoenen, Thomas White, Judith M. TI Clomiphene and Its Isomers Block Ebola Virus Particle Entry and Infection with Similar Potency: Potential Therapeutic Implications SO VIRUSES-BASEL LA English DT Article DE Ebola; filovirus; enclomiphene; zuclomiphene; anti-viral; Ebola Virus disease; Ebola virus survivors ID NONHUMAN-PRIMATES; CITRATE; DISEASE; ENCLOMIPHENE; ANTIBODY; RECEPTOR; PHARMACOKINETICS; ANTAGONISTS; DRUGS; SERUM AB The 2014 outbreak of Ebola virus (EBOV) in Western Africa highlighted the need for anti-EBOV therapeutics. Clomiphene is a U.S. Food and Drug Administration (FDA)-approved drug that blocks EBOV entry and infection in cells and significantly protects EBOV-challenged mice. As provided, clomiphene is, approximately, a 60: 40 mixture of two stereoisomers, enclomiphene and zuclomiphene. The pharmacokinetic properties of the two isomers vary, but both accumulate in the eye and male reproductive tract, tissues in which EBOV can persist. Here we compared the ability of clomiphene and its isomers to inhibit EBOV using viral-like particle (VLP) entry and transcription/replication-competent VLP (trVLP) assays. Clomiphene and its isomers inhibited the entry and infection of VLPs and trVLPs with similar potencies. This was demonstrated with VLPs bearing the glycoproteins from three filoviruses (EBOV Mayinga, EBOV Makona, and Marburg virus) and in two cell lines (293T/17 and Vero E6). Visual problems have been noted in EBOV survivors, and viral RNA has been isolated from semen up to nine months post-infection. Since the clomiphene isomers accumulate in these affected tissues, clomiphene or one of its isomers warrants consideration as an anti-EBOV agent, for example, to potentially help ameliorate symptoms in EBOV survivors. C1 [Nelson, Elizabeth A.; Barnes, Alyson B.; White, Judith M.] Univ Virginia, Dept Cell Biol, Charlottesville, VA 22908 USA. [Wiehle, Ronald D.; Fontenot, Gregory K.] Repros Therapeut Inc, The Woodlands, TX 77380 USA. [Hoenen, Thomas] Natl Inst Hlth, Div Intramural Res, Virol Lab, Hamilton, MT 59840 USA. [Hoenen, Thomas] Friedrich Loeffler Inst, D-17493 Greifswald, Germany. RP White, JM (reprint author), Univ Virginia, Dept Cell Biol, Charlottesville, VA 22908 USA. EM en2b@virginia.edu; abb9uu@virginia.edu; rwiehle@reprosrx.com; GFontenot@reprosrx.com; thomas.hoenen@fli.bund.de; jw7g@virginia.edu OI White, Judith/0000-0002-0532-996X; Hoenen, Thomas/0000-0002-5829-6305 FU NIH [RO1 AI114776]; Intramural Research program of the National Institutes of Health, NIAID FX The work was supported by a grant from the NIH to JMW (RO1 AI114776) and in part by the Intramural Research program of the National Institutes of Health, NIAID. The authors thank Heinz Feldmann (NIH, NIAID) for his support of this work. We thank Lisa Johansen for helpful discussions and a personal communication. NR 48 TC 1 Z9 1 U1 1 U2 1 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD AUG PY 2016 VL 8 IS 8 AR 206 DI 10.3390/v8080206 PG 15 WC Virology SC Virology GA DS4RA UT WOS:000380767300001 ER PT J AU Haughwout, SP Harford, TC Castle, IJP Grant, BF AF Haughwout, Sarah P. Harford, Thomas C. Castle, I-Jen P. Grant, Bridget F. TI Treatment Utilization Among Adolescent Substance Users: Findings from the 2002 to 2013 National Survey on Drug Use and Health SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Adolescents; Past-Year Substance Use; Substance Use Treatment; Substance Use Disorders; Gender Differences ID COMORBIDITY SURVEY-ADOLESCENT; USE DISORDERS; MENTAL-HEALTH; GENDER-DIFFERENCES; ALCOHOL-USE; COOCCURRING DISORDERS; BRIEF-INTERVENTION; UNITED-STATES; ABUSE; SERVICES AB BackgroundAdolescent substance users face serious health and social consequences and benefit from early diagnosis and treatment. The objectives of this study were to observe trends in treatment utilization; examine correlates of treatment utilization and treatment types/settings among adolescent substance users with and without substance use disorder (SUD); and assess gender differences. MethodsNational Survey on Drug Use and Health data were pooled across 2002 to 2013, with a combined sample of 79,885 past-year substance users ages 12 to 17 (17,510 with SUD and 62,375 without SUD). Treatment was defined as receiving treatment or counseling for use of alcohol or any drug, not counting cigarettes. Trends were assessed by joinpoint linear regression, and multivariable logistic regression assessed odds ratios of treatment utilization. ResultsPercentages of past-year treatment use did not change in 2002 to 2013. Treatment utilization was more prevalent among adolescents with SUD than without (11.4% vs. 1.4%) and among males than females. Among adolescents with and without SUD, criminal justice involvement and perceiving a need for treatment increased adolescent treatment utilization, while SUDs other than alcohol abuse, older age, and talking to parents increased treatment use among adolescents with SUD, and polysubstance use and male gender increased treatment among those without SUD. Treatment gaps persisted among non-Hispanic Blacks for both groups with and without SUD, male Hispanics with SUD, female non-Hispanic Asians without SUD, and private insurance coverages. Gender differences were observed in SUD, race/ethnicity, and insurance coverage. Most adolescents received treatment for both alcohol and drug use, and self-help group and outpatient rehabilitation facility were the most used treatment settings. ConclusionsTreatment utilization among adolescents with past-year substance use remained low and unimproved in 2002 to 2013. Treatment gaps among minority populations, insurance coverage, and in educating adolescents on seeking relevant treatment must be addressed. Using screening processes such as Screening, Brief Intervention, and Referral to Treatment, health professionals can help prevent lifelong SUD by recognizing and addressing substance misuse early. C1 [Haughwout, Sarah P.; Harford, Thomas C.; Castle, I-Jen P.] CSR Inc, 4250 N Fairfax Dr,Suite 500, Arlington, VA 22203 USA. [Grant, Bridget F.] NIAAA, NIH, Bethesda, MD USA. RP Haughwout, SP (reprint author), CSR Inc, 4250 N Fairfax Dr,Suite 500, Arlington, VA 22203 USA. EM shaughwout@csrincorporated.com FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health [HHSN275201 300016C] FX This article is based on a study conducted for the Alcohol Epidemiologic Data System project funded by the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health through Contract No. HHSN275201 300016C to CSR, Incorporated. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of the sponsoring agency or the Federal Government. NR 55 TC 0 Z9 0 U1 9 U2 11 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 AUG PY 2016 VL 40 IS 8 BP 1717 EP 1727 DI 10.1111/acer.13137 PG 11 WC Substance Abuse SC Substance Abuse GA DS4CP UT WOS:000380729300016 PM 27427179 ER PT J AU Slade, T Chiu, WT Glantz, M Kessler, RC Lago, L Sampson, N Al-Hamzawi, A Florescu, S Moskalewicz, J Murphy, S Navarro-Mateu, F de Galvis, YT Viana, MC Xavier, M Degenhardt, L AF Slade, Tim Chiu, Wai-Tat Glantz, Meyer Kessler, Ronald C. Lago, Luise Sampson, Nancy Al-Hamzawi, Ali Florescu, Silvia Moskalewicz, Jacek Murphy, Sam Navarro-Mateu, Fernando Torres de Galvis, Yolanda Viana, Maria Carmen Xavier, Miguel Degenhardt, Louisa TI A Cross-National Examination of Differences in Classification of Lifetime Alcohol Use Disorder Between DSM-IV and DSM-5: Findings from the World Mental Health Survey SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol Use Disorder; Prevalence; DSM-IV; DSM-5 ID SUBSTANCE-USE DISORDERS; DIAGNOSTIC ORPHANS; DEPENDENCE SYMPTOMS; DRUG-TREATMENT; CRITERIA; ABUSE; POPULATION; ORGANIZATION; ADOLESCENTS; PREVALENCE AB BackgroundThe current study sought to examine the diagnostic overlap in DSM-IV and DSM-5 alcohol use disorder (AUD) and determine the clinical correlates of changing diagnostic status across the 2 classification systems. MethodsDSM-IV and DSM-5 definitions of AUD were compared using cross-national community survey data in 9 low-, middle-, and high-income countries. Participants were 31,367 respondents to surveys in the World Health Organization's World Mental Health Survey Initiative. The Composite International Diagnostic Interview, version 3.0, was used to derive DSM-IV and DSM-5 lifetime diagnoses of AUD. Clinical characteristics, also assessed in the surveys, included lifetime DSM-IV anxiety; mood and drug use disorders; lifetime suicidal ideation, plan, and attempt; general functional impairment; and psychological distress. ResultsCompared with DSM-IV AUD (12.3%, SE=0.3%), the DSM-5 definition yielded slightly lower prevalence estimates (10.8%, SE=0.2%). Almost one-third (n=802) of all DSM-IV abuse cases switched to subthreshold according to DSM-5 and one-quarter (n=467) of all DSM-IV diagnostic orphans switched to mild AUD according to DSM-5. New cases of DSM-5 AUD were largely similar to those who maintained their AUD across both classifications. Similarly, new DSM-5 noncases were similar to those who were subthreshold across both classifications. The exception to this was with regard to the prevalence of any lifetime drug use disorder. ConclusionsIn this large cross-national community sample, the prevalence of DSM-5 lifetime AUD was only slightly lower than the prevalence of DSM-IV lifetime AUD. Nonetheless, there was considerable diagnostic switching, with a large number of people inconsistently identified across the 2 DSM classifications. C1 [Slade, Tim; Lago, Luise; Degenhardt, Louisa] UNSW Australia, Natl Drug & Alcohol Res Ctr, Sydney, NSW, Australia. [Chiu, Wai-Tat; Kessler, Ronald C.; Sampson, Nancy] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Glantz, Meyer] NIDA, DESPR, NIH, Bethesda, MD 20892 USA. [Al-Hamzawi, Ali] Al Qadisiya Univ, Coll Med, Diwania Governorate, Iraq. [Florescu, Silvia] Natl Sch Publ Hlth Management & Profess Dev, Bucharest, Romania. [Moskalewicz, Jacek] Inst Psychiat & Neurol, Dept Studies Alcoholism & Drug Dependence, Warsaw, Poland. [Murphy, Sam] Univ Ulster, Sch Psychol, Belfast, Antrim, Ireland. [Navarro-Mateu, Fernando] Serv Murciano Salud, Subdirecc Gen Salud Mental & Asistencia Psiquiatr, CIBERESP Murcia, IMIB Arrixaca, Murcia, Spain. [Torres de Galvis, Yolanda] CES Univ, Ctr Excellence Res Mental Hlth, Medellin, Colombia. [Viana, Maria Carmen] Univ Fed Espirito Santo, Dept Social Med, Vitoria, Brazil. [Xavier, Miguel] Univ Nova Lisboa, Fac Ciencias Med, Dept Mental Hlth, Nova Med Sch, Lisbon, Portugal. RP Slade, T (reprint author), UNSW, NDARC, Sydney, NSW 2052, Australia. EM tims@unsw.edu.au RI Degenhardt, Louisa/D-4515-2012; OI Degenhardt, Louisa/0000-0002-8513-2218; Al-Hamzawi, Ali/0000-0002-1241-0627 FU National Institute of Mental Health (NIMH) [R01 MH070884, U01-MH60220]; John D. and Catherine T. MacArthur Foundation; Pfizer Foundation; US Public Health Service [R13-MH066849, R01-MH069864, R01 DA016558]; Fogarty International Center (FIRCA) [R03-TW006481]; Pan American Health Organization; Eli Lilly and Company; Ortho-McNeil Pharmaceutical; GlaxoSmithKline; Bristol-Myers Squibb; Shire; Australian National Health and Medical Research Council (NHMRC) [1081984]; NHMRC [1041472]; Australian Government under Substance Misuse Prevention and Service Improvements Grant Fund; Australian Government Department of Health and Ageing; State of Sao Paulo Research Foundation (FAPESP) Thematic Project Grant [03/00204-3]; Center for Excellence on Research in Mental Health (CES University); Japanese and European Funds through United Nations Development Group Iraq Trust Fund (UNDG ITF); Health & Social Care Research & Development Division of the Public Health Agency; Norwegian Financial Mechanism; European Economic Area Mechanism; Polish Ministry of Health; Champalimaud Foundation; Gulbenkian Foundation; Foundation for Science and Technology (FCT); Ministry of Health; Ministry of Public Health; Eli Lilly Romania SRL; Regional Health Authorities of Murcia (Servicio Murciano de Salud); Regional Health Authorities of Murcia (Consejeria de Sanidad y Politica Social); Fundacion para la Formacion e Investigacion Sanitarias (FFIS) of Murcia; National Institute of Drug Abuse (NIDA); Substance Abuse and Mental Health Services Administration (SAMHSA); Robert Wood Johnson Foundation (RWJF) [044708]; John W. Alden Trust FX This work is carried out in conjunction with the World Health Organization's World Mental Health (WMH) Survey Initiative which is supported by the National Institute of Mental Health (NIMH; R01 MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the US Public Health Service (R13-MH066849, R01-MH069864, and R01 DA016558), the Fogarty International Center (FIRCA R03-TW006481), the Pan American Health Organization, Eli Lilly and Company, Ortho-McNeil Pharmaceutical, GlaxoSmithKline, and Bristol-Myers Squibb and Shire. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation, fieldwork, and consultation on data analysis. None of the funders had any role in the design, analysis, interpretation of results, or preparation of this paper. A complete list of all within-country and cross-national WMH publications can be found at . This work was supported by an Australian National Health and Medical Research Council (NHMRC) project grant (#1081984). LD is supported by an NHMRC Principal Research Fellowship (#1041472). The National Drug and Alcohol Research Centre at UNSW Australia is supported by funding from the Australian Government under the Substance Misuse Prevention and Service Improvements Grant Fund. The Australian National Survey of Mental Health and Wellbeing was funded by the Australian Government Department of Health and Ageing. The Sao Paulo Megacity Mental Health Survey is supported by the State of Sao Paulo Research Foundation (FAPESP) Thematic Project Grant 03/00204-3. The Mental Health Study Medellin Colombia was carried out and supported jointly by the Center for Excellence on Research in Mental Health (CES University) and the Secretary of Health of Medellin. Implementation of the Iraq Mental Health Survey (IMHS) and data entry were carried out by the staff of the Iraqi Minister of Health and Minister of Planning with direct support from the Iraqi IMHS team with funding from both the Japanese and European Funds through United Nations Development Group Iraq Trust Fund (UNDG ITF). The Northern Ireland Study of Mental Health was funded by the Health & Social Care Research & Development Division of the Public Health Agency. The Polish project Epidemiology of Mental Health and Access to CareEZOP Poland was carried out by the Institute of Psychiatry and Neurology in Warsaw in consortium with Department of PsychiatryMedical University in Wroclaw and National Institute of Public Health National Institute of Hygiene in Warsaw and in partnership with Psykiatrist Institut VinderenUniversitet, Oslo. The project was funded by the Norwegian Financial Mechanism and the European Economic Area Mechanism as well as Polish Ministry of Health. No support from pharmaceutical industry neither other commercial sources was received. The Portuguese Mental Health Study was carried out by the Department of Mental Health, Faculty of Medical Sciences, NOVA University of Lisbon, with collaboration of the Portuguese Catholic University, and was funded by Champalimaud Foundation, Gulbenkian Foundation, Foundation for Science and Technology (FCT) and Ministry of Health.; The Romania WMH study projects "Policies in Mental Health Area" and "National Study regarding Mental Health and Services Use" were carried out by National School of Public Health & Health Services Management (former National Institute for Research & Development in Health, present National School of Public Health Management & Professional Development, Bucharest), with technical support of Metro Media Transilvania, the National Institute of StatisticsNational Centre for Training in Statistics, SC. Cheyenne Services SRL, Statistics Netherlands, and were funded by Ministry of Public Health (former Ministry of Health) with supplemental support of Eli Lilly Romania SRL. The Psychiatric Enquiry to General Population in Southeast SpainMurcia (PEGASUS-Murcia) Project has been financed by the Regional Health Authorities of Murcia (Servicio Murciano de Salud and Consejeria de Sanidad y Politica Social) and Fundacion para la Formacion e Investigacion Sanitarias (FFIS) of Murcia. The US National Comorbidity Survey Replication (NCS-R) is supported by the National Institute of Mental Health (NIMH; U01-MH60220) with supplemental support from the National Institute of Drug Abuse (NIDA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; Grant 044708), and the John W. Alden Trust. NR 32 TC 0 Z9 0 U1 2 U2 5 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 AUG PY 2016 VL 40 IS 8 BP 1728 EP 1736 DI 10.1111/acer.13134 PG 9 WC Substance Abuse SC Substance Abuse GA DS4CP UT WOS:000380729300017 PM 27426631 ER PT J AU Hsu, RK Chai, BY Roy, JA Anderson, AH Bansal, N Feldman, HI Go, AS He, J Horwitz, EJ Kusek, JW Lash, JP Ojo, A Sondheimer, JH Townsend, RR Zhan, M Hsu, CY AF Hsu, Raymond K. Chai, Boyang Roy, Jason A. Anderson, Amanda H. Bansal, Nisha Feldman, Harold I. Go, Alan S. He, Jiang Horwitz, Edward J. Kusek, John W. Lash, James P. Ojo, Akinlolu Sondheimer, James H. Townsend, Raymond R. Zhan, Min Hsu, Chi-yuan CA CRIC Study Investigators TI Abrupt Decline in Kidney Function Before Initiating Hemodialysis and All-Cause Mortality: The Chronic Renal Insufficiency Cohort (CRIC) Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Kidney function; disease trajectory; estimated glomerular filtration rate (eGFR); eGFR decline; hemodialysis; mortality; end-stage renal disease (ESRD); transition to ESRD; renal replacement therapy (RRT) initiation; Chronic Renal Insufficiency Cohort (CRIC) ID GLOMERULAR-FILTRATION-RATE; BASE-LINE CHARACTERISTICS; SERUM CREATININE VALUES; BLOOD-PRESSURE CONTROL; REPLACEMENT THERAPY; UNITED-STATES; DIALYSIS; DISEASE; OUTCOMES; RISK AB Background: It is not clear whether the pattern of kidney function decline in patients with chronic kidney disease (CKD) may relate to outcomes after reaching end-stage renal disease (ESRD). We hypothesize that an abrupt decline in kidney function prior to ESRD predicts early death after initiating maintenance hemodialysis therapy. Study Design: Prospective cohort study. Setting & Participants: The Chronic Renal Insufficiency Cohort (CRIC) Study enrolled men and women with mild to moderate CKD. For this study, we studied 661 individuals who developed chronic kidney failure that required hemodialysis therapy initiation. Predictors: The primary predictor was the presence of an abrupt decline in kidney function prior to ESRD. We incorporated annual estimated glomerular filtration rates (eGFRs) into a mixed-effects model to estimate patient-specific eGFRs at 3 months prior to initiation of hemodialysis therapy. Abrupt decline was defined as having an extrapolated eGFR >= 30 mL/min/1.73 m(2) at that time point. Outcomes: All-cause mortality within 1 year after initiating hemodialysis therapy. Measurements: Multivariable Cox proportional hazards. Results: Among 661 patients with CKD initiating hemodialysis therapy, 56 (8.5%) had an abrupt predialysis decline in kidney function and 69 died within 1 year after initiating hemodialysis therapy. After adjustment for demographics, cardiovascular disease, diabetes, and cancer, abrupt decline in kidney function was associated with a 3-fold higher risk for death within the first year of ESRD (adjusted HR, 3.09; 95% CI, 1.65-5.76). Limitations: Relatively small number of outcomes; infrequent (yearly) eGFR determinations; lack of more granular clinical data. Conclusions: Abrupt decline in kidney function prior to ESRD occurred in a significant minority of incident hemodialysis patients and predicted early death in ESRD. (C) 2016 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Hsu, Raymond K.; Go, Alan S.; Hsu, Chi-yuan] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Chai, Boyang; Roy, Jason A.; Anderson, Amanda H.; Feldman, Harold I.; Townsend, Raymond R.] Univ Penn, Philadelphia, PA 19104 USA. [Bansal, Nisha] Univ Washington, Seattle, WA 98195 USA. [Go, Alan S.; Hsu, Chi-yuan] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Go, Alan S.] Stanford Univ, Stanford, CA 94305 USA. [He, Jiang] Tulane Univ, New Orleans, LA 70118 USA. [Horwitz, Edward J.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Kusek, John W.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Lash, James P.] Univ Illinois, Chicago, IL USA. [Ojo, Akinlolu] Univ Michigan, Ann Arbor, MI 48109 USA. [Sondheimer, James H.] Wayne State Univ, Detroit, MI USA. [Zhan, Min] Univ Maryland, Baltimore, MD 21201 USA. RP Hsu, RK (reprint author), Univ Calif San Francisco, Div Nephrol, 533 Parnassus Ave,U404, San Francisco, CA 94143 USA. EM raymond.hsu@ucsf.edu FU Astra-Zeneca FX Dr Go has received a research grant from Astra-Zeneca. The other authors declare that they have no other relevant financial interests. NR 28 TC 5 Z9 5 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2016 VL 68 IS 2 BP 193 EP 202 DI 10.1053/j.ajkd.2015.12.025 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA DS4LZ UT WOS:000380753900010 PM 26830447 ER PT J AU Dad, T Tighiouart, H Joseph, A Bostom, A Carpenter, M Hunsicker, L Kusek, JW Pfeffer, M Levey, AS Weiner, DE AF Dad, Taimur Tighiouart, Hocine Joseph, Alin Bostom, Andrew Carpenter, Myra Hunsicker, Lawrence Kusek, John W. Pfeffer, Marc Levey, Andrew S. Weiner, Daniel E. TI Aspirin Use and Incident Cardiovascular Disease, Kidney Failure, and Death in Stable Kidney Transplant Recipients: A Post Hoc Analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Kidney transplantation; kidney transplant recipient; dialysis; aspirin; cardiovascular disease (CVD); atherosclerosis; all-cause mortality; death; chronic kidney disease (CKD); renal failure ID LOW-DOSE ASPIRIN; HEART; PREVENTION; GUIDELINES; CORONARY; UPDATE AB Background: Cardiovascular disease (CVD) is the leading cause of death in kidney transplant recipients. Whether aspirin may reduce the risk for CVD, death, and kidney failure outcomes is uncertain. Study Design: Post hoc cohort analysis of FAVORIT, a randomized trial examining the effect of homocysteine-lowering vitamins on CVD in kidney transplant recipients. Setting & Participants: Prevalent adult kidney transplant recipients with hyperhomocysteinemia and stable kidney function from the United States, Canada, and Brazil participating in FAVORIT, with no known history of CVD. Predictor: Aspirin use, with aspirin users matched to nonusers using a propensity score. Outcomes: Incident CVD events, kidney failure, all-cause mortality, a composite of CVD events or mortality, and a composite of kidney failure or mortality. Cox proportional hazards models with a robust variance to account for the correlation in outcomes within matched pairs were sequentially adjusted for demographic, clinical, and laboratory characteristics to assess the association between aspirin use and events. Results: 981 aspirin users were matched to 981 nonusers. During a 4-year mean follow up, there were 225 CVD events, 200 deaths, 126 kidney failure events, 301 composite kidney failure or mortality events, and 324 composite CVD or mortality events. Adjusted models showed no significant difference associated with aspirin use in risk for CVD events, all-cause mortality, kidney failure, composite of kidney failure or mortality, or composite of primary CVD events or mortality (HRs of 1.20 [95% CI, 0.92-1.58], 0.92 [95% CI, 0.69-1.23], 1.19 [95% CI, 0.81-1.74], 1.03 [0.82-1.31], and 1.11 [95% CI, 0.88-1.38], respectively). Limitations: We did not examine dose or continued use of aspirin after randomization. CVD history is dependent on participant report at baseline. Aspirin use was non-randomly assigned. Conclusions: Aspirin use is not associated with reduced risk for incident CVD, all-cause mortality, or kidney failure in stable kidney transplant recipients with no history of CVD. (C) 2016 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Dad, Taimur; Tighiouart, Hocine; Joseph, Alin; Levey, Andrew S.; Weiner, Daniel E.] Tufts Med Ctr, Boston, MA USA. [Dad, Taimur; Tighiouart, Hocine; Joseph, Alin; Levey, Andrew S.; Weiner, Daniel E.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Tighiouart, Hocine] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Tighiouart, Hocine] Tufts Univ, Tufts Clin & Translat Sci Inst, Boston, MA 02111 USA. [Bostom, Andrew] Rhode Isl Hosp, Providence, RI USA. [Carpenter, Myra] Univ N Carolina, Chapel Hill, NC USA. [Hunsicker, Lawrence] Univ Iowa, Iowa City, IA USA. [Kusek, John W.] NIDDK, Bethesda, MD 20892 USA. [Pfeffer, Marc] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Weiner, DE (reprint author), 800 Washington St,Box 391, Boston, MA 02111 USA. EM dweiner@tuftsmedicalcenter.org FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK61700, T32DK007777] FX This study was funded by research support by cooperative agreement U01 DK61700 and by T32DK007777, both from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Funders of this study did not have any role in study design; collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. NR 22 TC 1 Z9 1 U1 2 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2016 VL 68 IS 2 BP 277 EP 286 DI 10.1053/j.ajkd.2016.01.019 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA DS4LZ UT WOS:000380753900019 PM 26947217 ER PT J AU Cai, ZY Zhang, AL Choksi, S Li, WH Li, T Zhang, XM Liu, ZG AF Cai, Zhenyu Zhang, Anling Choksi, Swati Li, Weihua Li, Tao Zhang, Xue-Min Liu, Zheng-Gang TI Activation of cell-surface proteases promotes necroptosis, inflammation and cell migration SO CELL RESEARCH LA English DT Article DE MLKL; ADAM metalloprotease; necroptosis; inflammation ID MIXED LINEAGE KINASE; DOMAIN-LIKE PROTEIN; E-CADHERIN; PROGRAMMED NECROSIS; DEATH; ADHESION; ADAM10; ALPHA; RIP3; PHOSPHORYLATION AB Necroptosis is a programmed, caspase-independent cell death that is morphologically similar to necrosis. TNF-induced necroptosis is mediated by receptor-interacting protein kinases, RIP1 and RIP3, and the mixed lineage kinase domain-like (MLKL). After being phosphorylated by RIP3, MLKL is translocated to the plasma membrane and mediates necroptosis. However, the execution of necroptosis and its role in inflammation and other cellular responses remain largely elusive. In this study, we report that MLKL-mediated activation of cell-surface proteases of the a disintegrin and metalloprotease (ADAM) family promotes necroptosis, inflammation and cell migration. ADAMs are specifically activated at the early stage of necroptosis when MLKL is phosphorylated and translocated to the cell plasma membrane. Activation of ADAMs induces ectodomain shedding of diverse cell-surface proteins including adhesion molecules, receptors, growth factors and cytokines. Importantly, the shedding of cell-surface proteins disrupts cell adhesion and accelerates necroptosis, while the soluble fragments of the cleaved proteins trigger the inflammatory responses. We also demonstrate that the shedding of E-cadherin ectodomain from necroptotic cells promotes cell migration. Thus, our study provides a novel mechanism of necroptosis-induced inflammation and new insights into the physiological and pathological functions of this unique form of cell death. C1 [Cai, Zhenyu; Zhang, Anling; Choksi, Swati; Liu, Zheng-Gang] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Li, Weihua; Li, Tao; Zhang, Xue-Min] Natl Ctr Biomed Anal, Inst Basic Med Sci, 27 Tai Ping Rd, Beijing 100850, Peoples R China. RP Liu, ZG (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM zgliu@helix.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX We thank J Han for MLKL-deficient MEF cells and MLKL antibody. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 38 TC 1 Z9 1 U1 4 U2 7 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYANG ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 EI 1748-7838 J9 CELL RES JI Cell Res. PD AUG PY 2016 VL 26 IS 8 BP 886 EP 900 DI 10.1038/cr.2016.87 PG 15 WC Cell Biology SC Cell Biology GA DS6WN UT WOS:000380923900007 PM 27444869 ER PT J AU Sidana, A Srinivasan, R AF Sidana, Abhinav Srinivasan, Ramaprasad TI Therapeutic Strategies for Hereditary Kidney Cancer SO Current Oncology Reports LA English DT Review DE Renal cell cancer; Hereditary; Inherited; Kidney cancer; Clear cell renal cell cancer; Papillary renal cell cancer; Tyrosine kinase inhibitors; Von Hippel-Lindau; HLRCC; HPRC; Tuberous sclerosis; Metastatic; Fumarate hydratase; Succinate dehydrogenase ID RENAL-CELL CARCINOMA; HOGG-DUBE-SYNDROME; TUBEROUS SCLEROSIS COMPLEX; TUMOR-SUPPRESSOR PROTEIN; PARENCHYMAL SPARING SURGERY; HIPPEL-LINDAU DISEASE; FUMARATE-HYDRATASE; SPORADIC LYMPHANGIOLEIOMYOMATOSIS; GENETIC-BASIS; MUTATIONS AB The study of hereditary forms of kidney cancer has vastly increased our understanding of metabolic and genetic pathways involved in the development of both inherited and sporadic kidney cancers. The recognition that diverse molecular events drive different forms of kidney cancers has led to the preclinical and clinical development of specific pathway-directed strategies tailored to treat distinct subgroups of kidney cancer. Here, we describe the molecular mechanisms underlying the pathogenesis of several different types of hereditary renal cancers, review their clinical characteristics, and summarize the treatment strategies for the management of these cancers. C1 [Sidana, Abhinav; Srinivasan, Ramaprasad] NCI, Urol Oncol Branch, Ctr Canc Res, Bldg 10 Hatfield CRC,Room 1-5940, Bethesda, MD 20892 USA. RP Sidana, A (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bldg 10 Hatfield CRC,Room 1-5940, Bethesda, MD 20892 USA. EM abhinav.sidana@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 57 TC 1 Z9 1 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3790 EI 1534-6269 J9 CURR ONCOL REP JI Curr. Oncol. Rep. PD AUG PY 2016 VL 18 IS 8 AR 50 DI 10.1007/s11912-016-0537-6 PG 9 WC Oncology SC Oncology GA DS3GE UT WOS:000380670300004 PM 27325049 ER PT J AU Constantin, S Wray, S AF Constantin, Stephanie Wray, Susan TI Galanin Activates G Protein Gated Inwardly Rectifying Potassium Channels and Suppresses Kisspeptin-10 Activation of GnRH Neurons SO ENDOCRINOLOGY LA English DT Article ID HORMONE-RELEASING-HORMONE; CENTRAL-NERVOUS-SYSTEM; GAL-R1 MESSENGER-RNA; ADULT FEMALE MICE; IN-VITRO; ARCUATE NUCLEUS; KNOCKOUT MICE; SYNAPTIC-TRANSMISSION; OVINE HYPOTHALAMUS; CALCIUM OSCILLATOR AB GnRH neurons are regulated by hypothalamic kisspeptin neurons. Recently, galanin was identified in a subpopulation of kisspeptin neurons. Although the literature thoroughly describes kisspeptin activation of GnRH neurons, little is known about the effects of galanin on GnRH neurons. This study investigated whether galanin could alter kisspeptin signaling to GnRH neurons. GnRH cells maintained in explants, known to display spontaneous calcium oscillations, and a long-lasting calcium response to kisspeptin-10 (kp-10), were used. First, transcripts for galanin receptors (GalRs) were examined. Only GalR1 was found in GnRH neurons. A series of experiments was then performed to determine the action of galanin on kp-10 activated GnRH neurons. Applied after kp-10 activation, galanin 1-16 (Gal1-16) rapidly suppressed kp-10 activation. Applied with kp-10, Gal1-16 prevented kp-10 activation until its removal. To determine the mechanism by which galanin inhibited kp-10 activation of GnRH neurons, Gal1-16 and galanin were applied to spontaneously active GnRH neurons. Both inhibited GnRH neuronal activity, independent of GnRH neuronal inputs. This inhibition was mimicked by a GalR1 agonist but not by GalR2 or GalR2/3 agonists. Although Gal1-16 inhibition relied on G(i/o) signaling, it was independent of cAMP levels but sensitive to blockers of G protein-coupled inwardly rectifying potassium channels. A newly developed bioassay for GnRH detection showed Gal1-16 decreased the kp-10-evoked GnRH secretion below detection threshold. Together, this study shows that galanin is a potent regulator of GnRH neurons, possibly acting as a physiological break to kisspeptin excitation. C1 [Constantin, Stephanie; Wray, Susan] NINDS, Cellular & Dev Neurobiol Sect, NIH, 35 Convent Dr,MSC 3703,Bldg 35,Room 3A1012, Bethesda, MD 20892 USA. RP Wray, S (reprint author), NINDS, Cellular & Dev Neurobiol Sect, NIH, 35 Convent Dr,MSC 3703,Bldg 35,Room 3A1012, Bethesda, MD 20892 USA. EM wrays@ninds.nih.gov OI Constantin, Stephanie/0000-0003-0596-9737; wray, susan/0000-0001-7670-3915 FU Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke [ZIA NS002824-25] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke Grant ZIA NS002824-25. NR 80 TC 1 Z9 1 U1 2 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 2016 VL 157 IS 8 BP 3197 EP 3212 DI 10.1210/en.2016-1064 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DS4JG UT WOS:000380746800024 PM 27359210 ER PT J AU Brewer, CC Zalewski, CK King, KA Zobay, O Riley, A Ferguson, MA Bird, JE McCabe, MM Hood, LJ Drayna, D Griffith, AJ Morell, RJ Friedman, TB Moore, DR AF Brewer, Carmen C. Zalewski, Christopher K. King, Kelly A. Zobay, Oliver Riley, Alison Ferguson, Melanie A. Bird, Jonathan E. McCabe, Margaret M. Hood, Linda J. Drayna, Dennis Griffith, Andrew J. Morell, Robert J. Friedman, Thomas B. Moore, David R. TI Heritability of non-speech auditory processing skills SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID AUTISM SPECTRUM DISORDERS; LANGUAGE IMPAIRMENT; READING DISORDERS; CHILDREN; APD; ETIOLOGY; COMMUNICATION; TWINS AB Recent insight into the genetic bases for autism spectrum disorder, dyslexia, stuttering, and language disorders suggest that neurogenetic approaches may also reveal at least one etiology of auditory processing disorder (APD). A person with an APD typically has difficulty understanding speech in background noise despite having normal pure-tone hearing sensitivity. The estimated prevalence of APD may be as high as 10% in the pediatric population, yet the causes are unknown and have not been explored by molecular or genetic approaches. The aim of our study was to determine the heritability of frequency and temporal resolution for auditory signals and speech recognition in noise in 96 identical or fraternal twin pairs, aged 6-11 years. Measures of auditory processing (AP) of non-speech sounds included backward masking (temporal resolution), notched noise masking (spectral resolution), pure-tone frequency discrimination (temporal fine structure sensitivity), and nonsense syllable recognition in noise. We provide evidence of significant heritability, ranging from 0.32 to 0.74, for individual measures of these non-speech-based AP skills that are crucial for understanding spoken language. Identification of specific heritable AP traits such as these serve as a basis to pursue the genetic underpinnings of APD by identifying genetic variants associated with common AP disorders in children and adults. C1 [Brewer, Carmen C.; Zalewski, Christopher K.; King, Kelly A.; Griffith, Andrew J.] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, 9000 Rockville Pike,Bldg 10-5C306, Bethesda, MD 20892 USA. [Zobay, Oliver; Riley, Alison; Ferguson, Melanie A.; Moore, David R.] Inst Hearing Res, Med Res Council, Nottingham, England. [Ferguson, Melanie A.] Nat Inst Hlth Res, Nottingham Hearing Biomed Res Unit, Nottingham, England. [Bird, Jonathan E.; Morell, Robert J.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Lab Mol Genet, NIH, Bethesda, MD USA. [McCabe, Margaret M.] Univ Maryland, Dept Hearing & Speech Sci, College Pk, MD USA. [Hood, Linda J.] Vanderbilt Univ, Dept Hearing & Speech Sci, Vanderbilt Bill Wilkerson Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA. [Drayna, Dennis] Natl Inst Deafness & Other Commun Disorders, Lab Commun Disorders, NIH, Bethesda, MD USA. [Morell, Robert J.] Natl Inst Deafness & Other Commun Disorders, Genom & Computat Biol Core, NIH, Bethesda, MD USA. [Moore, David R.] Cincinnati Childrens Hosp, Commun Sci Res Ctr, Cincinnati, OH USA. RP Brewer, CC (reprint author), Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, 9000 Rockville Pike,Bldg 10-5C306, Bethesda, MD 20892 USA. EM brewerc@nidcd.nih.gov OI Drayna, Dennis/0000-0002-1730-4532; Bird, Jonathan/0000-0001-5531-8794 FU National Institute on Deafness and Other Communication Disorders [DC000039, DC00046, DC000060, DC000064]; Medical Research Council [U135070147] FX This work was supported by intramural research funds from the National Institute on Deafness and Other Communication Disorders DC000039 to TBF, DC00046 to DPD, DC000060 to AJG, and DC000064 to CCB, and the Medical Research Council grant number U135070147 to DRM. We are grateful to Harold Sneider and Dorothy Bishop for insightful feedback on earlier versions of this manuscript. We thank Alyssa Baker, William Bologna, Sienna Burke, Tasha Cantelmo, Julie Cohen, Travis Conrad, Maureen D'Antuono, Christina Do, Alyse Firtel, Keithia Harding, Allison Hearn, Keena James, Samantha Kleindienst, Nikki Parker, Fabiola Peredo, Julia Rainsford, Danielle Zion, graduate students in Audiology from University of Maryland, Gallaudet University, Washington University of St Louis, and Vanderbilt University, for their help in administering study tests at the Annual Twins Days Festival. Thanks are extended to Lisa Hunter who provided oversight of participant processing and assisted in ensuring that nothing was overlooked. We are grateful to Barbara Zwiesler for performing the STR genotyping. We appreciate careful review of the manuscript by Lisa Cunningham and Meghan Drummond. We extend our thanks to the twins and their families for their participation in this research and thank Sandy Miller and the entire Annual Twins Days Festival committee for their support of our research efforts. NR 43 TC 1 Z9 1 U1 15 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD AUG PY 2016 VL 24 IS 8 BP 1137 EP 1144 DI 10.1038/ejhg.2015.277 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DS1VI UT WOS:000380390300011 PM 26883091 ER PT J AU Kan, MY Auer, PL Wang, GT Bucasas, KL Hooker, S Rodriguez, A Li, B Ellis, J Cupples, LA Chen, YDI Dupuis, J Fox, CS Gross, MD Smith, JD Heard-Costa, N Meigs, JB Pankow, JS Rotter, JI Siscovick, D Wilson, JG Shendure, J Jackson, R Peters, U Zhong, H Lin, DY Hsu, L Franceschini, N Carlson, C Abecasis, G Gabriel, S Bamshad, MJ Altshuler, D Nickerson, DA North, KE Lange, LA Reiner, AP Leal, SM AF Kan, Mengyuan Auer, Paul L. Wang, Gao T. Bucasas, Kristine L. Hooker, Stanley Rodriguez, Alejandra Li, Biao Ellis, Jaclyn Cupples, L. Adrienne Chen, Yii-Der Ida Dupuis, Josee Fox, Caroline S. Gross, Myron D. Smith, Joshua D. Heard-Costa, Nancy Meigs, James B. Pankow, James S. Rotter, Jerome I. Siscovick, David Wilson, James G. Shendure, Jay Jackson, Rebecca Peters, Ulrike Zhong, Hua Lin, Danyu Hsu, Li Franceschini, Nora Carlson, Chris Abecasis, Goncalo Gabriel, Stacey Bamshad, Michael J. Altshuler, David Nickerson, Deborah A. North, Kari E. Lange, Leslie A. Reiner, Alexander P. Leal, Suzanne M. CA NHLBI-Exome Sequencing Project TI Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID BODY-FAT DISTRIBUTION; NF-KAPPA-B; INDUCED INSULIN-RESISTANCE; GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; IKK-BETA; ABDOMINAL ADIPOSITY; GENERAL FRAMEWORK; QUALITY-CONTROL; OBESITY AB Waist-to-hip ratio (WHR), a relative comparison of waist and hip circumferences, is an easily accessible measurement of body fat distribution, in particular central abdominal fat. A high WHR indicates more intra-abdominal fat deposition and is an established risk factor for cardiovascular disease and type 2 diabetes. Recent genome-wide association studies have identified numerous common genetic loci influencing WHR, but the contributions of rare variants have not been previously reported. We investigated rare variant associations with WHR in 1510 European-American and 1186 African-American women from the National Heart, Lung, and Blood Institute-Exome Sequencing Project. Association analysis was performed on the gene level using several rare variant association methods. The strongest association was observed for rare variants in IKBKB (P = 4.0 x 10(-8)) in European-Americans, where rare variants in this gene are predicted to decrease WHRs. The activation of the IKBKB gene is involved in inflammatory processes and insulin resistance, which may affect normal food intake and body weight and shape. Meanwhile, aggregation of rare variants in COBLL1, previously found to harbor common variants associated with WHR and fasting insulin, were nominally associated (P = 2.23 x 10(-4)) with higher WHR in European-Americans. However, these significant results are not shared between African-Americans and European-Americans that may be due to differences in the allelic architecture of the two populations and the small sample sizes. Our study indicates that the combined effect of rare variants contribute to the inter-individual variation in fat distribution through the regulation of insulin response. C1 [Kan, Mengyuan; Wang, Gao T.; Bucasas, Kristine L.; Hooker, Stanley; Rodriguez, Alejandra; Li, Biao; Leal, Suzanne M.] Baylor Coll Med, Dept Mol & Human Genet, Ctr Stat Genet, One Baylor Plaza 700D, Houston, TX 77030 USA. [Kan, Mengyuan] Chinese Acad Sci, Grad Sch, Shanghai Inst Biol Sci, Inst Nutr Sci, Shanghai, Peoples R China. [Auer, Paul L.; Peters, Ulrike; Hsu, Li; Carlson, Chris; Reiner, Alexander P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Ellis, Jaclyn; Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Cupples, L. Adrienne; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Cupples, L. Adrienne; Dupuis, Josee; Fox, Caroline S.; Heard-Costa, Nancy] NHLBI, Framingham Heart Study, Framingham, MA USA. [Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Chen, Yii-Der Ida] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA. [Gross, Myron D.; Pankow, James S.; Nickerson, Deborah A.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Smith, Joshua D.; Shendure, Jay; Bamshad, Michael J.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Heard-Costa, Nancy] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Med Sch, Boston, MA USA. [Siscovick, David] Univ Washington, Dept Med, Seattle, WA USA. [Siscovick, David; Reiner, Alexander P.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Jackson, Rebecca] Ohio State Univ, Ctr Clin & Translat Sci, Columbus, OH 43210 USA. [Zhong, Hua] NYU, Langone Med Ctr, Dept Environm Med, Div Biostat, New York, NY USA. [Zhong, Hua] NYU, Langone Med Ctr, Dept Populat Hlth, New York, NY USA. [Lin, Danyu] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Gabriel, Stacey; Altshuler, David] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Auer, Paul L.] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Rodriguez, Alejandra] Univ Antioquia, Gene Mapping Grp, Medellin 050010, Colombia. RP Leal, SM (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Ctr Stat Genet, One Baylor Plaza 700D, Houston, TX 77030 USA. EM sleal@bcm.edu FU NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926] FX We thank the support of NHLBI and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO) and RC2 HL-102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). NR 51 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD AUG PY 2016 VL 24 IS 8 BP 1181 EP 1187 DI 10.1038/ejhg.2015.272 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DS1VI UT WOS:000380390300017 PM 26757982 ER PT J AU Joshi, AD Andersson, C Buch, S Stender, S Noordam, R Weng, LC Weeke, PE Auer, PL Boehm, B Chen, C Choi, H Curhan, G Denny, JC De Vivo, I Eicher, JD Ellinghaus, D Folsom, AR Fuchs, C Gala, M Haessler, J Hofman, A Hu, F Hunter, DJ Janssen, HLA Kang, JH Kooperberg, C Kraft, P Kratzer, W Lieb, W Lutsey, PL Murady, SD Nordestgaard, BG Pasquale, LR Reiner, AP Ridker, PM Rirnribi, E Rose, LM Shaffer, CM Schafmayer, C Tamimi, RM Uitterlinden, AG Volker, U Volzke, H Wakabayashi, Y Wiggs, JL Zhu, J Roden, DM Stricker, BH Tang, WH Teumer, A Hampe, J Tybjmrg-Hansen, A Chasman, DI Andrew, T Andrew, D AF Joshi, Amit D. Andersson, Charlotte Buch, Stephan Stender, Stefan Noordam, Raymond Weng, Lu-Chen Weeke, Peter E. Auer, Paul L. Boehm, Bernhard Chen, Constance Choi, Hyon Curhan, Gary Denny, Joshua C. De Vivo, Immaculata Eicher, John D. Ellinghaus, David Folsom, Aaron R. Fuchs, Charles Gala, Manish Haessler, Jeffrey Hofman, Albert Hu, Frank Hunter, David J. Janssen, Harry L. A. Kang, Jae H. Kooperberg, Charles Kraft, Peter Kratzer, Wolfgang Lieb, Wolfgang Lutsey, Pamela L. Murady, Sarwa Darwish Nordestgaard, Borge G. Pasquale, Louis R. Reiner, Alex P. Ridker, Paul M. Rirnribi, Eric Rose, Lynda M. Shaffer, Christian M. Schafmayer, Clemens Tamimi, Rulla M. Uitterlinden, Andre G. Volker, Uwe Volzke, Henry Wakabayashi, Yoshiyuki Wiggs, Janey L. Zhu, Jun Roden, Dan M. Stricker, Bruno H. Tang, Weihong Teumer, Alexander Hampe, Jochen Tybjmrg-Hansen, Anne Chasman, Daniel I. Chan, Andrew T. Johnson, Andrew D. TI Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies SO GASTROENTEROLOGY LA English DT Article DE Genetics; Risk Factors; SNP; GWAS ID HUMAN PREFRONTAL CORTEX; CORONARY-HEART-DISEASE; GENE-EXPRESSION; BREAST-CANCER; BILIRUBIN LEVELS; CANDIDATE GENES; HUMAN BRAIN; CHOLESTEROL TRANSPORTER; ENDOMETRIAL CANCER; PERIPHERAL-BLOOD AB BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 x 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 x 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 x 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 x 10-11, rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 x 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 x 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse. CONCLUSIONS: In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids. C1 [Joshi, Amit D.; Chen, Constance; De Vivo, Immaculata; Gala, Manish; Hunter, David J.; Kraft, Peter; Chan, Andrew T.] Harvard Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA. [De Vivo, Immaculata; Hu, Frank; Hunter, David J.; Kraft, Peter; Rirnribi, Eric; Tamimi, Rulla M.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hu, Frank; Rirnribi, Eric] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Joshi, Amit D.; Gala, Manish; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Joshi, Amit D.; Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Dept Med, Boston, MA 02114 USA. [Joshi, Amit D.; Chan, Andrew T.] Harvard Med Sch, Boston, MA USA. [Andersson, Charlotte; Eicher, John D.; Johnson, Andrew D.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Buch, Stephan; Hampe, Jochen] Tech Univ Dresden, Univ Hosp Dresden, Med Dept 1, Dresden, Germany. [Stender, Stefan; Tybjmrg-Hansen, Anne] Rigshosp, Ctr Heart, Dept Clin Biochem, Copenhagen, Denmark. [Weeke, Peter E.] Rigshosp, Ctr Heart, Dept Cardiol, Copenhagen, Denmark. [Noordam, Raymond; Uitterlinden, Andre G.; Stricker, Bruno H.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Noordam, Raymond; Hofman, Albert; Uitterlinden, Andre G.; Stricker, Bruno H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Janssen, Harry L. A.; Murady, Sarwa Darwish] Erasmus MC, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands. [Janssen, Harry L. A.; Murady, Sarwa Darwish] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Weng, Lu-Chen; Folsom, Aaron R.; Lutsey, Pamela L.; Tang, Weihong] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Weeke, Peter E.; Denny, Joshua C.; Shaffer, Christian M.; Roden, Dan M.] Vanderbilt Univ, Depat Biomed Informat, Nashville, TN USA. [Denny, Joshua C.] Univ Wisconsin, Joseph J Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA. [Auer, Paul L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Auer, Paul L.; Haessler, Jeffrey; Kooperberg, Charles; Reiner, Alex P.] Ulm Univ Hosp, Dept Internal Med 1, Ulm, Germany. [Boehm, Bernhard; Kratzer, Wolfgang] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Choi, Hyon] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA USA. [Curhan, Gary; De Vivo, Immaculata; Fuchs, Charles; Kang, Jae H.; Pasquale, Louis R.; Rirnribi, Eric; Tamimi, Rulla M.; Chan, Andrew T.] Brigham & Womens Hosp, Boston, MA USA. [Curhan, Gary; De Vivo, Immaculata; Fuchs, Charles; Kang, Jae H.; Pasquale, Louis R.; Rirnribi, Eric; Tamimi, Rulla M.; Chan, Andrew T.] Harvard Med Sch, Boston, MA USA. [Curhan, Gary] Brigham & Womens Hosp, Dept Med, Div Renal, 75 Francis St, Boston, MA 02115 USA. [Eicher, John D.; Johnson, Andrew D.] NHLBI, Populat Sci Branch, NIH, Framingham, MA USA. [Ellinghaus, David] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany. [Lieb, Wolfgang] Univ Kiel, Inst Epidemiol, Kiel, Germany. [Fuchs, Charles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles; Ridker, Paul M.; Rose, Lynda M.; Chasman, Daniel I.] Harvard Med Sch, Boston, MA USA. [Janssen, Harry L. A.] Toronto Western & Gen Hosp, Univ Hlth Network, Toronto Ctr Liver Dis, Toronto, ON, Canada. [Nordestgaard, Borge G.] Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Nordestgaard, Borge G.; Tybjmrg-Hansen, Anne] Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Nordestgaard, Borge G.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Ridker, Paul M.; Rose, Lynda M.; Chasman, Daniel I.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA USA. [Ridker, Paul M.; Rose, Lynda M.; Chasman, Daniel I.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Schafmayer, Clemens] Univ Kiel, Dept Gen Abdominal Thorac & Transplantat, Kiel, Germany. [Volker, Uwe] Univ Med Greifswald, Interfaculty Inst Genet & Funct Gen, Dept Funct Gen, Greifswald, Germany. [Volzke, Henry; Teumer, Alexander] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Volzke, Henry] German Ctr Cardiovasc Res, Greifswald, Germany. [Volzke, Henry] German Ctr Diabet Res, Greifswald, Germany. [Wakabayashi, Yoshiyuki; Zhu, Jun] NHLBI, DNA Sequencing Core Lab, Bldg 10, Bethesda, MD 20892 USA. RP Joshi, AD (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, Clin & Translat Epidemiol Unit, 55 Fruit St, Boston, MA USA.; Andersson, C (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA.; Andrew, T (reprint author), Massachusetts Gen Hosp, GRJ-825C, Boston, MA 02114 USA.; Andrew, T (reprint author), Harvard Med Sch, Clin & Translat Epidemiol Unit, Div Gastroenterol, GRJ-825C, Boston, MA 02114 USA.; Andrew, D (reprint author), NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM ajoshi@hsph.harvard.edu; achan@mgh.harvard.edu; johnsonad2@nhibimih.gov RI Johnson, Andrew/G-6520-2013; Ellinghaus, David/G-4467-2012; Lieb, Wolfgang/C-1990-2012; OI Hampe, Jochen/0000-0002-2421-6127 FU Intramural NIH HHS [Z99 HL999999]; NEI NIH HHS [R01 EY015473]; NHGRI NIH HHS [U01 HG006378, U01 HG008672]; NIDDK NIH HHS [K24 DK098311]; NIH HHS [S10 OD020069] NR 144 TC 3 Z9 3 U1 6 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2016 VL 151 IS 2 BP 351 EP + DI 10.1053/j.gastro.2016.04.007 PG 41 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DS4KK UT WOS:000380749800030 PM 27094239 ER PT J AU Oh, YS Appel, LJ Galis, ZS Hafler, DA He, J Hernandez, AL Joe, B Karumanchi, SA Maric-Bilkan, C Mattson, D Mehta, NN Randolph, G Ryan, M Sandberg, K Titze, J Tolunay, E Toney, GM Harrison, DG AF Oh, Young S. Appel, Lawrence J. Galis, Zorina S. Hafler, David A. He, Jiang Hernandez, Amanda L. Joe, Bina Karumanchi, S. Ananth Maric-Bilkan, Christine Mattson, David Mehta, Nehal N. Randolph, Gwendolyn Ryan, Michael Sandberg, Kathryn Titze, Jens Tolunay, Eser Toney, Glenn M. Harrison, David G. TI National Heart, Lung, and Blood Institute Working Group Report on Salt in Human Health and Sickness Building on the Current Scientific Evidence SO HYPERTENSION LA English DT Review ID PATHOGENIC T(H)17 CELLS; REGULATORY T-CELLS; CARDIOVASCULAR-DISEASE; SENSITIVE HYPERTENSION; DEPENDENT HYPERTENSION; RHEUMATOID-ARTHRITIS; AUTOIMMUNE-DISEASE; PRESSURE RESPONSES; GENDER-DIFFERENCE; SEX-DIFFERENCES C1 [Oh, Young S.; Galis, Zorina S.; Maric-Bilkan, Christine; Tolunay, Eser] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Mehta, Nehal N.] NHLBI, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Appel, Lawrence J.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Hafler, David A.; Hernandez, Amanda L.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. [Hafler, David A.; Hernandez, Amanda L.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [He, Jiang] Tulane Univ, Dept Epidemiol, New Orleans, LA 70118 USA. [Joe, Bina] Univ Toledo, Dept Physiol & Pharmacol, Toledo, OH USA. [Karumanchi, S. Ananth] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. [Karumanchi, S. Ananth] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Boston, MA USA. [Mattson, David] Med Coll Wisconsin, Dept Physiol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Randolph, Gwendolyn] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Ryan, Michael] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS USA. [Sandberg, Kathryn] Georgetown Univ, Dept Med, Washington, DC USA. [Titze, Jens; Harrison, David G.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Toney, Glenn M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. RP Oh, YS (reprint author), NHLBI, Vasc Biol & Hypertens Branch, Div Cardiovasc Sci, 6701 Rockledge Dr,8106, Bethesda, MD 20892 USA. EM yoh@mail.nih.gov FU National Heart, Lung, and Blood Institute FX The proceedings of the "Salt in Human Health and Sickness: Building on the Current Scientific Evidence" Working Group were supported through funds provided by the National Heart, Lung, and Blood Institute. NR 69 TC 2 Z9 2 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD AUG PY 2016 VL 68 IS 2 BP 281 EP 288 DI 10.1161/HYPERTENSIONAHA.116.07415 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DS1QP UT WOS:000380371700010 PM 27324228 ER PT J AU Li, CW He, J Chen, J Zhao, JY Gu, DF Hixson, JE Rao, DC Jaquish, CE Gu, CC Chen, JC Huang, JF Chen, SF Kelly, TN AF Li, Changwei He, Jiang Chen, Jing Zhao, Jinying Gu, Dongfeng Hixson, James E. Rao, Dabeeru C. Jaquish, Cashell E. Gu, Charles C. Chen, Jichun Huang, Jianfeng Chen, Shufeng Kelly, Tanika N. TI Genome-Wide Gene-Sodium Interaction Analyses on Blood Pressure The Genetic Epidemiology Network of Salt-Sensitivity Study SO HYPERTENSION LA English DT Article DE blood pressure; genes; genome-wide association study; sodium ID BARDET-BIEDL SYNDROME; 24-H URINARY SODIUM; ENVIRONMENT INTERACTION; IDENTIFIES 8; ASSOCIATION; LOCI; HYPERTENSION; METAANALYSIS; CEP290; ACTIVATION AB We performed genome-wide analyses to identify genomic loci that interact with sodium to influence blood pressure (BP) using single-marker-based (1 and 2 df joint tests) and gene-based tests among 1876 Chinese participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Among GenSalt participants, the average of 3 urine samples was used to estimate sodium excretion. Nine BP measurements were taken using a random zero sphygmomanometer. A total of 2.05 million single-nucleotide polymorphisms were imputed using Affymetrix 6.0 genotype data and the Chinese Han of Beijing and Japanese of Tokyo HapMap reference panel. Promising findings (P<1.00x10(-4)) from GenSalt were evaluated for replication among 775 Chinese participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Single-nucleotide polymorphism and gene-based results were meta-analyzed across the GenSalt and MESA studies to determine genome-wide significance. The 1 df tests identified interactions for UST rs13211840 on diastolic BP (P=3.13x10(-9)). The 2 df tests additionally identified associations for CLGN rs2567241 (P=3.90x10(-12)) and LOC105369882 rs11104632 (P=4.51x10(-8)) with systolic BP. The CLGN variant rs2567241 was also associated with diastolic BP (P=3.11x10(-22)) and mean arterial pressure (P=2.86x10(-15)). Genome-wide gene-based analysis identified MKNK1 (P=6.70x10(-7)), C2orf80 (P<1.00x10(-12)), EPHA6 (P=2.88x10(-7)), SCOC-AS1 (P=4.35x10(-14)), SCOC (P=6.46x10(-11)), CLGN (P=3.68x10(-13)), MGAT4D (P=4.73x10(-11)), ARHGAP42 (P=1.00x10(-12)), CASP4 (P=1.31x10(-8)), and LINC01478 (P=6.75x10(-10)) that were associated with at least 1 BP phenotype. In summary, we identified 8 novel and 1 previously reported BP loci through the examination of single-nucleotide polymorphism and gene-based interactions with sodium. C1 [Li, Changwei; He, Jiang; Zhao, Jinying; Kelly, Tanika N.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA. [He, Jiang; Chen, Jing] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Gu, Dongfeng; Chen, Jichun; Huang, Jianfeng; Chen, Shufeng] Chinese Acad Med Sci, State Key Lab Cardiovasc Dis, Fuwai Hosp, Natl Ctr Cardiovasc Dis, Beijing, Peoples R China. [Gu, Dongfeng; Chen, Jichun; Huang, Jianfeng; Chen, Shufeng] Peking Union Med Coll, Beijing, Peoples R China. [Hixson, James E.] Univ Texas, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Rao, Dabeeru C.; Gu, Charles C.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Jaquish, Cashell E.] NHLBI, Div Prevent & Populat Sci, Bldg 10, Bethesda, MD 20892 USA. RP Kelly, TN (reprint author), Tulane Univ, Dept Epidemiol, 1440 Canal St,Suite 2000, New Orleans, LA 70112 USA. EM tkelly@tulane.edu RI Li, Changwei/S-5615-2016 OI Li, Changwei/0000-0002-9203-304X FU National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD [U01HL072507, R01HL087263, R01HL090682]; National Heart, Lung, and Blood Institute (NHLBI); NHLBI Contract [N02-HL-64278]; [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]; [CTSA UL1-RR-024156] FX The Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) was supported by a cooperative agreement project grant (U01HL072507, R01HL087263, and R01HL090682) from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD. Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA was provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, and CTSA UL1-RR-024156. Fundingfor SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and MIT (Boston, MA) using the Affymetrix Genome-Wide Human SNP Array 6.0. NR 41 TC 1 Z9 1 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD AUG PY 2016 VL 68 IS 2 BP 348 EP + DI 10.1161/HYPERTENSIONAHA.115.06765 PG 27 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DS1QP UT WOS:000380371700020 PM 27271309 ER PT J AU Gallagher, EJ LeRoith, D Stasinopoulos, M Zelenko, Z Shiloach, J AF Gallagher, Emily J. LeRoith, Derek Stasinopoulos, Marilyn Zelenko, Zara Shiloach, Joseph TI Polyol accumulation in muscle and liver in a mouse model of type 2 diabetes SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE Type 2 diabetes; Polyol pathway; Metabolomics; Diabetic myopathy; Non-alcoholic fatty liver disease ID PENTOSE-PHOSPHATE PATHWAY; SKELETAL-MUSCLE; OXIDATIVE STRESS; DB/DB MICE; MKR MICE; IGF-I; INSULIN; METABOLISM; PLASMA; RATS AB Aims: Type 2 diabetes (T2D) is a complex metabolic disease leading to complications in multiple organs. Diabetic myopathy and liver disease are common complications of T2D, but are incompletely understood. To gain insight into the pathogenesis of these conditions we performed metabolomic analysis of skeletal muscle and liver in a mouse model of T2D. Methods: Tissue metabolomics were performed by GC/MS and LC/MS of the skeletal muscle and liver in the MKR mouse model of T2D, compared with control mice. MKR mice were treated with the beta-3 adrenergic receptor agonist, CL-316,243 to determine metabolite changes after correcting hyperglycemia. Results: Blood glucose was higher in MKR vs WT mice, and normalized with CL-316,243 treatment. Compared with WT mice, MKR mice had 2.5 fold higher concentrations of sorbitol and 1.7 fold lower concentrations of reduced glutathione in skeletal muscle. In liver, MKR mice had 2 fold higher concentrations of the pentitol ribitol. CL-316,243 treatment normalized sorbitol and ribitol concentrations in MKR skeletal muscle and liver, respectively to the levels of the WT mice. Conclusions: These results demonstrate tissue-specific accumulation of polyols in a mouse model of T2D and provide novel insights into the pathogenesis of myopathy and liver disease in T2D. (C) 2016 Elsevier Inc. All rights reserved. C1 [Gallagher, Emily J.; LeRoith, Derek; Stasinopoulos, Marilyn; Zelenko, Zara] Icahn Sch Med Sinai, Metab Inst, Div Endocrinol Diabet & Bone Dis & Diabet, Obes, 1 Gustave L Levy Pl,Atran 4th Floor 35,Box 1055, New York, NY 10029 USA. [Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, Bldg 14A, Bethesda, MD 20892 USA. RP Gallagher, EJ (reprint author), Icahn Sch Med Sinai, Metab Inst, Div Endocrinol Diabet & Bone Dis & Diabet, Obes, 1 Gustave L Levy Pl,Atran 4th Floor 35,Box 1055, New York, NY 10029 USA. EM Emily.gallagher@mssm.edu FU Intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; NCI/NIH [1K08CA190770, 2R01CA128799-06A1]; ADA [1-13-BS-108] FX Funding for the study was provided by the Intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. EJG received funding from NCI/NIH 1K08CA190770, DLR received funding from ADA 1-13-BS-108, and NCI/NIH 2R01CA128799-06A1. NR 40 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 EI 1873-460X J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD AUG PY 2016 VL 30 IS 6 BP 999 EP 1007 DI 10.1016/j.jdiacomp.2016.04.019 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DS2FY UT WOS:000380579000005 PM 27197688 ER PT J AU Grazziotin, MCB Grazziotin, AL Vidal, NM Freire, MHD da Silva, RPGVC AF Bonzanini Grazziotin, Maria Celestina Grazziotin, Ana Laura Vidal, Newton Medeiros de Souza Freire, Marcia Helena Vieira Cavalcante da Silva, Regina Paula Guimaraes TI Analysis of the Storage Methods for Raw Human Milk from Mothers with Infants Admitted to a Neonatal Intensive Care Unit, According to Brazilian Regulations SO JOURNAL OF HUMAN LACTATION LA English DT Article DE Brazil; breastfeeding; creamatocrit; Dornic acidity; energy content; human milk bank; milk quality ID BREAST-MILK; DORNIC ACIDITY; CREAMATOCRIT; PRETERM; BANK; FAT; CONSUMPTION; GUIDELINES; NICU AB Background: Milk safety is an important concern in neonatal units and human milk banks. Therefore, evidence-based recommendations regarding raw milk handling and storage are needed to safely promote supplying hospitalized infants with their mother's own milk. Objectives: To evaluate raw human milk storage methods according to Brazilian milk management regulations by investigating the effects of refrigeration (5 degrees C) for 12 hours and freezing (-20 degrees C) for 15 days on the acidity and energy content in a large number of raw milk samples. Methods: Expressed milk samples from 100 distinct donors were collected in glass bottles. Each sample was separated into 3 equal portions that were analyzed at room temperature and after either 12 hours of refrigeration or 15 days of freezing. Milk acidity and energy content were determined by Dornic titration and creamatocrit technique, respectively. Results: All samples showed Dornic acidity values within the established acceptable limit ( 8 degrees D), as required by Brazilian regulations. In addition, energy content did not significantly differ among fresh, refrigerated and frozen milk samples (median of similar to 50 kcal/100 mL for each). Conclusion: Most samples tested (> 80%) were considered top quality milk (< 4 degrees D) based on acidity values, and milk energy content was preserved after storage. We conclude that the storage methods required by Brazilian regulations are suitable to ensure milk safety and energy content of stored milk when supplied to neonates. C1 [Bonzanini Grazziotin, Maria Celestina] Univ Fed Parana, Banco Leite Humano Hosp Clin, Curitiba, Parana, Brazil. [Grazziotin, Ana Laura] Univ Estadual Norte Fluminense, Ctr Biociencias & Biotecnol, Campos Goytacazes, Rio De Janeiro, Brazil. [Vidal, Newton Medeiros] NIH, Natl Ctr Biotechnol Informat, Bldg 10, Bethesda, MD 20892 USA. [de Souza Freire, Marcia Helena] Univ Fed Parana, Dept Enfermagem, Setor Ciencias Saude, Curitiba, Parana, Brazil. [Vieira Cavalcante da Silva, Regina Paula Guimaraes] Univ Fed Parana, Dept Pediat, Serv Neonatol, Setor Ciencias Saude, Curitiba, Parana, Brazil. RP Grazziotin, AL (reprint author), Univ Iowa, Dept Biomed Engn, Coll Engn, Seamans Ctr Engn Arts & Sci 1402, Iowa City, IA 52242 USA. EM analauragrazziotin@gmail.com FU Intramural Research Program of the National Library of Medicine, National Institutes of Health; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico; National Institutes of Health FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was partially supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. NMV's postdoctoral fellowship is funded by a partnership between Conselho Nacional de Desenvolvimento Cientifico e Tecnologico and the National Institutes of Health. NR 43 TC 0 Z9 0 U1 2 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0890-3344 EI 1552-5732 J9 J HUM LACT JI J. Hum. Lact. PD AUG PY 2016 VL 32 IS 3 BP 446 EP 454 DI 10.1177/0890334416647710 PG 9 WC Nursing; Obstetrics & Gynecology; Pediatrics SC Nursing; Obstetrics & Gynecology; Pediatrics GA DS0HI UT WOS:000380275800014 PM 27165765 ER PT J AU Kusiak, JW Somerman, M AF Kusiak, John W. Somerman, Martha TI Data science at the National Institute of Dental and Craniofacial Research Changing dental practice SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Editorial Material C1 [Kusiak, John W.; Somerman, Martha] Natl Inst Dent & Craniofacial Res, NIH, Bldg 31,Room 2C-39, Bethesda, MD 20892 USA. RP Kusiak, JW (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bldg 31,Room 2C-39, Bethesda, MD 20892 USA. EM kusiakj@mail.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 EI 1943-4723 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD AUG PY 2016 VL 147 IS 8 BP 597 EP 599 DI 10.1016/j.adaj.2016.06.005 PG 3 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DS5TJ UT WOS:000380844900001 PM 27470520 ER PT J AU Wright, JT Tampi, MP Graham, L Estrich, C Crall, JJ Fontana, M Gillette, EJ Novy, BB Dhar, V Donly, K Hewlett, ER Quinonez, RB Chaffin, J Crespin, M Iafolla, T Siegal, MD Carrasco-Labra, A AF Wright, John T. Tampi, Malavika P. Graham, Laurel Estrich, Cameron Crall, James J. Fontana, Margherita Gillette, E. Jane Novy, Brian B. Dhar, Vineet Donly, Kevin Hewlett, Edmond R. Quinonez, Rocio B. Chaffin, Jeffrey Crespin, Matt Iafolla, Timothy Siegal, Mark D. Carrasco-Labra, Alonso TI Sealants for preventing and arresting pit-and-fissure occlusal caries in primary and permanent molars A systematic review of randomized controlled trials-a report of the American Dental Association and the American Academy of Pediatric Dentistry SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article DE Glass ionomer sealants; resin-based sealants; caries prevention; caries arrest; pit-and-fissure sealants; systematic review ID GLASS-IONOMER; CLINICAL-EVALUATION; FLUORIDE VARNISH; LOW-RISK; RETENTION AB Background. National Health and Nutrition Examination Survey 2011-2012 data indicated that, in the United States, nearly one-fourth of children and over one-half of adolescents experienced dental caries in their permanent teeth. The purpose of this review was to summarize the available clinical evidence regarding the effect of dental sealants for the prevention and management of pit-and-fissure occlusal carious lesions in primary and permanent molars, compared with a control without sealants, with fluoride varnishes, or with other head-to head comparisons. Type of Studies Reviewed. The authors included parallel and split-mouth randomized controlled trials that included at least 2 years of follow-up, which they identified using MEDLINE (via PubMed), Embase, LILACS, the Cochrane Central Register of Controlled Trials, and registers of ongoing trials. Pairs of reviewers independently conducted the selection of studies, data extraction, risk of bias assessments, and quality of the evidence assessments by using the Grading of Recommendations Assessment, Development and Evaluation approach. Results. Of 2,869 records screened, the authors determined that 24 articles (representing 23 studies) proved eligible. Moderate-quality evidence suggested that participants who received sealants had a reduced risk of developing carious lesions in occlusal surfaces of permanent molars compared with those who did not receive sealants (odds ratio [OR], 0.15; 95% confidence interval [CI], 0.08-0.27) after 7 or more years of follow-up. When the authors compared studies whose investigators had compared sealants with fluoride varnishes, they found that sealants reduced the incidence of carious lesions after 7 or more years of follow-up (OR, 0.19; 95% CI, 0.07-0.51); however, this finding was supported by low-quality evidence. On the basis of the evidence, the authors could not provide a hierarchy of effectiveness among the studies whose investigators had conducted head-to-head comparisons. The investigators of 2 trials provided information about adverse events, but they did not report any adverse events. Conclusions and Practical Implications. Available evidence suggests that sealants are effective and safe to prevent or arrest the progression of noncavitated carious lesions compared with a control without sealants or fluoride varnishes. Further research is needed to provide information about the relative merits of the different types of sealant materials. C1 [Wright, John T.] Univ N Carolina, Pediat Dent, Chapel Hill, NC USA. [Wright, John T.] Univ N Carolina, Sch Dent, Dept Pediat Dent, Strateg Initiat, Chapel Hill, NC USA. [Tampi, Malavika P.] Amer Dent Assoc, Inst Sci, Ctr Evidence Based Dent, 211 E Chicago Ave, Chicago, IL 60611 USA. [Graham, Laurel] Amer Acad Pediat Dent, Chicago, IL USA. [Estrich, Cameron] Amer Dent Assoc, Inst Sci, Sci Informat, Chicago, IL USA. [Crall, James J.] Univ Calif Los Angeles, Sch Dent, Div Publ Hlth & Community Dent, Los Angeles, CA 90024 USA. [Fontana, Margherita] Univ Michigan, Sch Dent, Dept Cariol Restorat Sci & Endodont, Ann Arbor, MI 48109 USA. [Gillette, E. Jane] Univ Washington, Sch Dent, Seattle, WA 98195 USA. [Novy, Brian B.] DentaQuest Inst, Westborough, MA USA. [Dhar, Vineet] Univ Maryland, Sch Dent, Div Pediat Dent, Baltimore, MD 21201 USA. [Donly, Kevin] Univ Texas Hlth Sci Ctr San Antonio, Sch Dent, Dept Dev Dent, San Antonio, TX 78229 USA. [Hewlett, Edmond R.] Univ Calif Los Angeles, Sch Dent, Sect Restorat Dent, Los Angeles, CA 90024 USA. [Quinonez, Rocio B.] Univ N Carolina, Sch Dent, Dept Pediat Dent & Pediat, Chapel Hill, NC USA. [Chaffin, Jeffrey] Delta Dent Iowa, Des Moines, IA USA. [Chaffin, Jeffrey] AT Still Univ, Coll Grad Hlth Studies, Mesa, AZ USA. [Chaffin, Jeffrey] Assoc State & Terr Dent Directors, Reno, NV USA. [Crespin, Matt] Childrens Hosp Wisconsin, Childrens Hlth Alliance Wisconsin, Milwaukee, WI 53201 USA. [Iafolla, Timothy] Natl Inst Dent & Craniofacial Res, Program Anal & Reports Branch, NIH, Bethesda, MD USA. [Siegal, Mark D.] Ohio State Univ, Coll Dent, Columbus, OH 43210 USA. [Siegal, Mark D.] Amer Assoc Publ Hlth Dent, Springfield, IL USA. [Carrasco-Labra, Alonso] Amer Dent Assoc, Ctr Evidence Based Dent, Chicago, IL USA. [Carrasco-Labra, Alonso] Univ Chile, Evidence Based Dent Unit, Santiago, Chile. [Carrasco-Labra, Alonso] Univ Chile, Dept Oral & Maxillofacial Surg, Fac Dent, Santiago, Chile. [Carrasco-Labra, Alonso] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. RP Tampi, MP (reprint author), Amer Dent Assoc, Inst Sci, Ctr Evidence Based Dent, 211 E Chicago Ave, Chicago, IL 60611 USA. EM tampim@ada.org FU American Academy of Pediatric Dentistry FX The American Dental Association's Council on Scientific Affairs commissioned this work, and the American Academy of Pediatric Dentistry partly funded this project. NR 44 TC 4 Z9 5 U1 7 U2 16 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 EI 1943-4723 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD AUG PY 2016 VL 147 IS 8 BP 631 EP + DI 10.1016/j.adaj.2016.06.003 PG 33 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DS5TJ UT WOS:000380844900009 PM 27470524 ER PT J AU Wright, JT Crall, JJ Fontana, M Gillette, EJ Novy, BB Dhar, V Donly, K Hewlett, ER Quinonez, RB Chaffin, J Crespin, M Iafolla, T Siegal, MD Tampi, MP Graham, L Estrich, C Carrasco-Labra, A AF Wright, John T. Crall, James J. Fontana, Margherita Gillette, E. Jane Novy, Brian B. Dhar, Vineet Donly, Kevin Hewlett, Edmond R. Quinonez, Rocio B. Chaffin, Jeffrey Crespin, Matt Iafolla, Timothy Siegal, Mark D. Tampi, Malavika P. Graham, Laurel Estrich, Cameron Carrasco-Labra, Alonso TI Evidence-based clinical practice guideline for the use of pit-and-fissure sealants A report of the American Dental Association and the American Academy of Pediatric Dentistry SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article DE Pit-and-fissure sealants; clinical recommendations; guideline; occlusal caries; caries prevention; caries arresting ID GLASS-IONOMER; CARIES PREVENTION; SCIENTIFIC AFFAIRS; LOW-RISK; TRIAL; RECOMMENDATIONS; QUALITY; CHILDREN; RETENTION; MEDICAID AB Background. This article presents evidence-based clinical recommendations for the use of pit-and-fissure sealants on the occlusal surfaces of primary and permanent molars in children and adolescents. A guideline panel convened by the American Dental Association (ADA) Council on Scientific Affairs and the American Academy of Pediatric Dentistry conducted a systematic review and formulated recommendations to address clinical questions in relation to the efficacy, retention, and potential side effects of sealants to prevent dental caries; their efficacy compared with fluoride varnishes; and a head-to-head comparison of the different types of sealant material used to prevent caries on pits and fissures of occlusal surfaces. Types of Studies Reviewed. This is an update of the ADA 2008 recommendations on the use of pit-and-fissure sealants on the occlusal surfaces of primary and permanent molars. The authors conducted a systematic search in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and other sources to identify randomized controlled trials reporting on the effect of sealants (available on the US market) when applied to the occlusal surfaces of primary and permanent molars. The authors used the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the quality of the evidence and to move from the evidence to the decisions. Results. The guideline panel formulated 3 main recommendations. They concluded that sealants are effective in preventing and arresting pit-and-fissure occlusal carious lesions of primary and permanent molars in children and adolescents compared with the nonuse of sealants or use of fluoride varnishes. They also concluded that sealants could minimize the progression of noncavitated occlusal carious lesions (also referred to as initial lesions) that receive a sealant. Finally, based on the available limited evidence, the panel was unable to provide specific recommendations on the relative merits of 1 type of sealant material over the others. Conclusions and Practical Implications. These recommendations are designed to inform practitioners during the clinical decision-making process in relation to the prevention of occlusal carious lesions in children and adolescents. Clinicians are encouraged to discuss the information in this guideline with patients or the parents of patients. The authors recommend that clinicians reorient their efforts toward increasing the use of sealants on the occlusal surfaces of primary and permanent molars in children and adolescents. C1 [Wright, John T.] Univ N Carolina, Sch Dent, Pediat Dent, Chapel Hill, NC 27514 USA. [Wright, John T.] Univ N Carolina, Sch Dent, Dept Pediat Dent, Strateg Initiat, Chapel Hill, NC 27514 USA. [Tampi, Malavika P.] Amer Dent Assoc, Ctr Evidence Based Dent, Inst Sci, 211 E Chicago Ave, Chicago, IL 60611 USA. [Graham, Laurel] Amer Acad Pediat Dent, Chicago, IL USA. [Estrich, Cameron] Amer Dent Assoc, Sci Informat, Inst Sci, Chicago, IL USA. [Crall, James J.] Univ Calif Los Angeles, Sch Dent, Div Publ Hlth & Community Dent, Los Angeles, CA 90024 USA. [Fontana, Margherita] Univ Michigan, Sch Dent, Dept Cariol Restorat Sci & Endodont, Ann Arbor, MI 48109 USA. [Gillette, E. Jane] Univ Washington, Sch Dent, Seattle, WA 98195 USA. [Novy, Brian B.] DentaQuest Inst, Practice Improvement, Westborough, MA USA. [Dhar, Vineet] Univ Maryland, Sch Dent, Div Pediat Dent, Baltimore, MD 21201 USA. [Donly, Kevin] Univ Texas Hlth Sci Ctr San Antonio, Sch Dent, Dept Dev Dent, San Antonio, TX USA. [Hewlett, Edmond R.] Univ Calif Los Angeles, Sch Dent, Sect Restorat Dent, Los Angeles, CA 90024 USA. [Quinonez, Rocio B.] Univ N Carolina, Sch Dent, Dept Pediat Dent & Pediat, Chapel Hill, NC 27599 USA. Delta Dent Iowa, Des Moines, IA USA. [Chaffin, Jeffrey] AT Still Univ, Coll Grad Hlth Studies, Mesa, AZ USA. [Crespin, Matt] Childrens Hosp Wisconsin, Childrens Hlth Alliance Wisconsin, Milwaukee, WI 53201 USA. [Iafolla, Timothy] Natl Inst Dent & Craniofacial Res, Program Anal & Reports Branch, NIH, Bethesda, MD USA. [Siegal, Mark D.] Ohio State Univ, Coll Dent, Columbus, OH 43210 USA. [Siegal, Mark D.] Amer Assoc Publ Hlth Dent, Springfield, IL USA. [Carrasco-Labra, Alonso] Amer Dent Assoc, Ctr Evidence Based Dent, Chicago, IL USA. [Carrasco-Labra, Alonso] Univ Chile, Fac Dent, Evidence Based Dent Unit, Santiago, Chile. [Carrasco-Labra, Alonso] Univ Chile, Fac Dent, Dept Oral & Maxillofacial Surg, Santiago, Chile. [Carrasco-Labra, Alonso] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. RP Tampi, MP (reprint author), Amer Dent Assoc, Ctr Evidence Based Dent, Inst Sci, 211 E Chicago Ave, Chicago, IL 60611 USA. EM tampim@ada.org FU American Academy of Pediatric Dentistry FX The American Dental Association Council on Scientific Affairs commissioned this work and the American Academy of Pediatric Dentistry partly funded this project. NR 59 TC 6 Z9 6 U1 8 U2 8 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 EI 1943-4723 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD AUG PY 2016 VL 147 IS 8 BP 672 EP + DI 10.1016/j.adaj.2016.06.001 PG 23 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DS5TJ UT WOS:000380844900014 PM 27470525 ER PT J AU Tempero, M AF Tempero, Margaret TI I'll Have Another Shot, Please! SO Journal of the National Comprehensive Cancer Network LA English DT Editorial Material C1 [Tempero, Margaret] UCSF Pancreas Ctr, San Francisco, CA 94143 USA. [Tempero, Margaret] ASCO Board Directors, Alexandria, VA 22314 USA. [Tempero, Margaret] ASCO, Alexandria, VA 22314 USA. [Tempero, Margaret] ASCO Conquer Canc Fdn Board, Alexandria, VA 22314 USA. [Tempero, Margaret] NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA. [Tempero, Margaret] NCI, Board Sci Counselors Subcomm, Bethesda, MD 20892 USA. [Tempero, Margaret] Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX 78701 USA. [Tempero, Margaret] UNMC Eppley Canc Ctr, Omaha, NE 68198 USA. [Tempero, Margaret] UCSF, Div Med Oncol, San Francisco, CA 94143 USA. [Tempero, Margaret] UCSF, Res Programs, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. RP Tempero, M (reprint author), UCSF Pancreas Ctr, San Francisco, CA 94143 USA.; Tempero, M (reprint author), ASCO Board Directors, Alexandria, VA 22314 USA.; Tempero, M (reprint author), ASCO, Alexandria, VA 22314 USA.; Tempero, M (reprint author), ASCO Conquer Canc Fdn Board, Alexandria, VA 22314 USA.; Tempero, M (reprint author), NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA.; Tempero, M (reprint author), NCI, Board Sci Counselors Subcomm, Bethesda, MD 20892 USA.; Tempero, M (reprint author), Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX 78701 USA.; Tempero, M (reprint author), UNMC Eppley Canc Ctr, Omaha, NE 68198 USA.; Tempero, M (reprint author), UCSF, Div Med Oncol, San Francisco, CA 94143 USA.; Tempero, M (reprint author), UCSF, Res Programs, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD AUG 1 PY 2016 VL 14 IS 8 BP 929 EP 929 PG 1 WC Oncology SC Oncology GA DS5JP UT WOS:000380818400001 PM 27496107 ER PT J AU Zanetti, KA Wang, ZM Aldrich, M Amos, CI Blot, WJ Bowman, ED Burdette, L Cai, QY Caporaso, N Chung, CC Gillanders, EM Haiman, CA Hansen, HM Henderson, BE Kolonel, LN Le Marchand, L Li, SC McNeil, LH Ryan, BM Schwartz, AG Sison, JD Spitz, MR Tucker, M Wenzlaff, AS Wiencke, JK Wilkens, L Wrensch, MR Wu, XF Zheng, W Zhou, WY Christiani, D Palmer, JR Penning, TM Rieber, AG Rosenberg, L Ruiz-Narvaez, EA Su, L Vachani, A Wei, YY Whitehead, AS Chanock, SJ Harris, CC AF Zanetti, Krista A. Wang, Zhaoming Aldrich, Melinda Amos, Christopher I. Blot, William J. Bowman, Elise D. Burdette, Laurie Cai, Qiuyin Caporaso, Neil Chung, Charles C. Gillanders, Elizabeth M. Haiman, Christopher A. Hansen, Helen M. Henderson, Brian E. Kolonel, Laurence N. Le Marchand, Loic Li, Shengchao McNeil, Lorna Haughton Ryan, Brid M. Schwartz, Ann G. Sison, Jennette D. Spitz, Margaret R. Tucker, Margaret Wenzlaff, Angela S. Wiencke, John K. Wilkens, Lynne Wrensch, Margaret R. Wu, Xifeng Zheng, Wei Zhou, Weiyin Christiani, David Palmer, Julie R. Penning, Trevor M. Rieber, Alyssa G. Rosenberg, Lynn Ruiz-Narvaez, Edward A. Su, Li Vachani, Anil Wei, Yongyue Whitehead, Alexander S. Chanock, Stephen J. Harris, Curtis C. TI Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population SO LUNG CANCER LA English DT Article DE Genome-wide association study; Lung neoplasms; Smoking; African Americans; Telomerase; Receptors, Cholinergic ID ACETYLCHOLINE-RECEPTOR GENES; NICOTINE DEPENDENCE; EUROPEAN-AMERICANS; RACIAL-DIFFERENCES; SMOKING-BEHAVIOR; CIGARETTE-SMOKING; HEAVY SMOKING; IDENTIFIES 2; RISK; VARIANTS AB Objectives: Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping. Materials and methods: We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p < 1.51 x 10(-8)) in an independent set of 866 cases and 796 controls in stage 2. Results and conclusion: In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p =1.3 x 10(-9); OR =1.32; 95% CI =1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p = 2.8 x 10(-9); OR =1.28; 95% CI = 1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p =1.3 x 10(-8); OR= 1.37; 95% CI= 1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15825.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans. Published by Elsevier Ireland Ltd. C1 [Zanetti, Krista A.; Gillanders, Elizabeth M.] NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Rockville, MD 20892 USA. [Wang, Zhaoming; Burdette, Laurie; Caporaso, Neil; Chung, Charles C.; Li, Shengchao; Tucker, Margaret; Zhou, Weiyin; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20892 USA. [Aldrich, Melinda; Blot, William J.; Cai, Qiuyin; Zheng, Wei] Vanderbilt Univ, Med Ctr, Div Epidemiol, 1161 21st Ave South,D-3100 Med Ctr North, Nashville, TN 37232 USA. [Aldrich, Melinda] Vanderbilt Univ, Med Ctr, Dept Thorac Surg, 609 Oxford House,1313 21st Ave South, Nashville, TN 37232 USA. [Amos, Christopher I.] Geisel Sch Med, Dept Biomed Data Sci, 1 Rope Ferry Rd, Lebanon, NH 03755 USA. [Bowman, Elise D.; Ryan, Brid M.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bldg 37,Room 3068A, Bethesda, MD 20892 USA. [Haiman, Christopher A.; Henderson, Brian E.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, 1975 Zonal Ave, Los Angeles, CA 90033 USA. [Haiman, Christopher A.; Henderson, Brian E.] Norris Comprehens Canc Ctr, 1975 Zonal Ave, Los Angeles, CA 90033 USA. [Hansen, Helen M.; Sison, Jennette D.; Wiencke, John K.; Wrensch, Margaret R.] Univ Calif San Francisco, Dept Neurol Surg, 505 Parnassus Ave,Room 779, San Francisco, CA 94143 USA. [Kolonel, Laurence N.; Le Marchand, Loic; Wilkens, Lynne] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [McNeil, Lorna Haughton] Univ Texas MD Anderson Canc Ctr, Div OVP Canc Prevent & Populat Sci, Dept Hlth Dispar Res, 1515 Holcombe Blvd,Unit 91, Houston, TX 77030 USA. [Schwartz, Ann G.; Wenzlaff, Angela S.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Dept Oncol, 4100 John R, Detroit, MI 48201 USA. [Wilkens, Lynne] Baylor Coll Med, Dept Mol & Cellular Biol, One Baylor Plaza,Mail Stop BCM225, Houston, TX 77030 USA. [Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Div OVP Canc Prevent & Populat Sci, Dept Epidemiol, Unit 1340,POB 301439, Houston, TX 77230 USA. [Christiani, David; Su, Li; Wei, Yongyue] Harvard Med Sch, Massachusetts Gen Hosp, Harvard Sch Publ Hlth, 25 Shattuck St, Boston, MA 02115 USA. [Palmer, Julie R.; Rosenberg, Lynn; Ruiz-Narvaez, Edward A.] Boston Univ, Slone Epidemiol Canc Ctr, 1010 Commonwealth Ave,4th Floor, Boston, MA 02215 USA. [Penning, Trevor M.; Vachani, Anil; Whitehead, Alexander S.] Univ Penn, Perelman Sch Med, Ctr Excellence Environm Toxicol, 3535 Market St, Philadelphia, PA 19104 USA. [Penning, Trevor M.; Whitehead, Alexander S.] Univ Penn, Perelman Sch Med, Dept Pharmacol, 3535 Market St, Philadelphia, PA 19104 USA. [Rieber, Alyssa G.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Gen Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Vachani, Anil] Univ Penn, Perelman Sch Med, Dept Med, 3535 Market St, Philadelphia, PA 19104 USA. RP Chanock, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20892 USA.; Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bldg 37,Room 3068A, Bethesda, MD 20892 USA. EM zanettik@mail.nih.gov; wangzha@mail.nih.gov; melinda.aldrich@Vanderbilt.Edu; Christopher.I.Amos@Dartmouth.edu; blotw@iei.us; bowmane@intra.nci.nih.gov; burdettl@mail.nih.gov; qiuyin.cai@Vanderbilt.Edu; caporasn@mail.nih.gov; chungcc@mail.nih.gov; lgilland@mail.nih.gov; haiman@usc.edu; helen.hansen@ucsf.edu; lkolonel@cc.hawaii.edu; Loic@cc.hawaii.edu; shengchao.li@nih.gov; lmcneill@mdanderson.org; ryanb@mail.nih.gov; schwarta@karmanos.org; jennette.sison@ucsf.edu; spitz@bcm.edu; tuckerp@mail.nih.gov; wenzlaff@karmanos.org; john.wiencke@ucsf.edu; lynne@cc.hawaii.edu; Margaret.Wrensch@ucsf.edu; xwu@mdanderson.org; wei.zheng@vanderbilt.edu; zhouw@mail.nih.gov; dchris@hsph.harvard.edu; jpalmer@bu.edu; PENNING@UPENN.EDU; arieber@mdanderson.org; Irosenbe@bu.edu; eruiznar@bu.edu; lisu@hsph.harvard.edu; avachani@mail.med.upenn.edu; ywei@hsph.harvard.edu; aswhiteh@mail.med.upenn.edu; chanocks@mail.nih.gov; Curtis_Harris@nih.gov RI Zheng, Wei/O-3351-2013 OI Zheng, Wei/0000-0003-1226-070X FU Black Women's Health Study (BWHS): NIH grants [R01CA098663, R01CA05842]; National Institutes of Health [CA63464, CA54281, CA1326792, CA164973, CA148085, CA138338, CA148127, HG004726]; Department of Defense Breast Cancer Research Program Era of Hope Scholar Award [W81XWH-08-1-0383]; Pennsylvania Department of Health [PA4100038714]; NCI [R21CA156087]; NIH-NIEHS grant [P30ES013508]; intramural research program of the National Institutes of Health, National Cancer Institute; federal funds from the National Cancer Institute, National Institutes of Health; National Institutes of Health through MD Anderson's Cancer Center Support Grant [CA016672]; NIH [R01CA092447]; Vanderbilt-Ingram Cancer Center [P30CA068485]; NIH/NCI grant [K07CA172294]; Karmanos Cancer Institute at Wayne State University: NIH [R01CA060691, R01CA87895, N01-PC35145, P30CA22453]; Department of Health and Human Services [HHSN261201000028C] FX The Black Women's Health Study (BWHS): NIH grants R01CA098663 and R01CA05842.; The Multiethnic Cohort Study (MEC): The MEC study, blood collection, DNA extraction and genotyping was supported by National Institutes of Health grants CA63464, CA54281, CA1326792, CA164973, CA148085, CA138338, CA148127 and HG004726 and a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to CAH (W81XWH-08-1-0383).; Philadelphia Lung Cancer Study on Gene Environment Interactions (Plus-Gene): This work was funded by grant PA4100038714 from the Pennsylvania Department of Health, NCI R21CA156087, and NIH-NIEHS grant P30ES013508 for the Center of Excellence in Environmental Toxicology.; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO): The NCI African American lung cancer GWAS was supported by the intramural research program of the National Institutes of Health, National Cancer Institute. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health.; Project CHURCH (Creating a Higher Understanding of Cancer Research & Community Health): University Cancer Foundation, the Duncan Family Institute through the Center for Community Engaged Translational Research, the Ms. Regina J. Rogers Gift: Health Disparities Research Program, the Cullen Trust for Health Care Endowed Chair Funds for Health Disparities Research, the Morgan Foundation Funds for Health Disparities Research and Educational Programs, and the National Institutes of Health through MD Anderson's Cancer Center Support Grant (CA016672).; The Southern Community Cohort Study (SCCS): Funding for the SCCS research was provided by NIH grant R01CA092447. DNA Sample preparation was conducted at the Survey and Biospecimen Shared Resources, which is supported in part by Vanderbilt-Ingram Cancer Center (P30CA068485), and Dr. Melinda Aldrich's effort was supported by NIH/NCI grant K07CA172294. Karmanos Cancer Institute at Wayne State University: NIH grants R01CA060691, R01CA87895, contracts N01-PC35145 and P30CA22453, Department of Health and Human Services contract HHSN261201000028C, and the Herrick Foundation. NR 70 TC 1 Z9 1 U1 7 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD AUG PY 2016 VL 98 BP 33 EP 42 DI 10.1016/j.lungcan.2016.05.008 PG 10 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DS2JS UT WOS:000380596400006 PM 27393504 ER PT J AU Seol, Y Strub, MP Neuman, KC AF Seol, Yeonee Strub, Marie-Paule Neuman, Keir C. TI Single molecule measurements of DNA helicase activity with magnetic tweezers and t-test based step-finding analysis SO METHODS LA English DT Article DE Single-molecule; Helicase; Molecular motor; Magnetic tweezers; RecQ ID STRANDED-DNA; FORCE-SPECTROSCOPY; RECQ HELICASE; MECHANISM; TRANSLOCATION; PROCESSIVITY; TEMPERATURE; MICROSCOPY; RESOLUTION; DYNAMICS AB Magnetic tweezers is a versatile and easy to implement single-molecule technique that has become increasingly prevalent in the study of nucleic acid based molecular motors. Here, we provide a description of the magnetic tweezers instrument and guidelines for measuring and analyzing DNA helicase activity. Along with experimental methods, we describe a robust method of single-molecule trajectory analysis based on the Student's t-test that accommodates continuous transitions in addition to the discrete transitions assumed in most widely employed analysis routines. To illustrate the single-molecule unwinding assay and the analysis routine, we provide DNA unwinding measurements of Escherichia coli RecQ helicase under a variety of conditions (Na+, ATP, temperature, and DNA substrate geometry). These examples reveal that DNA unwinding measurements under various conditions can aid in elucidating the unwinding mechanism of DNA helicase but also emphasize that environmental effects on DNA helicase activity must be considered in relation to in vivo activity and mechanism. Published by Elsevier Inc. C1 [Seol, Yeonee; Strub, Marie-Paule; Neuman, Keir C.] NHLBI, Lab Single Mol Biophys, NIH, 50 South Dr 3517, Bethesda, MD 20892 USA. RP Neuman, KC (reprint author), NHLBI, Lab Single Mol Biophys, NIH, 50 South Dr 3517, Bethesda, MD 20892 USA. EM seoly@mail.nih.gov; strub@mail.nih.gov; neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health - United States [HL001056]; Human Frontiers Science Program [RGY0072/2010] FX We thank Lynda Bradly for comments on the manuscript. This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health - United States (HL001056) and by the Human Frontiers Science Program (RGY0072/2010). NR 48 TC 2 Z9 2 U1 9 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD AUG 1 PY 2016 VL 105 BP 119 EP 127 DI 10.1016/j.ymeth.2016.04.030 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DS7NZ UT WOS:000380971500013 PM 27131595 ER PT J AU Do Monte, FH Quirk, GJ Li, B Penzo, MA AF Do Monte, F. H. Quirk, G. J. Li, B. Penzo, M. A. TI Retrieving fear memories, as time goes by ... SO MOLECULAR PSYCHIATRY LA English DT Review ID THALAMIC PARAVENTRICULAR NUCLEUS; ANTERIOR CINGULATE CORTEX; MEDIAL PREFRONTAL CORTEX; IMMEDIATE-EARLY GENE; PHASEOLUS-VULGARIS-LEUKOAGGLUTININ; PITUITARY-ADRENAL RESPONSES; LATERAL AMYGDALA NEURONS; CONDITIONED FEAR; CONTEXTUAL FEAR; BASOLATERAL AMYGDALA AB Research in fear conditioning has provided a comprehensive picture of the neuronal circuit underlying the formation of fear memories. In contrast, our understanding of the retrieval of fear memories is much more limited. This disparity may stem from the fact that fear memories are not rigid, but reorganize over time. To bring some clarity and raise awareness about the time-dependent dynamics of retrieval circuits, we review current evidence on the neuronal circuitry participating in fear memory retrieval at both early and late time points following auditory fear conditioning. We focus on the temporal recruitment of the paraventricular nucleus of the thalamus (PVT) for the retrieval and maintenance of fear memories. Finally, we speculate as to why retrieval circuits change with time, and consider the functional strategy of recruiting structures not previously considered as part of the retrieval circuit. C1 [Do Monte, F. H.; Quirk, G. J.] Univ Puerto Rico, Dept Psychiat & Anat & Neurobiol, Lab Fear Learning, Sch Med, Ofc A231,2nd Floor Main Bldg, San Juan, PR 00935 USA. [Li, B.] Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA. [Penzo, M. A.] NIMH, Unit Neurobiol Affect Memory, 35 Convent Dr,Bldg 35 A Room 2E621, Bethesda, MD 20892 USA. RP Do Monte, FH (reprint author), Univ Puerto Rico, Dept Psychiat & Anat & Neurobiol, Lab Fear Learning, Sch Med, Ofc A231,2nd Floor Main Bldg, San Juan, PR 00935 USA.; Penzo, MA (reprint author), NIMH, Unit Neurobiol Affect Memory, 35 Convent Dr,Bldg 35 A Room 2E621, Bethesda, MD 20892 USA. EM fabriciodomonte@gmail.com; mario.penzo@nih.gov FU NIMH [K99-MH105549, R37-MH058883, P50-MH086400, R01-MH101214]; Intramural Research Program of the NIMH FX This work was supported by NIMH grant K99-MH105549 to F.H.D.-M.; NIMH grants R37-MH058883 and P50-MH086400 to G.J.Q.; NIMH grant R01-MH101214 to B.L.; and the Intramural Research Program of the NIMH to M.A.P. NR 197 TC 1 Z9 1 U1 17 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD AUG PY 2016 VL 21 IS 8 BP 1027 EP 1036 DI 10.1038/mp.2016.78 PG 10 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DS4GN UT WOS:000380739500005 PM 27217148 ER PT J AU Smith, AS Avram, SKW Cymerblit-Sabba, A Song, J Young, WS AF Smith, A. S. Avram, S. K. Williams Cymerblit-Sabba, A. Song, J. Young, W. S. TI Targeted activation of the hippocampal CA2 area strongly enhances social memory SO MOLECULAR PSYCHIATRY LA English DT Article ID VASOPRESSIN 1B RECEPTOR; ARGININE-VASOPRESSIN; MALE-RATS; LATERAL SEPTUM; MUS-MUSCULUS; RECOGNITION; OXYTOCIN; MICE; INNERVATION; RETRIEVAL AB Social cognition enables individuals to understand others' intentions. Social memory is a necessary component of this process, for without it, subsequent encounters are devoid of any historical information. The CA2 area of the hippocampus, particularly the vasopressin 1b receptor (Avpr1b) expressed there, is necessary for memory formation. We used optogenetics to excite vasopressin terminals, originating from the hypothalamic paraventricular nucleus, in the CA2 of mice. This markedly enhanced their social memory if the stimulation occurred during memory acquisition, but not retrieval. This effect was blocked by an Avpr1b antagonist. Finally, this enhanced memory is resistant to the social distraction of an introduced second mouse, important for socially navigating populations of individuals. Our results indicate the CA2 can increase the salience of social signals. Targeted pharmacotherapy with Avpr1b agonists or deep brain stimulation of the CA2 are potential avenues of treatment for those with declining social memory as in various dementias. C1 [Smith, A. S.; Avram, S. K. Williams; Cymerblit-Sabba, A.; Song, J.; Young, W. S.] NIMH, Sect Neural Gene Express, NIH, 9000 Rockville Pike,Bldg 49,Room 5A56, Bethesda, MD 20892 USA. RP Smith, AS; Young, WS (reprint author), NIMH, Sect Neural Gene Express, NIH, 9000 Rockville Pike,Bldg 49,Room 5A56, Bethesda, MD 20892 USA. EM adam.smith@nih.gov; wsy@mail.nih.gov OI Smith, Adam/0000-0003-2837-6205; Young, W Scott/0000-0001-6614-5112 FU NIMH [ZIA-MH-002498-24] FX We thank Emily Shepard for assistance with mouse colony maintenance and genotyping. We are grateful for the gifts of the vasopressin antibody from Harold Gainer and HSV from Ted Usdin. Alex Avram kindly wrote the software we used to control the optogenetic stimulations. We also thank Stafford Lightman and Michael Brownstein for their comments on a previous version of this manuscript. This research was supported by the intramural research program of the NIMH (ZIA-MH-002498-24). NR 52 TC 6 Z9 6 U1 9 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD AUG PY 2016 VL 21 IS 8 BP 1137 EP 1144 DI 10.1038/mp.2015.189 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DS4GN UT WOS:000380739500018 PM 26728562 ER PT J AU Ding, X Chaudhuri, AR Callen, E Pang, Y Biswas, K Klarmann, KD Martin, BK Burkett, S Cleveland, L Stauffer, S Sullivan, T Dewan, A Marks, H Tubbs, AT Wong, N Buehler, E Akagi, K Martin, SE Keller, JR Nussenzweig, A Sharan, SK AF Ding, Xia Chaudhuri, Arnab Ray Callen, Elsa Pang, Yan Biswas, Kajal Klarmann, Kimberly D. Martin, Betty K. Burkett, Sandra Cleveland, Linda Stauffer, Stacey Sullivan, Teresa Dewan, Aashish Marks, Hanna Tubbs, Anthony T. Wong, Nancy Buehler, Eugen Akagi, Keiko Martin, Scott E. Keller, Jonathan R. Nussenzweig, Andre Sharan, Shyam K. TI Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies SO Nature Communications LA English DT Article ID OLAPARIB MAINTENANCE THERAPY; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; REPLICATION FORKS; OVARIAN-CANCER; MUTANT-CELLS; DNA-DAMAGE; REPAIR; PARP; LETHALITY AB Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib has been approved for treatment of advanced ovarian cancer associated with BRCA1 and BRCA2 mutations. BRCA1-and BRCA2-mutated cells, which are homologous recombination (HR) deficient, are hypersensitive to PARPi through the mechanism of synthetic lethality. Here we examine the effect of PARPi on HR-proficient cells. Olaparib pretreatment, PARP1 knockdown or Parp1 heterozygosity of Brca2(cko/ko) mouse embryonic stem cells (mESCs), carrying a null (ko) and a conditional (cko) allele of Brca2, results in viable Brca2ko/ko cells. PARP1 deficiency does not restore HR in Brca2(ko/ko) cells, but protects stalled replication forks from MRE11-mediated degradation through its impaired recruitment. The functional consequence of Parp1 heterozygosity on BRCA2 loss is demonstrated by a significant increase in tumorigenesis in Brca2(cko/cko) mice. Thus, while olaparib efficiently kills BRCA2-deficient cells, we demonstrate that it can also contribute to the synthetic viability if PARP is inhibited before BRCA2 loss. C1 [Ding, Xia; Pang, Yan; Biswas, Kajal; Klarmann, Kimberly D.; Martin, Betty K.; Burkett, Sandra; Cleveland, Linda; Stauffer, Stacey; Sullivan, Teresa; Dewan, Aashish; Marks, Hanna; Keller, Jonathan R.; Sharan, Shyam K.] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. [Chaudhuri, Arnab Ray; Callen, Elsa; Tubbs, Anthony T.; Wong, Nancy; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20893 USA. [Klarmann, Kimberly D.; Martin, Betty K.; Keller, Jonathan R.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Buehler, Eugen; Martin, Scott E.] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Akagi, Keiko] Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, Columbus, OH 43210 USA. [Martin, Scott E.] Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA. RP Sharan, SK (reprint author), NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA.; Nussenzweig, A (reprint author), NCI, Lab Genome Integr, NIH, Bethesda, MD 20893 USA. EM nussenza@exchange.nih.gov; sharans@mail.nih.gov FU Department of Defense [W81XWH-13-1-0362]; Intramural Research Program, Center for Cancer Research, National Cancer Institute, US National Institutes of Health FX We thank members of our laboratory for helpful discussions and suggestions. We also thank the staff of NCI-Frederick Pathology and Histotechnology Laboratory for help with tumour analysis. We thank Dr Terry Yamaguchi (NCI-Frederick, NIH) for help with phenotypic analysis of mouse embryos. We thank Dr John Petrini and Shawn Fox (MSKCC) for MRE11 expression construct. This research was sponsored by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, US National Institutes of Health. X.D. received Department of Defense, Breast Cancer Research Program, Postdoctoral Fellowship (W81XWH-13-1-0362). NR 43 TC 0 Z9 0 U1 10 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2016 VL 7 AR 12425 DI 10.1038/ncomms12425 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS6AL UT WOS:000380864000001 PM 27498558 ER PT J AU Park, YH Wood, G Kastner, DL Chae, JJ AF Park, Yong Hwan Wood, Geryl Kastner, Daniel L. Chae, Jae Jin TI Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS SO NATURE IMMUNOLOGY LA English DT Article ID FAMILIAL MEDITERRANEAN FEVER; NLRP3 INFLAMMASOME; CYCLIC-AMP; PROTEIN; MUTATIONS; KINASE; PHOSPHORYLATION; RECEPTOR; GENE; RESISTANCE AB Mutations in the genes encoding pyrin and mevalonate kinase (MVK) cause distinct interleukin-1 beta (IL-1 beta)-mediated autoinflammatory diseases: familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS). Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. The binding of 14-3-3 and PKN proteins to FMF-associated mutant pyrin was substantially decreased, and the constitutive IL-1 beta release from peripheral blood mononuclear cells of patients with FMF or HIDS was attenuated by activation of PKN1 and PKN2. Defects in prenylation, seen in HIDS, led to RhoA inactivation and consequent pyrin inflammasome activation. These data suggest a previously unsuspected fundamental molecular connection between two seemingly distinct autoinflammatory disorders. C1 [Park, Yong Hwan; Wood, Geryl; Kastner, Daniel L.; Chae, Jae Jin] NHGRI, Inflammatory Dis Sect, Metab Cardiovasc & Inflammatory Dis Genom Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Kastner, DL; Chae, JJ (reprint author), NHGRI, Inflammatory Dis Sect, Metab Cardiovasc & Inflammatory Dis Genom Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM kastnerd@mail.nih.gov; chaej@mail.nih.gov FU National Human Genome Research Institute FX We thank the patients enrolled in our clinical protocols for providing research specimens, B. Barham, A. Jones, T. Romeo, P. Hoffmann, D. Stone, P. Pinto-Patarroyo, A. Ombrello and K. Barron for help with caring for patients, I. Aksentijevich for assistance in genotyping patients and for discussions, V. Dixit (Genentech) for ASC-, NLRP3- and NLRC4-deficient mice, R. Flavell (Yale University) for caspase-1-deficient mice, E. Alnemri (Thomas Jefferson University) for AIM2-deficient mice, and S. Masters and F. Shao for sharing data before publication. This work was supported by the Intramural Research Program of the National Human Genome Research Institute. NR 40 TC 19 Z9 19 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2016 VL 17 IS 8 BP 914 EP + DI 10.1038/ni.3457 PG 10 WC Immunology SC Immunology GA DS2XK UT WOS:000380647000008 PM 27270401 ER PT J AU Akula, MK Shi, M Jiang, ZZ Foster, CE Miao, D Li, AS Zhang, XM Gavin, RM Forde, SD Germain, G Carpenter, S Rosadini, CV Gritsman, K Chae, JJ Hampton, R Silverman, N Gravallese, EM Kagan, JC Fitzgerald, KA Kastner, DL Golenbock, DT Bergo, MO Wang, DH AF Akula, Murali K. Shi, Man Jiang, Zhaozhao Foster, Celia E. Miao, David Li, Annie S. Zhang, Xiaoman Gavin, Ruth M. Forde, Sorcha D. Germain, Gail Carpenter, Susan Rosadini, Charles V. Gritsman, Kira Chae, Jae Jin Hampton, Randolph Silverman, Neal Gravallese, Ellen M. Kagan, Jonathan C. Fitzgerald, Katherine A. Kastner, Daniel L. Golenbock, Douglas T. Bergo, Martin O. Wang, Donghai TI Control of the innate immune response by the mevalonate pathway SO NATURE IMMUNOLOGY LA English DT Article ID PHOSPHOINOSITIDE 3-KINASE; PROTEIN PRENYLATION; KINASE-DEFICIENCY; CANCER-THERAPY; RAS; ACTIVATION; CELLS; LIPOPOLYSACCHARIDE; INFLAMMASOME; PHOSPHORYLATION AB Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110 delta. Macrophages that were deficient in GGTase I or p110 delta exhibited constitutive release of interleukin 1 beta that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome. C1 [Akula, Murali K.; Shi, Man; Miao, David; Wang, Donghai] Duke Univ, Sch Med, Dept Med, Div Rheumatol & Immunol, Durham, NC 27706 USA. [Akula, Murali K.; Shi, Man; Miao, David; Wang, Donghai] Duke Univ, Sch Med, Dept Immunol, Durham, NC 27706 USA. [Akula, Murali K.; Bergo, Martin O.] Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Sahlgrenska Canc Ctr, Gothenburg, Sweden. [Jiang, Zhaozhao; Foster, Celia E.; Li, Annie S.; Zhang, Xiaoman; Gavin, Ruth M.; Forde, Sorcha D.; Germain, Gail; Carpenter, Susan; Silverman, Neal; Fitzgerald, Katherine A.; Golenbock, Douglas T.; Wang, Donghai] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA 01655 USA. [Rosadini, Charles V.; Kagan, Jonathan C.] Boston Childrens Hosp, Div Gastroenterol, Boston, MA USA. [Rosadini, Charles V.; Kagan, Jonathan C.] Harvard Med Sch, Boston, MA USA. [Gritsman, Kira] Albert Einstein Coll Med, Dept Med, New York, NY USA. [Gritsman, Kira] Albert Einstein Coll Med, Dept Cell Biol, New York, NY USA. [Chae, Jae Jin; Kastner, Daniel L.] NHGRI, Inflammatory Dis Sect, Metab Cardiovasc & Inflammatory Dis Genom Branch, NIH, New York, NY USA. [Hampton, Randolph] Univ Calif San Diego, Div Biol, La Jolla, CA 92093 USA. [Akula, Murali K.; Shi, Man; Jiang, Zhaozhao; Foster, Celia E.] Univ Massachusetts, Sch Med, Dept Med, Div Rheumatol, Worcester, MA USA. RP Wang, DH (reprint author), Duke Univ, Sch Med, Dept Med, Div Rheumatol & Immunol, Durham, NC 27706 USA.; Wang, DH (reprint author), Duke Univ, Sch Med, Dept Immunol, Durham, NC 27706 USA.; Wang, DH (reprint author), Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA 01655 USA. EM donghai.wang@duke.edu FU US National Institutes of Health (National Institute of Allergy and Infectious Diseases) [1R01AI110695-01A1]; Arthritis Foundation; Swedish Research Council; Heart and Lung Foundation FX We thank S. Abusneineh for technical support, K. Halmen for lab management, and colleagues in the Golenbock, Fitzgerald and Kastner laboratories for helpful discussions. We also thank M. Birnbaum (University of Pennsylvania) for the Akt1-deficient mice femurs and M. Trombly for editing the manuscript. We are in debt to R. Finberg and E. St. Clair for critical reading of the manuscript. This work was supported in part by funds from the US National Institutes of Health (National Institute of Allergy and Infectious Diseases 1R01AI110695-01A1 to D.W.), an Innovative Research Grant from the Arthritis Foundation (D.W. and E.M.G.), the Swedish Research Council, and the Heart and Lung Foundation (M.B. and M.A.). NR 46 TC 11 Z9 11 U1 9 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2016 VL 17 IS 8 BP 922 EP + DI 10.1038/ni.3487 PG 9 WC Immunology SC Immunology GA DS2XK UT WOS:000380647000009 PM 27270400 ER PT J AU Vargas, AJ Harris, CC AF Vargas, Ashley J. Harris, Curtis C. TI Biomarker development in the precision medicine era: lung cancer as a case study SO NATURE REVIEWS CANCER LA English DT Review ID FLIGHT MASS-SPECTROMETRY; C-REACTIVE PROTEIN; REPORTING RECOMMENDATIONS; GENE-EXPRESSION; INTERNATIONAL-ASSOCIATION; PROGNOSTIC CLASSIFIER; COMPANION DIAGNOSTICS; NEVER-SMOKERS; AFRICAN-AMERICANS; SCREENING TRIAL AB Precision medicine relies on validated biomarkers with which to better classify patients by their probable disease risk, prognosis and/or response to treatment. Although affordable 'omics'-based technology has enabled faster identification of putative biomarkers, the validation of biomarkers is still stymied by low statistical power and poor reproducibility of results. This Review summarizes the successes and challenges of using different types of molecule as biomarkers, using lung cancer as a key illustrative example. Efforts at the national level of several countries to tie molecular measurement of samples to patient data via electronic medical records are the future of precision medicine research. C1 [Vargas, Ashley J.; Harris, Curtis C.] NCI, Lab Human Carcinogenesis, Ctr Canc Res, Room 3068A,MSC 425,837 Convent Dr, Bethesda, MD 20892 USA. [Vargas, Ashley J.] NCI, Canc Prevent Div, Rockville, MD 20850 USA. RP Harris, CC (reprint author), NCI, Lab Human Carcinogenesis, Ctr Canc Res, Room 3068A,MSC 425,837 Convent Dr, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov FU Intramural Program of the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA; Cancer Prevention Fellowship Program, National Cancer Institute, Rockville, Maryland, USA FX This work was supported by funding from the Intramural Program of the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA, and the Cancer Prevention Fellowship Program, National Cancer Institute, Rockville, Maryland, USA. NR 171 TC 8 Z9 8 U1 23 U2 45 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD AUG PY 2016 VL 16 IS 8 BP 525 EP 537 DI 10.1038/nrc.2016.56 PG 13 WC Oncology SC Oncology GA DS5HW UT WOS:000380813300008 PM 27388699 ER PT J AU Wikenheiser, AM Schoenbaum, G AF Wikenheiser, Andrew M. Schoenbaum, Geoffrey TI Over the river, through the woods: cognitive maps in the hippocampus and orbitofrontal cortex SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID ORBITAL PREFRONTAL CORTEX; SENSORY-SPECIFIC SATIETY; THETA PHASE PRECESSION; DECISION-MAKING; PLACE CELLS; VICARIOUS TRIAL; REINFORCER DEVALUATION; VENTRAL STRIATUM; NUCLEUS REUNIENS; CONDITIONED-STIMULUS AB The hippocampus and the orbitofrontal cortex (OFC) both have important roles in cognitive processes such as learning, memory and decision making. Nevertheless, research on the OFC and hippocampus has proceeded largely independently, and little consideration has been given to the importance of interactions between these structures. Here, evidence is reviewed that the hippocampus and OFC encode parallel, but interactive, cognitive 'maps' that capture complex relationships between cues, actions, outcomes and other features of the environment. A better understanding of the interactions between the OFC and hippocampus is important for understanding the neural bases of flexible, goal-directed decision making. C1 [Wikenheiser, Andrew M.; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Schoenbaum, Geoffrey] Univ Maryland, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA. RP Wikenheiser, AM (reprint author), NIDA, Intramural Res Program, Baltimore, MD 21224 USA. EM andrew.wikenheiser@nih.gov; geoffrey.schoenbaum@nih.gov FU US National Institute on Drug Abuse at the Intramural Research Program FX The authors thank members of the Schoenbaum laboratory for helpful discussions on the topics addressed here and for feedback on earlier versions of this manuscript. This work was supported by funding from the US National Institute on Drug Abuse at the Intramural Research Program. The opinions expressed in this article are the authors own and do not reflect the view of the US National Institutes of Health, the US Department of Health and Human Services or the US government. NR 177 TC 3 Z9 3 U1 14 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD AUG PY 2016 VL 17 IS 8 BP 513 EP 523 DI 10.1038/nrn.2016.56 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DS3BD UT WOS:000380656900009 PM 27256552 ER PT J AU Son, M Lee, Y Kim, KH AF Son, Moonil Lee, Yoonseung Kim, Kook-Hyung TI The Transcription Cofactor Swi6 of the Fusarium graminearum Is Involved in Fusarium Graminearum Virus 1 Infection-Induced Phenotypic Alterations SO Plant Pathology Journal LA English DT Article DE FgV1; Fusarium graminearum; Swi6; vegetative growth; virulence ID DEOXYNIVALENOL PRODUCTION; CRYPHONECTRIA-PARASITICA; DSRNA MYCOVIRUS; EXPRESSION; VIRULENCE; GENE; PATHWAY; STRESS; GROWTH; FUNGUS AB The transcription cofactor Swi6 plays important roles in regulating vegetative growth and meiosis in Saccharomyces cerevisiae. Functions of Swi6 ortholog were also characterized in Fusarium graminearum which is one of the devastating plant pathogenic fungi. Here, we report possible role of FgSwi6 in the interaction between F. graminearum and Fusarium graminearum virus 1 (FgV1) strain DK21. FgV1 perturbs biological characteristics of host fungi such as vegetative growth, sporulation, pigmentation, and reduction of the virulence (hypovirulence) of its fungal host. To characterize function(s) of FgSWI6 gene during FgV1 infection, targeted deletion, over-expression, and complementation mutants were generated and further infected successfully with FgV1. Deletion of FgSwi6 led to severe reduction of vegetative growth even aerial mycelia while over-expression did not affect any remarkable alteration of phenotype in virus-free isolates. Virus-infected (VI) FgSWI6 deletion isolate exhibited completely delayed vegetative growth. However, VI FgSWI6 over-expression mutant grew faster than any other VI isolates. To verify whether these different growth patterns in VI isolates, viral RNA quantification was carried out using qRT-PCR. Surprisingly, viral RNA accumulations in VI isolates were similar regardless of introduced mutations. These results provide evidence that FgSWI6 might play important role(s) in FgV1 induced phenotype alteration such as delayed vegetative growth. C1 [Son, Moonil; Kim, Kook-Hyung] Seoul Natl Univ, Coll Agr & Life Sci, Dept Agr Biotechnol, Seoul 08826, South Korea. [Son, Moonil; Kim, Kook-Hyung] Seoul Natl Univ, Coll Agr & Life Sci, Ctr Fungal Pathogenesis, Seoul 08826, South Korea. [Son, Moonil; Kim, Kook-Hyung] Seoul Natl Univ, Coll Agr & Life Sci, Res Inst Agr & Life Sci, Seoul 08826, South Korea. [Lee, Yoonseung; Kim, Kook-Hyung] Seoul Natl Univ, Coll Agr & Life Sci, Dept Appl Biol & Chem, Seoul 08826, South Korea. [Son, Moonil] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20852 USA. RP Kim, KH (reprint author), Seoul Natl Univ, Coll Agr & Life Sci, Dept Agr Biotechnol, Seoul 08826, South Korea.; Kim, KH (reprint author), Seoul Natl Univ, Coll Agr & Life Sci, Ctr Fungal Pathogenesis, Seoul 08826, South Korea.; Kim, KH (reprint author), Seoul Natl Univ, Coll Agr & Life Sci, Res Inst Agr & Life Sci, Seoul 08826, South Korea.; Kim, KH (reprint author), Seoul Natl Univ, Coll Agr & Life Sci, Dept Appl Biol & Chem, Seoul 08826, South Korea. EM kookkim@snu.ac.kr FU Center for Fungal Pathogenesis - National Research Foundation [20110000959]; Next-Generation BioGreen 21 Program [PJ01101301]; Rural Development Administration; Vegetable Breeding Research Center through the Agriculture Research Center program from the Ministry of Agriculture, Food and Rural Affairs, Republic of Korea [710001-07-05]; Ministry of Education through the Brain Korea 21 Plus Project FX This research was supported in part by grants from the Center for Fungal Pathogenesis (no. 20110000959) funded by the National Research Foundation, the Next-Generation BioGreen 21 Program (no. PJ01101301), Rural Development Administration, and the Vegetable Breeding Research Center (no. 710001-07-05) through the Agriculture Research Center program from the Ministry of Agriculture, Food and Rural Affairs, Republic of Korea. MS was supported by a graduate research fellowship from the Ministry of Education through the Brain Korea 21 Plus Project. We also thank Dr. Son and Professor Lee from the Center for Fungal Pathogenesis at the Seoul National University for the generous gift of pSKGen plasmid and technical helps. NR 19 TC 0 Z9 0 U1 6 U2 6 PU KOREAN SOC PLANT PATHOLOGY PI SUWON PA NATIONAL INST AGRICULTURAL SCIENCE & TECHNOLOGY, PLANT PATHOLOGY DIVISION, SUWON, 441-707, SOUTH KOREA SN 1598-2254 EI 2093-9280 J9 PLANT PATHOLOGY J JI Plant Pathol. J. PD AUG PY 2016 VL 32 IS 4 BP 281 EP 289 DI 10.5423/PPJ.OA.12.2015.0267 PG 9 WC Agriculture, Multidisciplinary; Plant Sciences SC Agriculture; Plant Sciences GA DS6BY UT WOS:000380867900001 PM 27493603 ER PT J AU Freidlin, B Othus, M Korn, EL AF Freidlin, Boris Othus, Megan Korn, Edward L. TI Information time scales for interim analyses of randomized clinical trials SO CLINICAL TRIALS LA English DT Article DE Futility; interim monitoring; group sequential design; maximum information design; spending function ID SEQUENTIAL BOUNDARIES; IRRADIATION; CANCER; IIA AB Background: Interim monitoring is a key component of randomized clinical trial design from both ethical and efficiency perspectives. In studies with time-to-event endpoints, timing of interim analyses is typically based on observing a pre-specified proportion of the total number of events required for the final analysis. While most randomized clinical trial designs pool events over the experimental and control arms in determining the analysis times, some designs use only the control-arm events for scheduling interim looks. Purpose: To evaluate the performance of the pooled and control-arm-based interim monitoring approaches and to propose a new procedure, the earliest information time procedure, that combines the benefits of the two approaches. Methods: The analytical and logistical considerations for the procedures are presented. The methodology is illustrated on data from three published randomized clinical trials. The procedures are compared in a simulation study. Results: The control-arm approach results in a slight inflation of the study type I error in one-sided randomized clinical trial designs. When the new treatment is no better than the control treatment, the pooled-arm approach results in, on average, earlier stopping times than the control-arm approach. When the new treatment works exceptionally well, the average stopping times under the control-arm approach are earlier than those under the pooled approach. The proposed earliest information time procedure is shown to result in stopping times corresponding to the best (earliest) of the two approaches over the entire range of alternatives. Limitations: The earliest information time procedure may result in a slight inflation of the type I error (especially in small trials); when exact control of the type I error is required, it is necessary to use a simulation-based method to correct the inflation. Conclusion: In time-to-event settings, the earliest information time procedure is an attractive alternative to the pooled and control-arm approaches. Improving the timing of interim analyses helps to minimize patient exposure to inferior treatments and to accelerate dissemination of the study results. C1 [Freidlin, Boris; Korn, Edward L.] NCI, Biometr Res Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Othus, Megan] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, 1124 Columbia St, Seattle, WA 98104 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov FU NCI [CA180819] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr Othus' work was supported in part by NCI grant CA180819. NR 18 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2016 VL 13 IS 4 BP 391 EP 399 DI 10.1177/1740774516644752 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DR8DV UT WOS:000380129500005 PM 27136947 ER PT J AU Marcus, PM Doria-Rose, VP Gareen, IF Brewer, B Clingan, K Keating, K Rosenbaum, J Rozjabek, HM Rathmell, J Sicks, J Miller, AB AF Marcus, Pamela M. Doria-Rose, Vincent Paul Gareen, Ilana F. Brewer, Brenda Clingan, Kathy Keating, Kristen Rosenbaum, Jennifer Rozjabek, Heather M. Rathmell, Joshua Sicks, JoRean Miller, Anthony B. TI Did death certificates and a death review process agree on lung cancer cause of death in the National Lung Screening Trial? SO CLINICAL TRIALS LA English DT Article DE Cancer screening; lung cancer; death review; performance measures; endpoint adjudication ID MORTALITY AB Background/aims: Randomized controlled trials frequently use death review committees to assign a cause of death rather than relying on cause of death information from death certificates. The National Lung Screening Trial, a randomized controlled trial of lung cancer screening with low-dose computed tomography versus chest X-ray for heavy and/or long-term smokers ages 55-74 years at enrollment, used a committee blinded to arm assignment for a subset of deaths to determine whether cause of death was due to lung cancer. Methods: Deaths were selected for review using a pre-determined computerized algorithm. The algorithm, which considered cancers diagnosed during the trial, causes and significant conditions listed on the death certificate, and the underlying cause of death derived from death certificate information by trained nosologists, selected deaths that were most likely to represent a death due to lung cancer (either directly or indirectly) and deaths that might have been erroneously assigned lung cancer as the cause of death. The algorithm also selected deaths that might be due to adverse events of diagnostic evaluation for lung cancer. Using the review cause of death as the gold standard and lung cancer cause of death as the outcome of interest (dichotomized as lung cancer versus not lung cancer), we calculated performance measures of the death certificate cause of death. We also recalculated the trial primary endpoint using the death certificate cause of death. Results: In all, 1642 deaths were reviewed and assigned a cause of death (42% of the 3877 National Lung Screening Trial deaths). Sensitivity of death certificate cause of death was 91%; specificity, 97%; positive predictive value, 98%; and negative predictive value, 89%. About 40% of the deaths reclassified to lung cancer cause of death had a death certificate cause of death of a neoplasm other than lung. Using the death certificate cause of death, the lung cancer mortality reduction was 18% (95% confidence interval: 4.2-25.0), as compared with the published finding of 20% (95% confidence interval: 6.7-26.7). Conclusion: Death review may not be necessary for primary-outcome analyses in lung cancer screening trials. If deemed necessary, researchers should strive to streamline the death review process as much as possible. C1 [Marcus, Pamela M.; Doria-Rose, Vincent Paul] NCI, 9609 Med Ctr Dr,4E-608, Bethesda, MD 20892 USA. [Gareen, Ilana F.] Brown Univ, Dept Epidemiol, Sch Publ Hlth, Providence, RI 02912 USA. [Gareen, Ilana F.; Sicks, JoRean] Brown Univ, Ctr Stat Sci, Sch Publ Hlth, Providence, RI 02912 USA. [Brewer, Brenda; Clingan, Kathy; Keating, Kristen; Rosenbaum, Jennifer] Westat Corp, Rockville, MD USA. [Rozjabek, Heather M.] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Rathmell, Joshua] Informat Management Syst Inc, Rockville, MD USA. [Miller, Anthony B.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. RP Marcus, PM (reprint author), NCI, 9609 Med Ctr Dr,4E-608, Bethesda, MD 20892 USA. EM marcusp@mail.nih.gov RI Gareen, Ilana/I-2816-2014; OI Gareen, Ilana/0000-0002-0457-5595; Doria-Rose, Vincent/0000-0002-8802-5143 FU American College of Radiology Imaging Network of the National Lung Screening Trial (NLST) [U01-CA-80098, U01-CA-79778]; Early Detection Research Group; Biometry Research Group, Division of Cancer Prevention: University of Colorado Denver [N01-CN-25514]; Georgetown University [N01-CN-25522]; Pacific Health Research and Education Institute [N01-CN-25515]; Henry Ford Health System [N01-CN-25512]; University of Minnesota [N01-CN-25513]; Washington University in St. Louis [N01-CN-25516]; University of Pittsburgh [N01-CN-25511]; University of Utah [N01-CN-25524]; Marshfield Clinic Research Foundation [N01-CN-25518]; University of Alabama at Birmingham [N01-CN-75022]; Westat [N01-CN-25476]; Information Management Services [N02-CN-63300] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Grant support: The American College of Radiology Imaging Network component of the National Lung Screening Trial (NLST) was funded through grants (U01-CA-80098 and U01-CA-79778) under a cooperative agreement with the Cancer Imaging Program, Division of Cancer Treatment and Diagnosis. The Lung Screening Study sites of the NLST were funded through contracts with the Early Detection Research Group and Biometry Research Group, Division of Cancer Prevention: University of Colorado Denver (N01-CN-25514), Georgetown University (N01-CN-25522), Pacific Health Research and Education Institute (N01-CN-25515), Henry Ford Health System (N01-CN-25512), University of Minnesota (N01-CN-25513), Washington University in St. Louis (N01-CN-25516), University of Pittsburgh (N01-CN-25511), University of Utah (N01-CN-25524), Marshfield Clinic Research Foundation (N01-CN-25518), University of Alabama at Birmingham (N01-CN-75022), Westat (N01-CN-25476), and Information Management Services (N02-CN-63300). NR 6 TC 1 Z9 1 U1 1 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2016 VL 13 IS 4 BP 434 EP 438 DI 10.1177/1740774516638345 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DR8DV UT WOS:000380129500010 PM 27006427 ER PT J AU Proschan, MA Dodd, LE AF Proschan, Michael A. Dodd, Lori E. TI A comparison of the barely Bayesian design with the triangular test for clinical trials in infectious diseases Response SO CLINICAL TRIALS LA English DT Letter C1 [Proschan, Michael A.; Dodd, Lori E.] NIAID, 5601 Fishers Lane,Room 4C30,MSC 9820, Bethesda, MD 20892 USA. RP Proschan, MA (reprint author), NIAID, 5601 Fishers Lane,Room 4C30,MSC 9820, Bethesda, MD 20892 USA. EM ProschaM@niaid.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2016 VL 13 IS 4 BP 454 EP 455 DI 10.1177/1740774516644906 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DR8DV UT WOS:000380129500015 PM 27136948 ER PT J AU Loeser, RF Pathmasiri, W Sumner, SJ McRitchie, S Beavers, D Saxena, P Nicklas, BJ Jordan, J Guermazi, A Hunter, DJ Messier, SP AF Loeser, R. F. Pathmasiri, W. Sumner, S. J. McRitchie, S. Beavers, D. Saxena, P. Nicklas, B. J. Jordan, J. Guermazi, A. Hunter, D. J. Messier, S. P. TI Association of urinary metabolites with radiographic progression of knee osteoarthritis in overweight and obese adults: an exploratory study SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Osteoarthritis; Metabolism; Biomarkers ID INTENSIVE DIET; WEIGHT-LOSS; CARTILAGE DEGRADATION; CLINICAL-TRIAL; OLDER-ADULTS; RISK-FACTORS; BODY-WEIGHT; ARTHRITIS; EXERCISE; INFLAMMATION AB Introduction: Metabolic factors may contribute to osteoarthritis (OA). This study employed metabolomics analyses to determine if differences in metabolite profiles could distinguish people with knee OA who exhibited radiographic progression. Methods: Urine samples obtained at baseline and 18 months from overweight and obese adults in the Intensive Diet and Exercise for Arthritis (IDEA) trial were selected from two subgroups (n <= 22 each) for metabolomics analysis: a group that exhibited radiographic progression (>= 0.7 mm decrease in joint space width, JSW) and an age, gender, and body mass index (BMI) matched group who did not progress (<= 0.35 mm decrease in JSW). Multivariate analysis methods, including orthogonal partial least square discriminate analysis, were used to identify metabolite profiles that separated progressors and nonprogressors. Plasma levels of IL-6 and C-reactive protein (CRP) were evaluated as inflammatory markers. Results: Multivariate analysis of the binned metabolomics data distinguished progressors from nonprogressors. Library matching revealed that glycolate, hippurate, and trigonelline were among the important metabolites for distinguishing progressors from non-progressors at baseline whereas alanine, N, N-dimethylglycine, glycolate, hippurate, histidine, and trigonelline, were among the metabolites that were important for the discrimination at 18 months. In non-progressors, IL-6 decreased from baseline to 18 months while IL-6 was unchanged in progressors; the change over time in IL-6 was significantly different between groups. Conclusion: These findings support a role for metabolic factors in the progression of knee OA and suggest that measurement of metabolites could be useful to predict progression. Further investigation in a larger sample that would include targeted investigation of specific metabolites is warranted. (C) 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Loeser, R. F.; Jordan, J.] Univ N Carolina, Sch Med, Div Rheumatol Allergy & Immunol, Thurston Arthrit Res Ctr, Chapel Hill, NC USA. [Pathmasiri, W.; Sumner, S. J.; McRitchie, S.] RTI Int, NIH Eastern Reg Comprehens Metabol Resource Core, Res Triangle Pk, NC USA. [Beavers, D.; Saxena, P.; Nicklas, B. J.] Wake Forest Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA. [Beavers, D.; Saxena, P.; Nicklas, B. J.] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Guermazi, A.] Boston Univ, Sch Med, Dept Radiol, Boston, MA 02215 USA. [Hunter, D. J.] Univ Sydney, Royal North Shore Hosp, Dept Rheumatol, Sydney, NSW, Australia. [Hunter, D. J.] Univ Sydney, Kolling Inst, Inst Bone & Joint Res, Sydney, NSW, Australia. [Messier, S. P.] Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC 27109 USA. RP Loeser, RF (reprint author), Univ N Carolina, Thurston Arthrit Res Ctr, 3300 Thurston Bldg,CB 7280, Chapel Hill, NC 27599 USA. EM richard_loeser@med.unc.edu OI Guermazi, Ali/0000-0002-9374-8266 FU National Institute of Arthritis, Musculoskeletal and Skin Disease [AR052528]; RTI NIH Eastern Regional Comprehensive Metabolomics Resource Core - NIH Common Fund Metabolomics Program [U24 DK097193] FX The IDEA study was funded by a grant from the National Institute of Arthritis, Musculoskeletal and Skin Disease (AR052528). The metabolomics pilot and feasibility study was funded by the RTI NIH Eastern Regional Comprehensive Metabolomics Resource Core funded by the NIH Common Fund Metabolomics Program under grant U24 DK097193. NR 45 TC 3 Z9 3 U1 2 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD AUG PY 2016 VL 24 IS 8 BP 1479 EP 1486 DI 10.1016/j.joca.2016.03.011 PG 8 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA DR9VV UT WOS:000380245100020 PM 27012755 ER PT J AU Root, DH Wang, HL Liu, B Barker, DJ Mod, L Szocsics, P Silva, AC Magloczky, Z Morales, M AF Root, David H. Wang, Hui-Ling Liu, Bing Barker, David J. Mod, Laszlo Szocsics, Peter Silva, Afonso C. Magloczky, Zsofia Morales, Marisela TI Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans SO SCIENTIFIC REPORTS LA English DT Article ID VENTRAL TEGMENTAL AREA; REWARD PREDICTION ERROR; LATERAL HABENULA; NUCLEUS-ACCUMBENS; NEURAL RESPONSES; MOTIVATIONAL CONTROL; SUBSTANTIA-NIGRA; SEEKING BEHAVIOR; GABA NEURONS; BRAIN AB The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson's disease. C1 [Root, David H.; Wang, Hui-Ling; Liu, Bing; Barker, David J.; Morales, Marisela] NIDA, Neuronal Networks Sect, Integrat Neurosci Res Branch, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. [Mod, Laszlo] Szent Borbala Hosp, Dept Psychol, H-2800 Tatabanya, Hungary. [Szocsics, Peter; Magloczky, Zsofia] Hungarian Acad Sci, Inst Expt Med, Lab Cerebral Cortex Res, H-1083 Budapest, Hungary. [Silva, Afonso C.] Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, Cerebral Microcirculat Sect, 49 Convent Dr,Bldg 49,Room 3A72, Bethesda, MD 20892 USA. RP Morales, M (reprint author), NIDA, Neuronal Networks Sect, Integrat Neurosci Res Branch, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM mmorales@intra.nida.nih.gov FU Intramural Research Program (IRP) of the National Institute on Drug Abuse (IRP/NIDA/NIH); IRP of the National Institute of Neurological Disorders and Stroke (IRP/NINDS/NIH); European Research Council [ERC-2011-ADG-294313] FX We thank Laszlo Havas, Lynn Cournoyer, and Eduardo Gigante for technical assistance. This work was made possible due to the financial support from the Intramural Research Program (IRP) of the National Institute on Drug Abuse (IRP/NIDA/NIH) to MM, the IRP of the National Institute of Neurological Disorders and Stroke (IRP/NINDS/NIH) to ACS, and the European Research Council (grant number ERC-2011-ADG-294313, SERRACO) to ZM. Funding sources were not involved in study design, data collection and interpretation, or the decision to submit this research for publication. NR 98 TC 1 Z9 1 U1 6 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD AUG 1 PY 2016 VL 6 AR 30615 DI 10.1038/srep30615 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS3LP UT WOS:000380684800001 PM 27477243 ER PT J AU Moscicki, AB Farhat, S Yao, TJ Ryder, MI Russell, JS Van Dyke, RB Hazra, R Shiboski, CH AF Moscicki, Anna-Barbara Farhat, Sepideh Yao, Tzy-Jyun Ryder, Mark I. Russell, Jonathan S. Van Dyke, Russell B. Hazra, Rohan Shiboski, Caroline H. CA Pediatr HIV AIDS Cohort Study TI Oral Human Papillomavirus in Youth From the Pediatric HIV/AIDS Cohort Study SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID HIV-INFECTED CHILDREN; RISK-FACTORS; PREVALENCE; TRANSMISSION; CAVITY; DNA AB In contrast to high rates of oral human papillomavirus (HPV) found in human immunodeficiency virus (HIV)-infected adults, only 2% of 209 perinatally HIV-infected youth had oral HPV. This rate was similar in HIV-exposed but uninfected youth. No association was found with sexual activity; however, low CD4 counts were associated with oral HPV. C1 [Moscicki, Anna-Barbara] Univ Calif San Francisco, Sch Med, Dept Pediat, Div Adolescent Med, San Francisco, CA 94143 USA. [Farhat, Sepideh] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA. [Yao, Tzy-Jyun; Ryder, Mark I.; Russell, Jonathan S.; Shiboski, Caroline H.] Harvard TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res CBAR, Boston, MA USA. [Van Dyke, Russell B.] Univ Calif San Francisco, Sch Dent, Dept Orofacial Sci, San Francisco, CA USA. [Hazra, Rohan] Tulane Univ, Sch Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD USA. RP Moscicki, AB (reprint author), Univ Calif Los Angeles, Dept Pediat, 10833 Le Conte Ave,22-432 MDCC, Los Angeles, CA 90095 USA. EM AMoscicki@mednet.ucla.edu FU National Institute of Dental and Craniofacial Research; 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 on Alcohol Abuse and Alcoholism; Harvard T. H. Chan School of Public Health [HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3]; Tulane University School of Medicine [HD052104, 3U01 HD052104-06S1] FX This study was supported by the National Institute of Dental and Craniofacial Research; 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; and the National Institute on Alcohol Abuse and Alcoholism; through cooperative agreements with the Harvard T. H. Chan School of Public Health [HD052102, 3 U01 HD052102-05S1, and 3 U01 HD052102-06S3 to PI: George Seage; Project Director: Julie Alperen]; and the Tulane University School of Medicine [HD052104, 3U01 HD052104-06S1 to PI: Russell Van Dyke; Co-PI: Kenneth Rich; Project Director: Patrick Davis]. Data management services were provided by Frontier Science and Technology Research Foundation to PI: Suzanne Siminski, and regulatory services and logistical support were provided by Westat, Inc. to PI: Julie Davidson. NR 16 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-5717 EI 1537-4521 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD AUG PY 2016 VL 43 IS 8 BP 498 EP 500 DI 10.1097/OLQ.0000000000000495 PG 3 WC Infectious Diseases SC Infectious Diseases GA DR9OR UT WOS:000380226500007 PM 27414680 ER PT J AU Pilowsky, DJ Rojas, G Price, LN Appiah-Poku, J Razzaque, B Sharma, M Schneider, M Seedat, S Bonini, BB Gureje, O Kola, L Lund, C Sorsdahl, K Araya, R Menezes, PR AF Pilowsky, Daniel J. Rojas, Graciela Price, LeShawndra N. Appiah-Poku, John Razzaque, Bushra Sharma, Mona Schneider, Marguerite Seedat, Soraya Bonini, Barbara B. Gureje, Oye Kola, Lola Lund, Crick Sorsdahl, Katherine Araya, Ricardo Menezes, Paulo R. TI Building Research Capacity Across and Within Low- and Middle-Income Countries: The Collaborative Hubs for International Research on Mental Health SO ACADEMIC PSYCHIATRY LA English DT Article ID CARE C1 [Pilowsky, Daniel J.] Columbia Univ, New York, NY USA. [Rojas, Graciela] Univ Chile, Santiago, Chile. [Price, LeShawndra N.] NIMH, NIH, Bethesda, MD 20892 USA. [Appiah-Poku, John] Kwame Nkrumah Univ Sci & Technol, Kumasi, Ghana. [Razzaque, Bushra] Inst Psychiat, Rawalpindi, Pakistan. [Sharma, Mona] Publ Hlth Fdn India, New Delhi, India. [Schneider, Marguerite; Lund, Crick; Sorsdahl, Katherine] Univ Cape Town, Cape Town, South Africa. [Seedat, Soraya] Univ Stellenbosch, Stellenbosch, South Africa. [Bonini, Barbara B.; Menezes, Paulo R.] Univ Sao Paulo, Sao Paulo, Brazil. [Gureje, Oye; Kola, Lola] Univ Ibadan, Ibadan, Nigeria. [Araya, Ricardo] London Sch Hyg & Trop Med, London, England. RP Pilowsky, DJ (reprint author), Columbia Univ, New York, NY USA. EM dp14@cumc.columbia.edu RI Menezes, Paulo/C-9985-2010; OI Menezes, Paulo/0000-0001-6330-3314; Schneider, Marguerite/0000-0002-1223-1266 FU US National Institute of Mental Health of the National Institutes of Health [U19MH98718, U19MH95699, U19MH95718, U19MH98780, U19MH95687] FX Research reported in this article was supported by the US National Institute of Mental Health of the National Institutes of Health under award numbers U19MH98718, U19MH95699, U19MH95718, U19MH98780, and U19MH95687. The views expressed are those of the authors and do not necessarily represent those of the National Institute of Mental Health, the National Institutes of Health, the Department of Health and Human Services, or the US Government. NR 10 TC 2 Z9 2 U1 3 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD AUG PY 2016 VL 40 IS 4 BP 686 EP 691 DI 10.1007/s40596-016-0493-3 PG 6 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA DR2BE UT WOS:000379709200024 PM 26895931 ER PT J AU Collins, PY Pringle, BA AF Collins, Pamela Y. Pringle, Beverly A. TI Building a Global Mental Health Research Workforce: Perspectives from the National Institute of Mental Health SO ACADEMIC PSYCHIATRY LA English DT Editorial Material ID DISORDERS C1 [Collins, Pamela Y.; Pringle, Beverly A.] NIMH, Bethesda, MD 20892 USA. RP Collins, PY (reprint author), NIMH, Bethesda, MD 20892 USA. EM pamela.collins@nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 18 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD AUG PY 2016 VL 40 IS 4 BP 723 EP 726 DI 10.1007/s40596-015-0453-3 PG 4 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA DR2BE UT WOS:000379709200033 PM 26586615 ER PT J AU Price, DK Chau, CH Till, C Goodman, PJ Leach, RJ Johnson-Pais, TL Hsing, AW Hoque, A Parnes, HL Schenk, JM Tangen, CM Thompson, IM Reichardt, JKV Figg, WD AF Price, Douglas K. Chau, Cindy H. Till, Cathee Goodman, Phyllis J. Leach, Robin J. Johnson-Pais, Teresa L. Hsing, Ann W. Hoque, Ashraful Parnes, Howard L. Schenk, Jeannette M. Tangen, Catherine M. Thompson, Ian M. Reichardt, Juergen K. V. Figg, William D. TI Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: Results from the Prostate Cancer Prevention Trial SO CANCER LA English DT Article DE androgen; genetics; metabolism; polymorphism; prostate cancer ID ENDOGENOUS SEX-HORMONES; STEROID-HORMONE; CYP1B1 POLYMORPHISMS; V89L POLYMORPHISM; COHORT CONSORTIUM; PLACEBO ARM; METAANALYSIS; FINASTERIDE; VARIANTS; SRD5A2 AB BACKGROUNDProstate cancer is highly influenced by androgens and genes. The authors investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or with the risk of prostate cancer or high-grade disease from finasteride treatment. METHODSA nested case-control study from the Prostate Cancer Prevention Trial using data from men who had biopsy-proven prostate cancer (cases) and a group of biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with overall (total), low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. RESULTSThere were significant associations of genetic polymorphisms in steroid 5-reductase 1 (SRD5A1) (reference SNPs: rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with the risk of high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial; 2 SNPs were significantly associated with an increased risk (SRD5A1 rs472402 [odds ratio, 1.70; 95% confidence interval, 1.05-2.75; P-trend = .03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; P-trend = .01]). Eleven SNPs in SRD5A1, SRD5A2, cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), and CYP3A4 were associated with modifying the mean concentrations of serum androgen and sex hormone-binding globulin; and 2 SNPs (SRD5A1 rs824811 and CYP1B1 rs10012; P-trend < .05) consistently and significantly altered all androgen concentrations. Several SNPs (SRD5A1 rs3822430, SRD5A2 rs2300700, CYP3A43 rs800672, and CYP19 rs700519; P-trend < .05) were significantly associated with both circulating hormone levels and prostate cancer risk. CONCLUSIONSGermline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and the risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. Cancer 2016;122:2332-2340. (c) 2016 American Cancer Society. C1 [Price, Douglas K.; Chau, Cindy H.; Figg, William D.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Till, Cathee; Goodman, Phyllis J.; Tangen, Catherine M.] Fred Hutchinson Canc Res Ctr, Southwest Oncol Grp Stat Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Leach, Robin J.; Johnson-Pais, Teresa L.; Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Hsing, Ann W.] Canc Prevent Inst Calif, Fremont, CA USA. [Hsing, Ann W.] Stanford Canc Inst, Palo Alto, CA USA. [Hoque, Ashraful] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. [Parnes, Howard L.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Schenk, Jeannette M.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA. [Reichardt, Juergen K. V.] James Cook Univ, Div Trop Hlth & Med, Townsville, Qld, Australia. RP Figg, WD (reprint author), NCI, Ctr Canc Res, 9000 Rockville Pike,Bldg 10 Room 5A01, Bethesda, MD 20892 USA.; Reichardt, JKV (reprint author), Yachay Tech Univ, San Miguel De Urcuqui 100119, Ecuador. EM jreichardt@yachaytech.edu.ec; figgw@helix.nih.gov RI Figg Sr, William/M-2411-2016; OI Reichardt, Juergen/0000-0001-6458-2773 FU National Institutes of Health, National Cancer Institute (NCI), Center for Cancer Research; NCI [P01 CA108964]; Cancer Therapy and Research Center Support Grant at the University of Texas Health Science Center at San Antonio [P30 CA054174]; Public Health Service grants from the NCI [CA37429, CA182883] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Center for Cancer Research; the Biology of the Prostate Cancer Prevention Trial (P01 CA108964) from the NCI; the Cancer Therapy and Research Center Support Grant (P30 CA054174) at the University of Texas Health Science Center at San Antonio; and Public Health Service grants (CA37429 and CA182883) from the NCI. NR 42 TC 0 Z9 0 U1 2 U2 10 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 AUG 1 PY 2016 VL 122 IS 15 BP 2332 EP 2340 DI 10.1002/cncr.30071 PG 9 WC Oncology SC Oncology GA DR7CY UT WOS:000380058800008 PM 27164191 ER PT J AU Belani, CP Dahlberg, SE Rudin, CM Fleisher, M Chen, HX Takebe, N Velasco, MR Tester, WJ Sturtz, K Hann, CL Shanks, JC Monga, M Ramalingam, SS Schiller, JH AF Belani, Chandra P. Dahlberg, Suzanne E. Rudin, Charles M. Fleisher, Martin Chen, Helen X. Takebe, Naoko Velasco, Mario R. Tester, William J. Sturtz, Keren Hann, Christine L. Shanks, James C. Monga, Manish Ramalingam, Suresh S. Schiller, Joan H. TI Vismodegib or cixutumumab in combination with standard chemotherapy for patients with extensive-stage small cell lung cancer: A trial of the ECOG-ACRIN Cancer Research Group (E1508) SO CANCER LA English DT Article DE circulating tumor cell (CTC); cixutumumab; small cell lung cancer; extensive disease; vismodegib ID HEDGEHOG PATHWAY; INHIBITION; EFFICACY; GROWTH; SAFETY AB BACKGROUNDPreclinical targeting of the hedgehog pathway by vismodegib and of insulin-like growth factor 1 receptor by cixutumumab enhances the efficacy of chemotherapy and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in small cell lung cancer. METHODSPatients with newly diagnosed extensive-stage small cell lung cancer (SCLC-ED) were randomized to receive four 21-day cycles of cisplatin and etoposide alone (cisplatin at 75 mg/m(2) on day 1 and etoposide at 100 mg/m(2) on days 1-3; arm A) or in combination with either vismodegib (150 mg/d by mouth; arm B) or cixutumumab (6 mg/kg/wk intravenously on day 1; arm C). The primary endpoint was progression-free survival (PFS). Circulating tumor cells (CTCs) were isolated/enumerated with the Veridex CellSearch platform at the baseline. RESULTSOne hundred fifty-two eligible patients were treated. Patient demographics and disease characteristics were well balanced between the 3 arms except for the higher rate with a performance status of 0 in arm B (P = .03). The median PFS times in arms A, B, and C were 4.4, 4.4, and 4.6 months, respectively; the median overall survival (OS) times were 8.8, 9.8, and 10.1 months, respectively; and the response rates were 48%, 56%, and 50%, respectively. None of the comparisons of these outcomes were statistically significant. The median OS was 10.5 months for those with low CTC counts (100/7.5 mL) at baseline and 7.2 months for those with high CTC counts (hazard ratio, 1.74; P = .006). CONCLUSIONSThere was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC-ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016;122:2371-2378. (c) 2016 American Cancer Society. C1 [Belani, Chandra P.] Penn State Hershey Canc Inst, 500 Univ Dr,CH72, Hershey, PA 17033 USA. [Dahlberg, Suzanne E.] Dana Farber Canc Inst, ECOG ACRIN Biostat Ctr, Boston, MA 02115 USA. [Rudin, Charles M.; Fleisher, Martin; Hann, Christine L.] Johns Hopkins Univ, Baltimore, MD USA. [Fleisher, Martin] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Chen, Helen X.; Takebe, Naoko] NCI, Rockville, MD USA. [Velasco, Mario R.] Decatur Mem Hosp, Decatur, IL USA. [Tester, William J.] Albert Einstein Canc Ctr, Philadelphia, PA USA. [Sturtz, Keren] Colorado Canc Res Program, Denver, CO USA. [Shanks, James C.] HealthEast Canc Care, Maplewood, MN USA. [Monga, Manish] West Virginia Univ, Morgantown, WV USA. [Ramalingam, Suresh S.] Emory Univ, Atlanta, GA 30322 USA. [Schiller, Joan H.] Univ Texas Southwestern Med Ctr, Dallas, TX USA. RP Belani, CP (reprint author), Penn State Hershey Canc Inst, 500 Univ Dr,CH72, Hershey, PA 17033 USA. EM cbelani@psu.edu FU Public Health Service Grants from the National Cancer Institute (National Institutes of Health, Department of Health and Human Services) [CA180794, CA180820, CA180802, CA180791, CA189830, CA180790, CA189805, CA189863, CA180844, CA180864, CA180870] FX This study was coordinated by the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (Robert L. Comis, MD, and Mitchell D. Schnall, MD, PhD, group cochairs) and was supported in part by Public Health Service Grants CA180794, CA180820, CA180802, CA180791, CA189830, CA180790, CA189805, CA189863, CA180844, CA180864, and CA180870 from the National Cancer Institute (National Institutes of Health, Department of Health and Human Services). This article's content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. NR 18 TC 4 Z9 4 U1 2 U2 2 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 AUG 1 PY 2016 VL 122 IS 15 BP 2371 EP 2378 DI 10.1002/cncr.30062 PG 8 WC Oncology SC Oncology GA DR7CY UT WOS:000380058800013 PM 27163943 ER PT J AU Suneja, G Lin, CC Simard, EP Han, XS Engels, EA Jemal, A AF Suneja, Gita Lin, Chun Chieh Simard, Edgar P. Han, Xuesong Engels, Eric A. Jemal, Ahmedin TI Disparities in cancer treatment among patients infected with the human immunodeficiency virus SO CANCER LA English DT Article DE access to cancer treatment; acquired immunodeficiency syndrome (AIDS)-defining cancer; cancer treatment disparities; health services research; human immunodeficiency virus (HIV)-associated cancer ID UNITED-STATES; ANTIRETROVIRAL THERAPY; MEDICATION ADHERENCE; SUBSTANCE-ABUSE; CLINICAL-TRIALS; HIV-INFECTION; INDIVIDUALS; MORTALITY; AIDS; AGE AB BACKGROUNDPatients with cancer who are infected with the human immunodeficiency virus (HIV) are less likely to receive cancer treatment compared with HIV-uninfected individuals. However, to the authors' knowledge, the impact of insurance status and comorbidities is unknown. METHODSData from the National Cancer Data Base were used to study nonelderly adults diagnosed with several common cancers from 2003 to 2011. Cancer treatment was defined as chemotherapy, surgery, radiotherapy, or any combination during the first course of treatment. Multivariate logistic regression was used to examine associations between HIV status and lack of cancer treatment, and identify predictors for lack of treatment among HIV-infected patients. RESULTSA total of 10,265 HIV-infected and 2,219,232 HIV-uninfected cases were included. In multivariate analysis, HIV-infected patients with cancer were found to be more likely to lack cancer treatment for cancers of the head and neck (adjusted odds ratio [aOR], 1.48; 95% confidence interval [95% CI], 1.09-2.01), upper gastrointestinal tract (aOR, 2.62; 95% CI, 2.04-3.37), colorectum (aOR, 1.70; 95% CI, 1.17-2.48), lung (aOR, 2.46; 95% CI, 2.19-2.76), breast (aOR, 2.14; 95% CI, 1.16-3.98), cervix (aOR, 2.81; 95% CI, 1.77-4.45), prostate (aOR, 2.16; 95% CI, 1.69-2.76), Hodgkin lymphoma (aOR, 1.92; 95% CI, 1.66-2.22), and diffuse large B-cell lymphoma (aOR, 1.82; 95% CI, 1.65-2.00). Predictors of a lack of cancer treatment among HIV-infected individuals varied by tumor type (solid tumor vs lymphoma), but black race and a lack of private insurance were found to be predictors for both groups. CONCLUSIONSIn the United States, HIV-infected patients with cancer appear to be less likely to receive cancer treatment regardless of insurance and comorbidities. To the authors' knowledge, the current study is the largest study of cancer treatment in HIV-infected patients with cancer in the United States and provides evidence of cancer treatment disparities even after controlling for differences with regard to insurance status and comorbidities. Further work should focus on addressing differential cancer treatment. Cancer 2016;122:2399-2407. (c) 2016 American Cancer Society. C1 [Suneja, Gita] Univ Utah, Sch Med, Dept Radiat Oncol, Salt Lake City, UT USA. [Lin, Chun Chieh; Han, Xuesong; Jemal, Ahmedin] Amer Canc Soc, Surveillance & Hlth Serv Res, Intramural Res Dept, Atlanta, GA 30329 USA. [Simard, Edgar P.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Suneja, G (reprint author), Univ Utah, Dept Radiat Oncol, 1950 Circle Hope,Room 1570, Salt Lake City, UT 84112 USA. EM gita.suneja@icloud.com FU American Cancer Society Intramural Research Department; National Cancer Institute FX Chun Chieh Lin, Xuesong Han, and Ahmedin Jemal were supported by the American Cancer Society Intramural Research Department. Eric A. Engels was supported by the intramural research program of the National Cancer Institute. NR 26 TC 4 Z9 4 U1 4 U2 4 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 AUG 1 PY 2016 VL 122 IS 15 BP 2399 EP 2407 DI 10.1002/cncr.30052 PG 9 WC Oncology SC Oncology GA DR7CY UT WOS:000380058800016 PM 27187086 ER PT J AU Yang, XY Zhou, XL Tone, P Durkin, ME Popescu, NC AF Yang, Xuyu Zhou, Xiaoling Tone, Paul Durkin, Marian E. Popescu, Nicholas C. TI Cooperative antiproliferative effect of coordinated ectopic expression of DLC1 tumor suppressor protein and silencing of MYC oncogene expression in liver cancer cells: Therapeutic implications SO ONCOLOGY LETTERS LA English DT Article DE deleted in liver cancer 1; c-Myc; hepatocellular carcinoma; Ras homolog gene family guanosine triphosphatase; tumorigenesis ID GTPASE-ACTIVATING PROTEIN; HEPATOCELLULAR-CARCINOMA; RHO GTPASES; GENE; TUMORIGENICITY; CLASSIFICATION; IDENTIFICATION; PROLIFERATION; PROGRESSION; THERAPIES AB Human hepatocellular carcinoma (HCC) is one of the most common types of cancer and has a very poor prognosis; thus, the development of effective therapies for the treatment of advanced HCC is of high clinical priority. In the present study, the anti-oncogenic effect of combined knockdown of c-Myc expression and ectopic restoration of deleted in liver cancer 1 (DLC1) expression was investigated in human liver cancer cells. Expression of c-Myc in human HCC cells was knocked down by stable transfection with a Myc-specific short hairpin (sh) RNA vector. DLC1 expression in Huh7 cells was restored by adenovirus transduction, and the effects of DLC1 expression and c-Myc knockdown on Ras homolog gene family, member A (RhoA) levels, cell proliferation, soft agar colony formation and cell invasion were measured. Downregulation of c-Myc or re-expression of DLC1 led to a marked reduction in RhoA levels, which was associated with decreases in cell proliferation, soft agar colony formation and invasiveness; this inhibitory effect was augmented with a combination of DLC1 transduction and c-Myc suppression. To determine whether liver cell-specific delivery of DLC1 was able to enhance the inhibitory effect of c-Myc knockdown on tumor growth in vivo, DLC1 vector DNA complexed with galactosylated polyethylene glycol-linear polyethyleneimine was administered by tail vein injection to mice bearing subcutaneous xenografts of Huh7 cells transfected with shMyc or control shRNA. A cooperative inhibitory effect of DLC1 expression and c-Myc knockdown on the growth of Huh7-derived tumors was observed, suggesting that targeted liver cell delivery of DLC1 and c-Myc shRNA may serve as a possible gene therapy modality for the treatment of human HCC. C1 [Yang, Xuyu; Zhou, Xiaoling; Durkin, Marian E.; Popescu, Nicholas C.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yang, Xuyu] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Sect Cellular Neurobiol, Bethesda, MD USA. [Zhou, Xiaoling] NCI, LaboratoryCanc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Tone, Paul] Univ Richmond, Med Ctr, Dept Med, Staten Isl, NY 10310 USA. [Durkin, Marian E.; Popescu, Nicholas C.] NCI, Lab Cellular Oncol, NIH, Bldg 37 Room 4112,9000 Rockville Pike, Bethesda, MD 20892 USA. RP Durkin, ME (reprint author), NCI, Lab Cellular Oncol, NIH, Bldg 37 Room 4112,9000 Rockville Pike, Bethesda, MD 20892 USA. EM durkinm@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX The present study was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 35 TC 2 Z9 2 U1 1 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1792-1074 EI 1792-1082 J9 ONCOL LETT JI Oncol. Lett. PD AUG PY 2016 VL 12 IS 2 BP 1591 EP 1596 DI 10.3892/ol.2016.4781 PG 6 WC Oncology SC Oncology GA DR6AC UT WOS:000379982500127 ER PT J AU Karpyak, VM Biernacka, JM Geske, JR Abulseoud, OA Brunner, MD Chauhan, M Hall-Flavin, DK Lewis, KA Loukianova, LL Melnyk, GJ Onsrud, DA Proctor, BD Schneekloth, TD Skime, MK Wittkopp, JE Frye, MA Mrazek, DA AF Karpyak, Victor M. Biernacka, Joanna M. Geske, Jennifer R. Abulseoud, Osama A. Brunner, Michael D. Chauhan, Mohit Hall-Flavin, Daniel K. Lewis, Kriste A. Loukianova, Larissa L. Melnyk, George J. Onsrud, David A. Proctor, Brian D. Schneekloth, Terry D. Skime, Michelle K. Wittkopp, John E. Frye, Mark A. Mrazek, David A. TI Gender-specific effects of comorbid depression and anxiety on the propensity to drink in negative emotional states SO ADDICTION LA English DT Article DE Alcohol use disorder; anxiety; craving; depression; gender; substance-induced ID NATIONAL EPIDEMIOLOGIC SURVEY; SUBSTANCE USE DISORDERS; ALCOHOL-USE DISORDERS; PSYCHIATRIC RESEARCH INTERVIEW; DSM-IV; MENTAL-DISORDERS; PSYCHOMETRIC PROPERTIES; UNITED-STATES; DEPENDENCE; RELAPSE AB Background and AimsDepression and anxiety are often comorbid with alcoholism and contribute to craving and relapse. We aimed to estimate the prevalence of life-time diagnoses of major depressive disorder (MDD), substance-induced depression (SID), anxiety disorder (AnxD) and substance-induced anxiety (SIA), the effects of these comorbidities on the propensity to drink in negative emotional states (negative craving), and test whether these effects differ by sex. DesignSecondary analyses of baseline data collected in a single-arm study of pharmacogenetic predictors of acamprosate response. SettingAcademic medical center and affiliated community-based treatment programs in the American upper mid-west. ParticipantsA total of 287 males and 156 females aged 18-80years, meeting DSM-IV criteria for alcohol dependence. MeasurementsThe primary outcome measure was propensity to drink in negative emotional situations' (determined by the Inventory of Drug Taking Situations) and the key predictors/covariates were sex and psychiatric comorbidities, including MDD, SID, AnxD and SIA (determined by Psychiatric Research Interview of Substance and Mood Disorders). FindingsThe prevalence of the MDD, SID and AnxD was higher in females compared with males (33.1 versus 18.4%, 44.8 versus 26.4% and 42.2 versus 27.4%, respectively; P<0.01, each), while SIA was rare (3.3%) and did not differ by sex. Increased propensity to drink in negative emotional situations was associated with comorbid MDD (=6.6, P=0.013) and AnxD (=4.8, P=0.042) as well as a SIDxsex interaction effect (P=0.003), indicating that the association of SID with propensity to drink in negative emotional situations differs by sex and is stronger in males (=7.9, P=0.009) compared with females (=-6.6, P=0.091). ConclusionsThere appears to be a higher prevalence of comorbid depression and anxiety disorders as well as propensity to drink in negative emotional situations in female compared with male alcoholics. Substance-induced depression appears to have a sex-specific effect on the increased risk for drinking in negative emotional situations in males. C1 [Karpyak, Victor M.; Biernacka, Joanna M.; Abulseoud, Osama A.; Hall-Flavin, Daniel K.; Lewis, Kriste A.; Loukianova, Larissa L.; Schneekloth, Terry D.; Skime, Michelle K.; Frye, Mark A.; Mrazek, David A.] Mayo Clin, Dept Psychiat & Psychol, 200 First St SW, Rochester, MN 55905 USA. [Biernacka, Joanna M.; Geske, Jennifer R.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Brunner, Michael D.] Mayo Clin Hlth Syst, Fountain Ctr, Albert Lea, MN USA. [Chauhan, Mohit; Wittkopp, John E.] Mayo Clin Hlth Syst, Addict Recovery Serv, Austin, MN USA. [Melnyk, George J.; Proctor, Brian D.] Mayo Clin Hlth Syst Franciscan Healthcare, Dept Psychiat, La Crosse, WI USA. [Onsrud, David A.] Mayo Clin Hlth Syst Franciscan Healthcare, Dept Family Med, La Crosse, WI USA. [Abulseoud, Osama A.] NIDA, Chem & Drug Metab, IRP, NIH, Baltimore, MD USA. [Chauhan, Mohit] Piedmont Med Ctr, Rock Hill, SC USA. [Lewis, Kriste A.] Reg Hosp, St Paul, MN USA. RP Karpyak, VM (reprint author), Mayo Clin, Dept Psychiat & Psychol, 200 First St SW, Rochester, MN 55905 USA. EM karpyak.victor@mayo.edu FU NIH/NIAAA [P20 1P20AA017830-01]; SC Johnson Genomics of Addictions Program FX The results reported in this study were based on the data collected for the NIH/NIAAA grant P20 1P20AA017830-01 (The Mayo Clinic Center for Individualized Treatment of Alcohol Dependence), and the SC Johnson Genomics of Addictions Program. The study drug for this research was provided by Forest Pharmaceuticals. The National Institute on Alcohol Abuse and Alcoholism, SC Johnson Genomics of Addictions Program, and Forest Pharmaceuticals, Inc., or its affiliates, had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review or approval of the manuscript; nor decision to submit the manuscript for publication. The authors would like to acknowledge the contributions of Misty Leidal BSN, Christine Hanzel BA, Katrina Schaefer BA, Evan Loehle-Conger MA, Sharon Schulz BSN and Joni Burns-Duenes BSN for their assistance with patient recruitment and data collection, and the Mayo Clinic Psychiatry Information Technology group for their assistance with data management. All these individuals were employed by Mayo Clinic or Mayo Clinic Health System and did not receive additional compensation for the work. NR 66 TC 2 Z9 2 U1 18 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD AUG PY 2016 VL 111 IS 8 BP 1366 EP 1375 DI 10.1111/add.13386 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DR5NE UT WOS:000379948900011 PM 27009547 ER PT J AU Ling, W Hillhouse, MP Saxon, AJ Mooney, LJ Thomas, CM Ang, A Matthews, AG Hasson, A Annon, J Sparenborg, S Liu, DS McCormack, J Church, S Swafford, W Drexler, K Schuman, C Ross, S Wiest, K Korthuis, PT Lawson, W Brigham, GS Knox, PC Dawes, M Rotrosen, J AF Ling, Walter Hillhouse, Maureen P. Saxon, Andrew J. Mooney, Larissa J. Thomas, Christie M. Ang, Alfonso Matthews, Abigail G. Hasson, Albert Annon, Jeffrey Sparenborg, Steve Liu, David S. McCormack, Jennifer Church, Sarah Swafford, William Drexler, Karen Schuman, Carolyn Ross, Stephen Wiest, Katharina Korthuis, P. Todd Lawson, William Brigham, Gregory S. Knox, Patricia C. Dawes, Michael Rotrosen, John TI Buprenorphine plus naloxone plus naltrexone for the treatment of cocaine dependence: the Cocaine Use Reduction with Buprenorphine (CURB) study SO ADDICTION LA English DT Article DE Buprenorphine plus naloxone; cocaine use disorder; double-blind; multi-site trial; naltrexone; pharmacotherapy; placebo-controlled; treatment ID ABUSE CLINICAL-TRIALS; OPIOID DEPENDENCE; RANDOMIZED-TRIAL; ADDICTION; ANTAGONIST; MODULATION; METHADONE; MODELS AB AimsTo examine the safety and effectiveness of buprenorphine+naloxone sublingual tablets (BUP, as Suboxone((R))) provided after administration of extended-release injectable naltrexone (XR-NTX, as Vivitrol((R))) to reduce cocaine use in participants who met DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. MethodsThis multi-centered, double-blind, placebo-controlled study, conducted under the auspices of the National Drug Abuse Treatment Clinical Trials Network, randomly assigned 302 participants at sites in California, Oregon, Washington, Colorado, Texas, Georgia, Ohio, New York and Washington DC, USA to one of three conditions provided with XR-NTX: 4mg/day BUP (BUP4, n=100), 16mg/day BUP (BUP16, n=100, or no buprenorphine (placebo; PLB, n=102). Participants received pharmacotherapy for 8weeks, with three clinic visits per week. Cognitive behavioral therapy was provided weekly. Follow-up assessments occurred at 1 and 3months post-intervention. The planned primary outcome was urine drug screen (UDS)-corrected, self-reported cocaine use during the last 4weeks of treatment. Planned secondary analyses assessed cocaine use by UDS, medication adherence, retention and adverse events. ResultsNo group differences were found between groups for the primary outcome (BUP4 versus PLB, P=0.262; BUP16 versus PLB, P=0.185). Longitudinal analysis of UDS data during the evaluation period using generalized linear mixed equations found a statistically significant difference between BUP16 and PLB [P=0.022, odds ratio (OR)=1.71] but not for BUP4 (P=0.105, OR=1.05). No secondary outcome differences across groups were found for adherence, retention or adverse events. ConclusionsBuprenorphine+naloxone, used in combination with naltrexone, may be associated with reductions in cocaine use among people who meet DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. C1 [Ling, Walter; Hillhouse, Maureen P.; Mooney, Larissa J.; Thomas, Christie M.; Ang, Alfonso; Hasson, Albert; Annon, Jeffrey] Univ Calif Los Angeles, Los Angeles, CA USA. [Saxon, Andrew J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Sparenborg, Steve; Liu, David S.] NIDA, Bethesda, MD 20892 USA. [Matthews, Abigail G.; McCormack, Jennifer] Emmes Corp, Rockville, MD USA. [Church, Sarah] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Swafford, William] ARTS, Denver, CO USA. [Drexler, Karen] Atlanta VA Med Ctr, Atlanta, GA USA. [Schuman, Carolyn] BAART Programs, San Francisco, CA USA. [Ross, Stephen] Bellevue Hosp Ctr, New York, NY 10016 USA. [Wiest, Katharina] CODA, Portlad, OR USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Lawson, William] Howard Univ, Washington, DC 20059 USA. [Brigham, Gregory S.] Maryhaven Treatment Ctr, Columbus, OH USA. [Knox, Patricia C.] RCKC, Kent, WA USA. [Dawes, Michael] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Rotrosen, John] NYU, Sch Med, New York, NY USA. RP Ling, W (reprint author), UCLA Integrated Subst Abuse Programs, 1640 South Sepulveda Blvd,Suite 120, Los Angeles, CA 90025 USA. EM lwalter@ucla.edu FU National Institute on Drug Abuse [DA13045, DA13035, DA13046, DA015815, HHSN271200900034C / N01DA-92217, HHSN271201200017C / N01DA-12-2229, HHSN271201400028C / N01DA-14-2237]; Reckitt Benckiser Pharmaceuticals; Alkermes Pharmaceuticals FX Support provided through the National Institute on Drug Abuse (DA13045; DA13035; DA13046, DA015815, HHSN271200900034C / N01DA-92217, HHSN271201200017C / N01DA-12-2229, HHSN271201400028C / N01DA-14-2237); Reckitt Benckiser Pharmaceuticals, Alkermes Pharmaceuticals. NR 27 TC 1 Z9 1 U1 5 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD AUG PY 2016 VL 111 IS 8 BP 1416 EP 1427 DI 10.1111/add.13375 PG 12 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DR5NE UT WOS:000379948900017 PM 26948856 ER PT J AU Lingala, S Lau, DTY Koh, C Auh, S Ghany, MG Hoofnagle, JH AF Lingala, S. Lau, D. T. -Y. Koh, C. Auh, S. Ghany, M. G. Hoofnagle, J. H. TI Long-term lamivudine therapy in chronic hepatitis B SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID TENOFOVIR DISOPROXIL FUMARATE; ADEFOVIR DIPIVOXIL; ENTECAVIR; HBSAG; HBV AB BackgroundOne to 5years of therapy of chronic hepatitis B with oral nucleoside analogues result in significant clinical improvements, but effects of more prolonged therapy are not well defined. AimTo describe outcomes of chronic hepatitis B with long-term lamivudine therapy. MethodsForty-two patients with chronic hepatitis B treated with lamivudine were followed for 3.2-19.5 (median=16.1)years. Therapy was switched to other agents (n=16) if patients developed lamivudine resistance and relapse of disease. ResultsAmong 22 HBeAg-positive patients, 17 (77%) became HBeAg negative, of whom 5 (23%) subsequently cleared HBsAg. Among 20 HBeAg-negative patients, 10 (50%) cleared HBsAg. The time to HBsAg clearance ranged from 0.9 to 16.8 (median=9.3) years. Lamivudine resistance arose in 24 patients (57%) of whom 6 (25%) lost HBsAg. HBsAg clearance was not always accompanied by seroconversion; anti-HBs appearing concurrently in only five patients (33%). Nevertheless, HBsAg loss allowed for stopping therapy in all patients, none re-developing HBsAg or suffering relapse; all having normal alanine aminotransferase levels and no (n=13) or unquantifiable HBV DNA levels (n=2) when last seen. In contrast, seven of 27 patients (26%) who remained HBsAg-positive died of liver disease or liver cancer or underwent liver transplantation, all of whom had cirrhosis. ConclusionsLong-term viral suppression with nucleoside analogues leads to HBsAg loss in a substantial proportion of patients, particularly if HBeAg-negative. Serious outcomes during the first 10-20years of treatment occur largely among patients with pre-existing cirrhosis who do not clear HBsAg with therapy. C1 [Lingala, S.; Koh, C.; Ghany, M. G.; Hoofnagle, J. H.] NIDDK, Liver Dis Branch, Intramural Div, NIH, Bethesda, MD 20892 USA. [Lau, D. T. -Y.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Auh, S.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Hoofnagle, JH (reprint author), Liver Dis Res Branch, Democracy 2,Room 6005,6707 Democracy Blvd, Bethesda, MD 20852 USA. EM hoofnaglej@extra.niddk.nih.gov FU Intramural Division of NIDDK FX Lamivudine was supplied for the initial 10 years of the open-label study of lamivudine for chronic hepatitis B by GlaxoSmithKline through a Clinical Trial Agreement with the National Institutes of Health. This study was supported in part by the Intramural Division of NIDDK. NR 23 TC 0 Z9 0 U1 4 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD AUG PY 2016 VL 44 IS 4 BP 380 EP 389 DI 10.1111/apt.13707 PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA DR5QI UT WOS:000379957100006 PM 27375283 ER PT J AU Stevenson, DA Schill, L Schoyer, L Andresen, BS Bakker, A Bayrak-Toydemir, P Burkitt-Wright, E Chatfield, K Elefteriou, F Elgersma, Y Fisher, MJ Franz, D Gelb, BD Goriely, A Gripp, KW Hardan, AY Keppler-Noreuil, KM Kerr, B Korf, B Leoni, C McCormick, F Plotkin, SR Rauen, KA Reilly, K Roberts, A Sandler, A Siegel, D Walsh, K Widemann, BC AF Stevenson, David A. Schill, Lisa Schoyer, Lisa Andresen, Brage S. Bakker, Annette Bayrak-Toydemir, Pinar Burkitt-Wright, Emma Chatfield, Kathryn Elefteriou, Florent Elgersma, Ype Fisher, Michael J. Franz, David Gelb, Bruce D. Goriely, Anne Gripp, Karen W. Hardan, Antonio Y. Keppler-Noreuil, Kim M. Kerr, Bronwyn Korf, Bruce Leoni, Chiara McCormick, Frank Plotkin, Scott R. Rauen, Katherine A. Reilly, Karlyne Roberts, Amy Sandler, Abby Siegel, Dawn Walsh, Karin Widemann, Brigitte C. TI The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE RASopathy; Ras; MAPK; cancer; rare disorders; clinical trials; experimental models ID NEUROFIBROMATOSIS TYPE-1; PLEXIFORM NEUROFIBROMAS; CLINICAL-TRIALS; YOUNG-ADULTS; CHILDREN; INHIBITION; SPECTRUM; NOONAN AB The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. (c) 2016 Wiley Periodicals, Inc. C1 [Stevenson, David A.; Hardan, Antonio Y.] Stanford Univ, Stanford, CA 94305 USA. [Schill, Lisa; Schoyer, Lisa] RASopathies Network, Berkeley, CA USA. [Andresen, Brage S.] Univ Southern Denmark, Odense, Denmark. [Bakker, Annette] Childrens Tumor Fdn, New York, NY USA. [Bayrak-Toydemir, Pinar] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Burkitt-Wright, Emma; Kerr, Bronwyn] Univ Manchester, Manchester M13 9PL, Lancs, England. [Chatfield, Kathryn] Univ Colorado, Denver, CO 80202 USA. [Elefteriou, Florent] Baylor Coll Med, Houston, TX 77030 USA. [Elgersma, Ype] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Fisher, Michael J.] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. [Franz, David] Univ Cincinnati, Cincinnati, OH USA. [Gelb, Bruce D.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Goriely, Anne] Univ Oxford, Oxford, England. [Gripp, Karen W.] Alfred I DuPont Hosp Children, Div Med Genet, Wilmington, DE USA. [Keppler-Noreuil, Kim M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Korf, Bruce] Univ Alabama Birmingham, Birmingham, AL USA. [Leoni, Chiara] Fdn Policlin Univ A Gemelli, Rome, Italy. [McCormick, Frank; Reilly, Karlyne; Sandler, Abby; Widemann, Brigitte C.] NCI, NIH, Bethesda, MD 20892 USA. [Plotkin, Scott R.] Massachussets Gen Hosp, Boston, MA USA. [Rauen, Katherine A.] Univ Calif Davis, Dept Pediat, Div Genom Med, Sacramento, CA USA. [Roberts, Amy] Boston Childrens Hosp, Boston, MA USA. [Siegel, Dawn] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Walsh, Karin] George Washington Univ, Sch Med, Washington, DC USA. RP Stevenson, DA (reprint author), Stanford Univ, Div Med Genet, 300 Pasteur Dr H315, Stanford, CA 94305 USA. EM dasteven@stanford.edu RI Andresen, Brage/D-2515-2012; OI Andresen, Brage/0000-0001-7488-3035; Goriely, Anne/0000-0001-9229-7216 FU National Institutes of Health [1R13TR001272-01]; International Costello Syndrome; March of Dimes; Noonan Syndrome Foundation; Children's Tumor Foundation; NF Network; NCI CCR intramural research program; CFC International; Costello Syndrome Family Network; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Disease [5RO1AR062165] FX Grant sponsor: National Institutes of Health; Grant number: 1R13TR001272-01; Grant sponsor: International Costello Syndrome; Grant sponsor: March of Dimes; Grant sponsor: Noonan Syndrome Foundation; Grant sponsor: Children's Tumor Foundation; Grant sponsor: NF Network; Grant sponsor: NCI CCR intramural research program; Grant sponsor: CFC International; Grant sponsor: Costello Syndrome Family Network; Grant sponsor: National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Disease; Grant number: 5RO1AR062165. NR 16 TC 1 Z9 1 U1 6 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2016 VL 170 IS 8 BP 1959 EP 1966 DI 10.1002/ajmg.a.37723 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA DR5MZ UT WOS:000379948400003 PM 27155140 ER PT J AU Cologna, SM Shieh, C Toth, CL Cougnoux, A Burkert, KR Bianconi, SE Wassif, CA Porter, FD AF Cologna, Stephanie M. Shieh, Christine Toth, Cynthia L. Cougnoux, Antony Burkert, Kathryn R. Bianconi, Simona E. Wassif, Christopher A. Porter, Forbes D. TI Altered cerebrospinal fluid proteins in Smith-Lemli-Opitz syndrome patients SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Smith-Lemli-Opitz; SLOS; biomarkers; cerebrospinal fluid ID MATRIX METALLOPROTEINASES; NEURODEGENERATIVE DISEASES; REDUCTASE GENE; OXYSTEROLS; MUTATIONS; MICE; SUPPLEMENTATION; PATHOGENESIS; CHOLESTEROL; ACTIVATION AB Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation syndrome with neurocognitive impairment. SLOS arises from mutations in the 7-dehydrocholesterol reductase gene which results in impaired enzymatic conversion of 7-dehydrocholesterol to cholesterol. In the current work, we sought to measure proteins that were altered in the cerebrospinal fluid from SLOS patients compared to pediatric controls. Using a multi-analyte antibody-based assay, we found that 12 proteins are altered in SLOS patients. Validation studies were carried out and the findings from this study suggest alterations in extracellular matrix remodeling and further evidence of oxidative stress within the disease pathophysiology. The results of this study will be used to explore biological pathways altered in SLOS and identifies a set of CSF proteins that can be evaluated as biomarkers in future therapeutic trials. (c) 2016 Wiley Periodicals, Inc. C1 [Cologna, Stephanie M.; Shieh, Christine; Toth, Cynthia L.; Cougnoux, Antony; Burkert, Kathryn R.; Bianconi, Simona E.; Wassif, Christopher A.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Dysmorphol, NIH, US Dept HHS, Bethesda, MD USA. RP Cologna, SM (reprint author), Univ Illinois, Dept Chem, 845 W Taylor St,M-C 111, Chicago, IL 60607 USA. EM cologna@uic.edu FU Intramural Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development; DHHS; NIH; Smith-Lemli-Opitz/RSH Foundation FX Grant sponsor: Intramural Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development; Grant sponsor: DHHS; Grant sponsor: NIH; Grant sponsor: Smith-Lemli-Opitz/RSH Foundation. NR 41 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2016 VL 170 IS 8 BP 2060 EP 2068 DI 10.1002/ajmg.a.37720 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DR5MZ UT WOS:000379948400014 PM 27148958 ER PT J AU Rothwell, S Cooper, RG Lundberg, IE Miller, FW Gregersen, PK Bowes, J Vencovsky, J Danko, K Limaye, V Selva-O'Callaghan, A Hanna, MG Machado, PM Pachman, LM Reed, AM Rider, LG Cobb, J Platt, H Molberg, O Benveniste, O Mathiesen, P Radstake, T Doria, A De Bleecker, J De Paepe, B Maurer, B Ollier, WE Padyukov, L O'Hanlon, TP Lee, A Amos, CI Gieger, C Meitinger, T Winkelmann, J Wedderburn, LR Chinoy, H Lamb, JA AF Rothwell, Simon Cooper, Robert G. Lundberg, Ingrid E. Miller, Frederick W. Gregersen, Peter K. Bowes, John Vencovsky, Jiri Danko, Katalin Limaye, Vidya Selva-O'Callaghan, Albert Hanna, Michael G. Machado, Pedro M. Pachman, Lauren M. Reed, Ann M. Rider, Lisa G. Cobb, Joanna Platt, Hazel Molberg, Oyvind Benveniste, Olivier Mathiesen, Pernille Radstake, Timothy Doria, Andrea De Bleecker, Jan De Paepe, Boel Maurer, Britta Ollier, William E. Padyukov, Leonid O'Hanlon, Terrance P. Lee, Annette Amos, Christopher I. Gieger, Christian Meitinger, Thomas Winkelmann, Juliane Wedderburn, Lucy R. Chinoy, Hector Lamb, Janine A. CA Myositis Genetics Consortium TI Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID GENOME-WIDE ASSOCIATION; INCLUSION-BODY MYOSITIS; SUSCEPTIBILITY LOCI; TYROSINE-PHOSPHATASE; DISEASE; VARIANTS; DERMATOMYOSITIS; POPULATION; POLYMYOSITIS; EXPRESSION AB Objectives The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. Results The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5x10(-8)). Nine regions were associated at a significance level of p<2.25x10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM. Conclusions This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups. C1 [Rothwell, Simon; Bowes, John] Univ Manchester, Arthrit Res UK, Ctr Genet & Genom, Manchester M13 9PT, Lancs, England. [Cooper, Robert G.] Univ Liverpool, Inst Ageing & Chron Dis, Dept Musculoskeletal Biol, Liverpool, Merseyside, England. [Lundberg, Ingrid E.; Padyukov, Leonid] Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden. [Miller, Frederick W.; Rider, Lisa G.; O'Hanlon, Terrance P.] NIEHS, Environm Autoimmun Grp, Clin Res Branch, NIH, Bethesda, MD USA. [Gregersen, Peter K.; Lee, Annette] Feinstein Inst Med Res, Robert S Boas Ctr Genom & Human Genet, Manhasset, NY USA. [Vencovsky, Jiri] Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic. [Vencovsky, Jiri] Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic. [Danko, Katalin] Univ Debrecen, Dept Internal Med, Div Clin Immunol, Debrecen, Hungary. [Limaye, Vidya] Royal Adelaide Hosp, Adelaide, SA, Australia. [Limaye, Vidya] Univ Adelaide, Adelaide, SA, Australia. [Selva-O'Callaghan, Albert] Vall dHebron Hosp, Dept Internal Med, Barcelona, Spain. [Hanna, Michael G.; Machado, Pedro M.] UCL Inst Neurol, MRC Ctr Neuromuscular Dis, London, England. [Pachman, Lauren M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Pachman, Lauren M.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Reed, Ann M.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Cobb, Joanna] Univ Manchester, NIHR Manchester Musculoskeletal Biomed Res Unit, Cent Manchester NHS Fdn Trust, Arthrit Res UK,Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Platt, Hazel; Ollier, William E.; Lamb, Janine A.] Univ Manchester, Ctr Integrated Genom Med Res, Manchester, Lancs, England. [Molberg, Oyvind] Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway. [Benveniste, Olivier] Univ Paris 06, Pitie Salpetriere Hosp, APHP, Paris, France. [Mathiesen, Pernille] Naestved Hosp, Dept Paediat, Naestved, Denmark. [Radstake, Timothy] Univ Med Ctr Utrecht, Dept Rheumatol & Clin Immunol, Utrecht, Netherlands. [Doria, Andrea] Univ Padua, Dept Med, Padua, Italy. [De Bleecker, Jan; De Paepe, Boel] Ghent Univ Hosp, Dept Neurol, Neuromuscular Reference Ctr, Ghent, Belgium. [Maurer, Britta] Univ Zurich Hosp, Dept Rheumatol, Zurich, Switzerland. [Maurer, Britta] Univ Zurich Hosp, Ctr Expt Rheumatol, Zurich, Switzerland. [Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA. [Gieger, Christian] Helmholtz Zentrum Munchen, Deutsch Forschungszentrum Gesundheit & Umwelt Gmb, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, Munich, Germany. [Meitinger, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Winkelmann, Juliane] Tech Univ Munich, Klinikum Rechts Isar, Neurol Klin & Poliklin, Munich, Germany. [Winkelmann, Juliane] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Neurogen, Neuherberg, Germany. [Wedderburn, Lucy R.] UCL, Arthrit Res UK Ctr Adolescent Rheumatol, London, England. [Wedderburn, Lucy R.] UCL, Inst Child Hlth, London, England. [Chinoy, Hector] Univ Manchester, Ctr Musculoskeletal Res, Manchester Musculoskeletal Biomed Res Unit, Natl Inst Hlth Res, Manchester, Lancs, England. RP Rothwell, S (reprint author), Univ Manchester, Arthrit Res UK, Ctr Genet & Genom, Manchester M13 9PT, Lancs, England. EM s.rothwell@manchester.ac.uk RI De Paepe, Boel/B-7548-2013; Mann, Herman/G-5871-2014; OI Chinoy, Hector/0000-0001-6492-1288; Padyukov, Leonid/0000-0003-2950-5670; De Paepe, Boel/0000-0001-9403-4401; Mann, Herman/0000-0002-4243-235X; Gieger, Christian/0000-0001-6986-9554; Doria, Andrea/0000-0003-0548-4983; Winkelmann, Juliane/0000-0003-2667-9691; Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593; Cobb, Joanna/0000-0002-2760-3114 FU Association Francaise Contre Les Myopathies (AFM); European Union Sixth Framework Programme (project AutoCure) [LSH-018661]; European Science Foundation (ESF) in the framework of the Research Networking Programme European Myositis Network (EUMYONET); Swedish Research Council; Stockholm County Council; Karolinska Institutet; National Institute of Environmental Health Sciences (NIEHS); National Institutes of Health (NIH); European Community's FP6; AutoCure LSHB [CT-2006-018661]; UK Myositis Support Group; Arthritis Research UK [18474]; Cure JM Foundation; European Science Foundation; Wellcome Trust; Henry Smith Charity UK; Action Medical UK; Project for Conceptual Development of Research Organization from Ministry of Health in the Czech Republic [00023728] FX This study was supported in part by: Association Francaise Contre Les Myopathies (AFM), The European Union Sixth Framework Programme (project AutoCure; LSH-018661), European Science Foundation (ESF) in the framework of the Research Networking Programme European Myositis Network (EUMYONET), The Swedish Research Council and The regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the intramural research programme of the National Institute of Environmental Health Sciences (NIEHS), the National Institutes of Health (NIH); European Community's FP6, AutoCure LSHB CT-2006-018661; The UK Myositis Support Group; Arthritis Research UK (18474); The Cure JM Foundation; the European Science Foundation; the Wellcome Trust; the Henry Smith Charity UK; Action Medical UK; and the Swedish Research Council. The Czech cohort was supported by Project for Conceptual Development of Research Organization 00023728 from Ministry of Health in the Czech Republic. NR 47 TC 6 Z9 6 U1 5 U2 10 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 AUG PY 2016 VL 75 IS 8 BP 1558 EP 1566 DI 10.1136/annrheumdis-2015-208119 PG 9 WC Rheumatology SC Rheumatology GA DR2NL UT WOS:000379741100031 PM 26362759 ER PT J AU Zhao, YN Zhang, J Shi, XY Li, J Wang, R Song, RW Wei, Q Cai, HB Luo, J AF Zhao, Yane Zhang, Jin Shi, Xiaoyu Li, Jing Wang, Rui Song, Ruiwen Wei, Qun Cai, Huaibin Luo, Jing TI Quercetin targets the interaction of calcineurin with LxVP-type motifs in immunosuppression SO BIOCHIMIE LA English DT Article DE Calcineurin; Quercetin; RCAN1; NFAT; LxVP-motif; Cyclosporine A; Cytokine expression ID CYCLOSPORINE-A; CRYSTAL-STRUCTURE; GENE-EXPRESSION; INHIBITION; NFAT; REGULATORS; CYCLOPHILIN; ACTIVATION; RCAN; IDENTIFICATION AB Calcineurin (CN) is a unique calcium/calmodulin (CaM)-activated serine/threonine phosphatase. To perform its diverse biological functions, CN communicates with many substrates and other proteins. In the physiological activation of T cells, CN acts through transcriptional factors belonging to the NFAT family and other transcriptional effectors. The classic immunosuppressive drug cyclosporin A (CsA) can bind to cyclophilin (CyP) and compete with CN for the NFAT LxVP motif. CsA has debilitating side effects, including nephrotoxicity, hypertension and tremor. It is desirable to develop alternative immunosuppressive agents. To this end, we first tested the interactions between CN and the LxVP-type substrates, including endogenous regulators of calcineurin (RCAN1) and NFAT. Interestingly, we found that quercetin, the primary dietary flavonol, can inhibit the activity of CN and significantly disrupt the associations between CN and its LxVP-type substrates. We then validated the inhibitory effects of quercetin on the CN-NFAT interactions in cell-based assays. Further, quercetin also shows dose-dependent suppression of cytokine gene expression in mouse spleen cells. These data raise the possibility that the interactions of CN with its LxVP-type substrates are potential targets for immunosuppressive agents. (C) 2016 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. C1 [Zhao, Yane; Zhang, Jin; Shi, Xiaoyu; Li, Jing; Wang, Rui; Song, Ruiwen; Wei, Qun; Luo, Jing] Beijing Normal Univ, Inst Life Sci, Dept Biochem & Mol Biol, Gene Engn & Biotechnol Beijing Key Lab, Beijing 100875, Peoples R China. [Cai, Huaibin] NIA, Transgen Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Li, Jing] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60635 USA. RP Luo, J (reprint author), Beijing Normal Univ, Inst Life Sci, Dept Biochem & Mol Biol, Gene Engn & Biotechnol Beijing Key Lab, Beijing 100875, Peoples R China. EM luojing@bnu.edu.cn FU Intramural NIH HHS [Z01 AG000944-01] NR 34 TC 0 Z9 0 U1 7 U2 14 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0300-9084 EI 1638-6183 J9 BIOCHIMIE JI Biochimie PD AUG PY 2016 VL 127 BP 50 EP 58 DI 10.1016/j.biochi.2016.04.011 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR7LZ UT WOS:000380082500007 PM 27109380 ER PT J AU Weinberg, JG Evans, FJ Burns, KM Pearson, GD Kaltman, JR AF Weinberg, Jacqueline G. Evans, Frank J. Burns, Kristin M. Pearson, Gail D. Kaltman, Jonathan R. TI Surgical ligation of patent ductus arteriosus in premature infants: trends and practice variation SO CARDIOLOGY IN THE YOUNG LA English DT Article DE Patent ductus arteriosus; preterm infant; surgical ligation; neonate ID BIRTH-WEIGHT INFANTS; PRETERM INFANTS; SPONTANEOUS CLOSURE; 1000 GRAMS; INDOMETHACIN; OUTCOMES; TRIAL; MORTALITY; DISCHARGE; TREAT AB Objective: We sought to analyse the variation in the incidence of patent ductus arteriosus over three recent time points and characterise ductal ligation practices in preterm infants in the United States, adjusting for demographic and morbidity factors. Methods: Using the Kids' Inpatient Database from 2003, 2006, and 2009, we identified infants born at <= 32 weeks of gestation with International Classification of Diseases, Ninth Revision diagnosis of patent ductus arteriosus and ligation code. We examined patient and hospital characteristics and identified patient and hospital variables associated with ligation. Results: Of 182,610 preterm births, 30,714 discharges included a patent ductus arteriosus diagnosis. The rate of patent ductus arteriosus diagnosis increased from 14% in 2003 to 21% in 2009 (p<0.001). A total of 4181 ligations were performed, with an overall ligation rate of 14%. Ligation rate in infants born at <= 28 weeks of gestation was 20% overall, increasing from 18% in 2003 to 21% in 2009 (p<0.001). The ligation rate varied by state (4-28%), and ligation was associated with earlier gestational age, associated diagnoses, hospital type, teaching hospital status, and region (p<0.001). Conclusion: The rates of patent ductus arteriosus diagnosis and ligation have increased in the recent years. Variation exists in the practice of patent ductus arteriosus ligation and is influenced by patient and non-patient factors. C1 [Weinberg, Jacqueline G.; Evans, Frank J.; Burns, Kristin M.; Pearson, Gail D.; Kaltman, Jonathan R.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Weinberg, Jacqueline G.; Burns, Kristin M.; Pearson, Gail D.; Kaltman, Jonathan R.] Childrens Natl Hlth Syst, Div Cardiol, Dept Pediat, Washington, DC USA. RP Weinberg, JG (reprint author), Childrens Natl Med Ctr, Div Cardiol, 111 Michigan Ave NW,Suite W3-200, Washington, DC 20010 USA. EM jacqui.gale@gmail.com RI min, guo/F-3813-2014 NR 42 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1047-9511 EI 1467-1107 J9 CARDIOL YOUNG JI Cardiol. Young PD AUG PY 2016 VL 26 IS 6 BP 1107 EP 1114 DI 10.1017/S1047951115001869 PG 8 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA DR4AP UT WOS:000379844100010 PM 26395077 ER PT J AU Anic, GM Albanes, D Rohrmann, S Kanarek, N Nelson, WG Bradwin, G Rifai, N McGlynn, KA Platz, EA Mondul, AM AF Anic, Gabriella M. Albanes, Demetrius Rohrmann, Sabine Kanarek, Norma Nelson, William G. Bradwin, Gary Rifai, Nader McGlynn, Katherine A. Platz, Elizabeth A. Mondul, Alison M. TI Association between serum 25-hydroxyvitamin D and serum sex steroid hormones among men in NHANES SO CLINICAL ENDOCRINOLOGY LA English DT Article ID VITAMIN-D STATUS; PROSTATE-CANCER RISK; TESTOSTERONE; HYPOGONADISM; PREVENTION AB BackgroundRecent literature suggests that high circulating vitamin D may increase prostate cancer risk. Although the mechanism through which vitamin D may increase risk is unknown, vitamin D concentration could influence circulating sex steroid hormones that may be associated with prostate cancer; an alternate explanation is that it could be associated with prostate-specific antigen (PSA) concentration causing detection bias. ObjectiveWe examined whether serum vitamin D concentration was associated with sex steroid hormone and PSA concentrations in a cross-sectional analysis of men in the National Health and Nutrition Examination Surveys (NHANES). DesignTestosterone, oestradiol, sex hormone-binding globulin (SHBG), androstanediol glucuronide, and 25-hydroxyvitamin D (25(OH)D) were measured in serum from men aged 20 and older participating in NHANES III (n = 1315) and NHANES 2001-2004 (n = 318). Hormone concentrations were compared across 25(OH)D quintiles, adjusting for age, race/ethnicity, body fat percentage, and smoking. PSA concentration was estimated by 25(OH)D quintile in 4013 men from NHANES 2001-2006. ResultsIn NHANES III, higher testosterone (quintile (Q) 1 = 172, 95% confidence interval (CI) = 161-186; Q5 = 196, 95% CI = 187-206 nmol/l, P-trend = 00002) and SHBG (Q1 = 338, 95% CI = 308-370; Q5 = 384, 95% CI = 358-412 nmol/l, P-trend = 00005) were observed with increasing 25(OH)D. Similar results were observed in NHANES 2001-2004. PSA concentration was not associated with serum 25(OH)D (P-trend = 034). ConclusionResults from these nationally representative studies support a positive association between serum 25(OH)D and testosterone and SHBG. The findings support an indirect mechanism through which vitamin D may increase prostate cancer risk, and suggest the link to prostate cancer is not due to PSA-detection bias. C1 [Anic, Gabriella M.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Anic, Gabriella M.; Albanes, Demetrius; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Rohrmann, Sabine] Univ Zurich, Div Chron Dis, Epidemiol Biostat & Prevent Inst, Zurich, Switzerland. [Kanarek, Norma; Nelson, William G.; Platz, Elizabeth A.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Kanarek, Norma; Nelson, William G.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Nelson, William G.; Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21205 USA. [Nelson, William G.; Platz, Elizabeth A.] Johns Hopkins Univ, Sch Med, James Buchanan Brady Urol Inst, Baltimore, MD USA. [Bradwin, Gary; Rifai, Nader] Harvard Med Sch, Dept Lab Med, Boston, MA USA. [Bradwin, Gary; Rifai, Nader] Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Mondul, Alison M.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. RP Mondul, AM (reprint author), 4646 SPH Tower,1415 Washington Hts, Ann Arbor, MI 48109 USA. EM amondul@umich.edu OI Mondul, Alison/0000-0002-8843-1416 FU Maryland Cigarette Restitution Fund at Johns Hopkins; NCI [P30 CA006973] FX Authors have no conflict of interest to declare. This is the 23rd paper from the Hormone Demonstration Program funded by the Maryland Cigarette Restitution Fund at Johns Hopkins. The work was also supported by NCI P30 CA006973 (Nelson). The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the Maryland Department of Health and Mental Hygiene or the National Institutes of Health. NR 34 TC 3 Z9 3 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD AUG PY 2016 VL 85 IS 2 BP 258 EP 266 DI 10.1111/cen.13062 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DR5FT UT WOS:000379929600015 PM 26991691 ER PT J AU Foki, T Vanbellingen, T Lungu, C Pirker, W Bohlhalter, S Nyffeler, T Kraemmer, J Haubenberger, D Fischmeister, FPS Auff, E Hallett, M Beisteiner, R AF Foki, T. Vanbellingen, T. Lungu, C. Pirker, W. Bohlhalter, S. Nyffeler, T. Kraemmer, J. Haubenberger, D. Fischmeister, F. Ph. S. Auff, E. Hallett, M. Beisteiner, R. TI Limb-kinetic apraxia affects activities of daily living in Parkinson's disease: a multi-center study SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE activities of daily living; buttoning; dexterity; limb-kinetic apraxia; Parkinson's disease ID IMPAIRED FINGER DEXTERITY; VALIDATION; TASK; QUESTIONNAIRE; BRADYKINESIA; DYSFUNCTION AB Background and purposeImpaired dexterity (fine hand movements) is often present in Parkinson's disease (PD), even at early to moderate disease stages. It has a detrimental impact on activities of daily living (ADL) such as buttoning, contributing to reduced quality of life. Limb-kinetic apraxia, a loss of the ability to make precise, independent but coordinated finger and hand movements, may contribute to impaired dexterity even more than bradykinesia per se. However, the impact of limb-kinetic apraxia on ADL remains controversial. Our aim was to identify the strongest predictor of buttoning and unbuttoning in PD. It was hypothesized that coin rotation (a surrogate of limb-kinetic apraxia) represents the most important determinant. MethodsSixty-four right-handed, early to moderate PD patients were recruited from three movement disorder centers (Hoehn andYahr stages 1-3). Buttoning, unbuttoning and coin rotation (right and left hand) represented the target tasks. Motor impairment was assessed according to the Unified Parkinson's Disease Rating Scale. ResultsMultiple linear regression analysis showed that coin rotation with the right hand was the only significant predictor of buttoning (P < 0.001) and unbuttoning (P = 0.002). Notably, measures of bradykinesia or overall motor impairment did not represent significant predictors. ConclusionsConstituting the novel key finding, limb-kinetic apraxia seems to be particularly relevant for ADL requiring dexterity skills in PD, even at early to moderate disease stages. Our results prompt research into the pathophysiological background and therapeutic options to treat limb-kinetic apraxia. The simple coin rotation test provides valuable information about ADL-related dexterity skills. C1 [Foki, T.; Pirker, W.; Kraemmer, J.; Haubenberger, D.; Fischmeister, F. Ph. S.; Auff, E.; Beisteiner, R.] Med Univ Vienna, Dept Neurol, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. [Foki, T.; Fischmeister, F. Ph. S.; Beisteiner, R.] Med Univ Vienna, MR Ctr Excellence, Vienna, Austria. [Vanbellingen, T.; Bohlhalter, S.; Nyffeler, T.] Univ Hosp Bern, Percept & Eye Movement Lab, Inselspital, Dept Neurol, Bern, Switzerland. [Vanbellingen, T.; Bohlhalter, S.; Nyffeler, T.] Univ Hosp Bern, Percept & Eye Movement Lab, Inselspital, Dept Clin Res, Bern, Switzerland. [Vanbellingen, T.; Bohlhalter, S.; Nyffeler, T.] Luzerner Kantonsspital, Neurol & Neurorehabil Ctr, Luzern, Switzerland. [Lungu, C.; Haubenberger, D.] NINDS, Off Clin Director, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Hallett, M.] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Foki, T (reprint author), Med Univ Vienna, Dept Neurol, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. EM thomas.foki@meduniwien.ac.at OI Fischmeister, Florian Ph.S/0000-0003-4573-7666 NR 22 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 EI 1468-1331 J9 EUR J NEUROL JI Eur. J. Neurol. PD AUG PY 2016 VL 23 IS 8 BP 1301 EP 1307 DI 10.1111/ene.13021 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DR7TJ UT WOS:000380102300015 PM 27132653 ER PT J AU Shah, S Caruso, A Cash, H Van Waes, C Allen, CT AF Shah, Sujay Caruso, Andria Cash, Harrison Van Waes, Carter Allen, Clint T. TI Pools of programmed death-ligand within the oral cavity tumor microenvironment: Variable alteration by targeted therapies SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE programmed death; oral cancer; targeted therapy; interferon ID INFILTRATING LYMPHOCYTES; PD-L1 EXPRESSION; ANTI-PD-L1 ANTIBODY; CANCER; MOUSE; ACTIVATION; RESISTANCE; RAPAMYCIN; BLOCKADE; PATHWAY AB BackgroundEnhanced understanding of programmed death-ligand (PD-L) expression in oral cancer is important for establishing rational combinations of emerging immune checkpoint and molecular targeted therapies. MethodsWe assessed PD-L and interferon (IFN) expression in immunogenic murine oral cancer-1 (MOC1) and poorly immunogenic MOC2 cell models after treatment with mammalian target of rapamycin (mTOR) and MEK1/2 small molecule inhibitors in vitro and in vivo. ResultsPD-L1 but not PD-L2 is expressed on MOC1 and 2 cells and is type I and II IFN-dependent. PD-L1 is differentially expressed on cancer and endothelial cells and infiltrating myeloid-derived suppressor cells, macrophages, and regulatory T cells (Tregs) in highly and poorly immunogenic tumors. PD-L1 expression is variably altered after treatment with inhibitors in vivo, with an imperfect relationship to alterations in IFN levels in the tumor microenvironment. ConclusionPD-L1 expressed on cancer and infiltrating immune cells is variably altered by targeted therapies and may, in part, reflect changes in tumor IFN. (c) 2016 Wiley Periodicals, Inc. Head Neck 38:1176-1186, 2016 C1 [Shah, Sujay; Cash, Harrison; Van Waes, Carter; Allen, Clint T.] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, 10 Ctr Dr,CRC 4-2740, Bethesda, MD 20892 USA. [Caruso, Andria] Walter Reed Natl Mil Med Ctr, Dept Otolaryngol Head & Neck Surg, Bethesda, MD USA. [Allen, Clint T.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. RP Allen, CT (reprint author), Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, 10 Ctr Dr,CRC 4-2740, Bethesda, MD 20892 USA. EM allen.clint@nih.gov FU Intramural Program of NIDCD; National Institutes of Health (NIH) Medical Research Scholars Program; NIH FX Contract grant sponsor: This work was supported by the Intramural Program of NIDCD. H.C. was supported through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer, The Doris Duke Charitable Foundation, The Newport Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. NR 31 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD AUG PY 2016 VL 38 IS 8 BP 1176 EP 1186 DI 10.1002/hed.24269 PG 11 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA DR5JY UT WOS:000379940500011 PM 27061215 ER PT J AU Kaji, K Factor, VM Andersen, JB Durkin, ME Tomokuni, A Marquardt, JU Matter, MS Hoang, T Conner, EA Thorgeirsson, SS AF Kaji, Kosuke Factor, Valentina M. Andersen, Jesper B. Durkin, Marian E. Tomokuni, Akira Marquardt, Jens U. Matter, Matthias S. Hoang, Tanya Conner, Elizabeth A. Thorgeirsson, Snorri S. TI DNMT1 Is a Required Genomic Regulator for Murine Liver Histogenesis and Regeneration SO HEPATOLOGY LA English DT Article ID DNA METHYLATION; PROGENITOR CELLS; DUCTULAR REACTIONS; DRUG-METABOLISM; GENE-EXPRESSION; HEPATOCYTES; MICE; STEM; INJURY; MOUSE AB DNA methyltransferase 1 (DNMT1) is an essential regulator maintaining both epigenetic reprogramming during DNA replication and genome stability. We investigated the role of DNMT1 in the regulation of postnatal liver histogenesis under homeostasis and stress conditions. We generated Dnmt1 conditional knockout mice (Dnmt1(Delta alb)) by crossing Dnmt1(fl/fl) with albumin-cyclization recombination transgenic mice. Serum, liver tissues, and primary hepatocytes were collected from 1-week-old to 20-week old mice. The Dnmt1(Delta alb) phenotype was assessed by histology, confocal and electron microscopy, biochemistry, as well as transcriptome and methylation profiling. Regenerative growth was induced by partial hepatectomy and exposure to carbon tetrachloride. The impact of Dnmt1 knockdown was also analyzed in hepatic progenitor cell lines; proliferation, apoptosis, DNA damage, and sphere formation were assessed. Dnmt1 loss in postnatal hepatocytes caused global hypomethylation, enhanced DNA damage response, and initiated a senescence state causing a progressive inability to maintain tissue homeostasis and proliferate in response to injury. The liver regenerated through activation and repopulation from progenitors due to lineage-dependent differences in albumin-cyclization recombination expression, providing a basis for selection of less mature and therefore less damaged hepatic progenitor cell progeny. Consistently, efficient knockdown of Dnmt1 in cultured hepatic progenitor cells caused severe DNA damage, cell cycle arrest, senescence, and cell death. Mx1-cyclization recombination-driven deletion of Dnmt1 in adult quiescent hepatocytes did not affect liver homeostasis. Conclusion: These results establish the indispensable role of DNMT1-mediated epigenetic regulation in postnatal liver growth and regeneration; Dnmt1(Delta alb) mice provide a unique experimental model to study the role of senescence and the contribution of progenitor cells to physiological and regenerative liver growth. C1 [Kaji, Kosuke; Factor, Valentina M.; Andersen, Jesper B.; Durkin, Marian E.; Tomokuni, Akira; Marquardt, Jens U.; Matter, Matthias S.; Hoang, Tanya; Conner, Elizabeth A.; Thorgeirsson, Snorri S.] NCI, Lab Expt Carcinogenesis, Ctr Canc Res, NIH, 37 Convent Dr,MSC 4262,Bldg 37,Room 4146A, Bethesda, MD 20892 USA. [Andersen, Jesper B.] Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark. [Marquardt, Jens U.] Johannes Gutenberg Univ Mainz, Dept Med 1, Mainz, Germany. RP Thorgeirsson, SS (reprint author), NCI, Lab Expt Carcinogenesis, Ctr Canc Res, NIH, 37 Convent Dr,MSC 4262,Bldg 37,Room 4146A, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov OI Andersen , Jesper B/0000-0003-1760-5244 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; German Cancer Aid [DKH 110989]; Volkswagen Foundation (Lichtenberg program) FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. J.U.M. is supported by grants from the German Cancer Aid (DKH 110989) and the Volkswagen Foundation (Lichtenberg program). NR 45 TC 1 Z9 1 U1 3 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD AUG PY 2016 VL 64 IS 2 BP 582 EP 598 DI 10.1002/hep.28563 PG 17 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DR6TP UT WOS:000380034500027 PM 26999257 ER PT J AU Gill, RM Buelow, B Mather, C Joseph, NM Alves, V Brunt, EM Liu, TC Makhlouf, H Marginean, C Nalbantoglu, I Sempoux, C Snover, DC Thung, SN Yeh, MM Ferrell, LD AF Gill, Ryan M. Buelow, Benjamin Mather, Cheryl Joseph, Nancy M. Alves, Venancio Brunt, Elizabeth M. Liu, Ta-Chiang Makhlouf, Hata Marginean, Celia Nalbantoglu, ILKe Sempoux, Christine Snover, Dale C. Thung, Swan N. Yeh, Matthew M. Ferrell, Linda D. TI Hepatic small vessel neoplasm, a rare infiltrative vascular neoplasm of uncertain malignant potential SO HUMAN PATHOLOGY LA English DT Article DE Liver; Hemangioma; Angiosarcoma; Hepatic small vessel neoplasm; GNAQ ID ADULT CAPILLARY HEMANGIOMA; STURGE-WEBER SYNDROME; ANASTOMOSING HEMANGIOMA; MIMICKING-ANGIOSARCOMA; UVEAL MELANOMA; LIVER; MUTATIONS; GNAQ; TUMORS; MULTIPOTENCY AB Characteristic but rare vascular neoplasms in the adult liver composed of small vessels with an infiltrative border were collected from an international group of collaborators over a 5-year period (N = 17). These tumors were teemed hepatic small vessel neoplasm (HSVN), and the histologic differential diagnosis was angiosarcoma (AS). The average age of patients was 54 years (range, 24-83 years). HSVN was more common in men. The average size was 2.1 cm (range, 0.2-5.5 cm). Diagnosis was aided by immunohistochemical stains for vascular lineage (CD31, CD34, FLI-1), which were uniformly positive in HSVN. Immunohistochemical stains (p53, c-Myc, GLUT-1, and Ki-67) for possible malignant potential are suggestive of a benign/low-grade tumor. Capture-based next-generation sequencing (using an assay that targets the coding regions of more than 500 cancer genes) identified an activating hotspot GNAQ mutation in 2 of 3 (67%) tested samples, and one of these cases also had a hotspot mutation in PIK3CA. When compared with hepatic AS (n = 10) and cavernous hemangioma (n = 6), the Ki-67 proliferative index is the most helpful tool in excluding AS, which demonstrated a tumor cell proliferative index greater than 10% in all cases. Strong p53 and diffuse c-Myc staining was also significantly associated with AS but not with HSVN or cavernous hemangioma. There have been no cases with rupture/hemorrhage, disseminated intravascular coagulation, or Kasabach-Merritt syndrome. Thus far, there has been no metastasis or recurrence of HSVN, but complete resection and close clinical follow-up are recommended because the outcome remains unknown. (C) 2016 Elsevier Inc. All rights reserved. C1 [Gill, Ryan M.; Buelow, Benjamin; Mather, Cheryl; Joseph, Nancy M.; Ferrell, Linda D.] Univ Calif San Francisco, Dept Pathol, 505 Parnassus Ave,M590,Box 0102, San Francisco, CA 94143 USA. [Alves, Venancio] Univ Sao Paulo, Dept Pathol, BR-05508090 Sao Paulo, Brazil. [Brunt, Elizabeth M.; Liu, Ta-Chiang; Nalbantoglu, ILKe] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Makhlouf, Hata] NCI, NIH, Rockville, MD 20850 USA. [Marginean, Celia] Ottawa Hosp, Dept Pathol, Ottawa, ON K1H 8L6, Canada. [Sempoux, Christine] CHU Vaudois, Inst Univ Pathol, CH-1011 Lausanne, Switzerland. [Snover, Dale C.] Fairview Southdale Hosp, Edina, MN 55435 USA. [Snover, Dale C.] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55435 USA. [Thung, Swan N.] Mt Sinai Hlth Syst, Dept Pathol, New York, NY 10029 USA. [Yeh, Matthew M.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. RP Gill, RM (reprint author), Univ Calif San Francisco, Dept Pathol, 505 Parnassus Ave,M590,Box 0102, San Francisco, CA 94143 USA. EM ryan.gill@ucsf.edu OI Gill, Ryan/0000-0001-6229-7928 FU UCSF Department of Pathology Research Endowment (San Francisco, CA) FX Research was supported by the UCSF Department of Pathology Research Endowment (San Francisco, CA) awards to R. M. G. NR 34 TC 0 Z9 0 U1 6 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 EI 1532-8392 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 2016 VL 54 BP 143 EP 151 DI 10.1016/j.humpath.2016.03.018 PG 9 WC Pathology SC Pathology GA DR6CP UT WOS:000379990000019 PM 27090685 ER PT J AU Ryan, C Ged, Y Quinn, F Walker, J Kennedy, J Gillham, C Pittaluga, S McDermott, R Vandenberghe, E Grant, C Flavin, R AF Ryan, Ciara Ged, Yasser Quinn, Fiona Walker, Jan Kennedy, John Gillham, Charles Pittaluga, Stefania McDermott, Ronan Vandenberghe, Elisabeth Grant, Cliona Flavin, Richard TI Classical Hodgkin Lymphoma Arising Adjacent to a Breast Implant SO INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE breast; lymphoma; breast implant; Hodgkin lymphoma; follicular lymphoma ID LARGE-CELL LYMPHOMA; CENTER B-CELL; OF-THE-LITERATURE; FOLLICULAR LYMPHOMA; COMPOSITE LYMPHOMAS; DISEASE; ASSOCIATION; ENTITY; SPECTRUM; WOMEN AB Breast implant-associated lymphoma has recently gained wide recognition. Anaplastic large cell lymphoma (ALCL) is the most frequently diagnosed subtype in this setting but the spectrum is broadening. A 66-year-old woman developed swelling and itch around her saline implant 6 years after its insertion. Imaging revealed a fluid collection surrounding the implant with an adjacent mass. Microscopy showed sclerotic tissue punctuated by discrete cellular nodules comprising small lymphocytes, eosinophils and interspersed large atypical Hodgkin Reed-Sternberg (HRS)-like cells. The HRS-like cells stained positively for CD30 and CD15 by immunohistochemistry. Small T-lymphocytes formed rosettes around HRS-like cells. Appearances were consistent with classical Hodgkin lymphoma (HL). Multiplex polymerase chain reaction demonstrated no clonal rearrangements of immunoglobulin or T-cell receptor genes, however, a t(14;18)(q32;q21)BCL2-JH translocation involving the major breakpoint region of the bcl2 gene was present. Staging positron emission tomography-computed tomography scan revealed FDG-avid masses in the right axilla and pelvis. Subsequent pathological examination identified low-grade follicular lymphoma (FL) with a t(14;18) translocation at these sites. To our knowledge, this is the first case of HL arising adjacent to a breast implant. An awareness of this diagnosis is important as classical HL, with its prominent mixed inflammatory background, may be overlooked as a reactive process when histologically assessing capsulectomy specimens. It is also important in the differential diagnosis for implant-associated ALCL as both contain large atypical CD30-positive cells highlighting the need for full immunohistochemical and molecular workup in such cases. This case also adds to the large body of literature regarding the association between HL and FL. C1 [Ryan, Ciara; Ged, Yasser; Quinn, Fiona; Walker, Jan; Kennedy, John; Gillham, Charles; McDermott, Ronan; Vandenberghe, Elisabeth; Grant, Cliona; Flavin, Richard] St James Hosp, Dublin, Ireland. [Pittaluga, Stefania] NCI, NIH, Bethesda, MD USA. RP Ryan, C (reprint author), St James Hosp, Dept Histopathol, Dublin 8, Ireland. EM ciaraeryan@gmail.com NR 36 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1066-8969 EI 1940-2465 J9 INT J SURG PATHOL JI Int. J. Surg. Pathol. PD AUG PY 2016 VL 24 IS 5 BP 448 EP 455 DI 10.1177/1066896916632587 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA DR5PA UT WOS:000379953700013 PM 26888955 ER PT J AU Byun, H Kwon, S Ahn, HJ Liu, H Forrest, D Demb, JB Kim, IJ AF Byun, Haewon Kwon, Soohyun Ahn, Hee-Jeong Liu, Hong Forrest, Douglas Demb, Jonathan B. Kim, In-Jung TI Molecular Features Distinguish Ten Neuronal Types in the Mouse Superficial Superior Colliculus SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE retinal ganglion cells; transcription factors; cell adhesion molecules; neuropeptides; calcium binding proteins; RRID: nif-0000-00509; RRID: nif-0000-30467; RRID: AB_2167523; RRID: AB_91338; RRID: AB_10000240; RRID: AB_732196; RRID: AB_2298772; RRID: AB_10000344; RRID: AB_1288870; RRID: AB_518614; RRID: AB_2079751; RRID: AB_305869 ID LATERAL GENICULATE-NUCLEUS; RETINAL GANGLION-CELLS; PARVALBUMIN-IMMUNOREACTIVE NEURONS; RECEPTIVE-FIELD PROPERTIES; POSTNATAL-DEVELOPMENT; CORTICAL INTERNEURONS; TRANSCRIPTION FACTOR; PATTERNED ACTIVITY; EYE ENUCLEATION; GAZE SHIFTS AB The superior colliculus (SC) is a midbrain center involved in controlling head and eye movements in response to inputs from multiple sensory modalities. Visual inputs arise from both the retina and visual cortex and converge onto the superficial layer of the SC (sSC). Neurons in the sSC send information to deeper layers of the SC and to thalamic nuclei that modulate visually guided behaviors. Presently, our understanding of sSC neurons is impeded by a lack of molecular markers that define specific cell types. To better understand the identity and organization of sSC neurons, we took a systematic approach to investigate gene expression within four molecular families: transcription factors, cell adhesion molecules, neuropeptides, and calcium binding proteins. Our analysis revealed 12 molecules with distinct expression patterns in mouse sSC: cadherin 7, contactin 3, netrin G2, cadherin 6, protocadherin 20, retinoid-related orphan receptor beta, brain-specific homeobox/POU domain protein 3b, Ets variant gene 1, substance P, somatostatin, vasoactive intestinal polypeptide, and parvalbumin. Double labeling experiments, by either in situ hybridization or immunostaining, demonstrated that the 12 molecular markers collectively define 10 different sSC neuronal types. The characteristic positions of these cell types divide the sSC into four distinct layers. The 12 markers identified here will serve as valuable tools to examine molecular mechanisms that regulate development of sSC neuronal types. These markers could also be used to examine the connections between specific cell types that form retinocollicular, corticocollicular, or colliculothalamic pathways. (C) 2016 Wiley Periodicals, Inc. C1 [Byun, Haewon; Kwon, Soohyun; Ahn, Hee-Jeong; Demb, Jonathan B.; Kim, In-Jung] Yale Univ, Sch Med, Dept Ophthalmol & Visual Sci, 333 Cedar St, New Haven, CT 06511 USA. [Demb, Jonathan B.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, 333 Cedar St, New Haven, CT 06511 USA. [Kim, In-Jung] Yale Univ, Sch Med, Dept Neurosci, 333 Cedar St, New Haven, CT 06511 USA. [Liu, Hong; Forrest, Douglas] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. RP Kim, IJ (reprint author), 300 George St,Suite 8100, New Haven, CT 06511 USA. EM in-jung.kim@yale.edu OI Demb, Jonathan/0000-0003-2227-9041 FU National Eye Institute, National Institutes of Health [R00 EY019355, R01 EY014454]; Whitehall Foundation; E. Matilda Ziegler Foundation; Research to Prevent Blindness; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX Grant sponsor: National Eye Institute, National Institutes of Health; Grant numbers: R00 EY019355 and R01 EY014454; Grant sponsor: the Whitehall Foundation; Grant sponsor: the E. Matilda Ziegler Foundation; Grant sponsor: an unrestricted grant from Research to Prevent Blindness to Yale University; Grant sponsor: the intramural research program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 100 TC 0 Z9 0 U1 3 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD AUG 1 PY 2016 VL 524 IS 11 BP 2300 EP 2321 DI 10.1002/cne.23952 PG 22 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA DR5TI UT WOS:000379964900008 PM 26713509 ER PT J AU Weisenthal, SJ Folio, L Kovacs, W Seff, A Derderian, V Summers, RM Yao, JH AF Weisenthal, Samuel J. Folio, Les Kovacs, William Seff, Ari Derderian, Vana Summers, Ronald M. Yao, Jianhua TI Open-Source Radiation Exposure Extraction Engine (RE3) with Patient-Specific Outlier Detection SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE Radiation dose; Quality control; Software design; PACS implementation; PACS integration; Open source; Medical informatics applications; Imaging informatics; Data mining; Data extraction; Computers in medicine; Clinical workflow; Automated measurement; Statistical analysis; Quality assurance ID COMPUTED-TOMOGRAPHY; CANCER-RISKS; CT AB We present an open-source, picture archiving and communication system (PACS)-integrated radiation exposure extraction engine (RE3) that provides study-, series-, and slice-specific data for automated monitoring of computed tomography (CT) radiation exposure. RE3 was built using open-source components and seamlessly integrates with the PACS. RE3 calculations of dose length product (DLP) from the Digital imaging and communications in medicine (DICOM) headers showed high agreement (R (2) = 0.99) with the vendor dose pages. For study-specific outlier detection, RE3 constructs robust, automatically updating multivariable regression models to predict DLP in the context of patient gender and age, scan length, water-equivalent diameter (D (w)), and scanned body volume (SBV). As proof of concept, the model was trained on 811 CT chest, abdomen + pelvis (CAP) exams and 29 outliers were detected. The continuous variables used in the outlier detection model were scan length (R (2) = 0.45), D (w) (R (2) = 0.70), SBV (R (2) = 0.80), and age (R (2) = 0.01). The categorical variables were gender (male average 1182.7 +/- 26.3 and female 1047.1 +/- 26.9 mGy cm) and pediatric status (pediatric average 710.7 +/- 73.6 mGy cm and adult 1134.5 +/- 19.3 mGy cm). C1 [Weisenthal, Samuel J.; Folio, Les; Kovacs, William; Seff, Ari; Derderian, Vana; Summers, Ronald M.; Yao, Jianhua] NIH, Ctr Clin, Radiol & Imaging Sci, Clin Image Proc Serv, 10 Ctr Dr, Bethesda, MD 20892 USA. [Weisenthal, Samuel J.] Univ Rochester, Med Ctr, 601 Elmwood Ave, Rochester, NY 14642 USA. RP Yao, JH (reprint author), NIH, Ctr Clin, Radiol & Imaging Sci, Clin Image Proc Serv, 10 Ctr Dr, Bethesda, MD 20892 USA. EM samuel_weisenthal@urmc.rochester.edu; jyao@cc.nih.gov FU Intramural Research Program of the National Institutes of Health, Clinical Center FX This research was funded by the Intramural Research Program of the National Institutes of Health, Clinical Center. NR 26 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0897-1889 EI 1618-727X J9 J DIGIT IMAGING JI J. Digit. Imaging PD AUG PY 2016 VL 29 IS 4 BP 406 EP 419 DI 10.1007/s10278-015-9852-y PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DR2RI UT WOS:000379751200001 PM 26644157 ER PT J AU Roy, B Chheda, SG Bates, C Dunn, K Karani, R Willett, LL AF Roy, Brita Chheda, Shobhina G. Bates, Carol Dunn, Kathel Karani, Reena Willett, Lisa L. TI For the General Internist: A Summary of Key Innovations in Medical Education SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Review DE medical education; medical education-undergraduate; medical education-graduate; review ID CARE; PROGRAM; QUALITY; EXERCISE; STUDENTS; ASSOCIATION; RESIDENTS; TEAMWORK; OUTCOMES; FELLOWS AB We conducted a review of published medical education articles to identify high-quality research and innovation relevant to educators in general medicine. Our review team consisted of six general internists with expertise in medical education and a professional medical librarian. We manually searched 15 journals in pairs (a total of 3062 citations) for original research articles in medical education published in 2014. Each pair of reviewers independently rated the relevance, importance, and generalizability of articles on medical education in their assigned journals using a 27-point scale (maximum of 9 points for each characteristic). From this list, each team member independently reviewed the 22 articles that received a score of 20 or higher from both initial reviewers, and for each selected article rated the quality and global relevance for the generalist educator. We included the seven top-rated articles for presentation in this review, and categorized the studies into four general themes: continuity clinic scheduling, remediation, interprofessional education, and quality improvement and patient safety. We summarized key findings and identified significant limitations of each study. Further studies assessing patient outcomes are needed to strengthen the literature in medical education. This summary of relevant medical education articles can inform future research, teaching, and practice. C1 [Roy, Brita] Yale Univ, Sch Med, Sect Gen Internal Med, POB 208025, New Haven, CT 06520 USA. [Chheda, Shobhina G.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Bates, Carol] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Dunn, Kathel] Natl Lib Med, Bethesda, MD USA. [Karani, Reena] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Willett, Lisa L.] Univ Alabama Birmingham, Birmingham, AL USA. RP Roy, B (reprint author), Yale Univ, Sch Med, Sect Gen Internal Med, POB 208025, New Haven, CT 06520 USA. EM brita.roy@yale.edu NR 26 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2016 VL 31 IS 8 BP 941 EP 946 DI 10.1007/s11606-016-3669-3 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DR4KY UT WOS:000379871600025 PM 27084757 ER PT J AU Brown, GT Kleiner, DE AF Brown, Gregory Thomas Kleiner, David E. TI Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Steatohepatitis; Liver biopsy; Steatosis; Histology ID MORBIDLY OBESE-PATIENTS; BARIATRIC SURGERY; GASTRIC BYPASS; SCORING SYSTEM; PROGRESSION; STEATOSIS; CIRRHOSIS; FEATURES; LESIONS; WEIGHT AB Nonalcoholic fatty liver disease (NAFLD) is the liver injury most often associated with disorders of insulin resistance, including obesity, diabetes and the metabolic syndrome. The term encompasses several patterns of liver injury, including a relatively benign condition of steatosis without hepatocellular injury, nonalcoholic steatohepatitis (NASH), and a pattern of zone 1 steatosis, inflammation and fibrosis mainly observed in prepubertal children. Staging and grading systems have been developed to characterize the histological changes in NAFLD, mainly as a tool for clinical research. The histological features of NAFLD across these different manifestations and the scoring systems used to evaluate disease severity are discussed. Published by Elsevier Inc. C1 [Brown, Gregory Thomas; Kleiner, David E.] NCI, Pathol Lab, Bldg 10,Room 25235,MSC 1500,10 Ctr Dr, Bethesda, MD 20892 USA. RP Kleiner, DE (reprint author), NCI, Pathol Lab, Bldg 10,Room 25235,MSC 1500,10 Ctr Dr, Bethesda, MD 20892 USA. EM kleinerd@mail.nih.gov OI Kleiner, David/0000-0003-3442-4453 FU Intramural Research Program of the National Institutes of Health, National Cancer institute FX This work was funded by the Intramural Research Program of the National Institutes of Health, National Cancer institute. NR 56 TC 2 Z9 2 U1 3 U2 14 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD AUG PY 2016 VL 65 IS 8 BP 1080 EP 1086 DI 10.1016/j.metabol.2015.11.008 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DR4RH UT WOS:000379889400007 PM 26775559 ER PT J AU de Wit, E van Doremalen, N Falzarano, D Munster, VJ AF de Wit, Emmie van Doremalen, Neeltje Falzarano, Darryl Munster, Vincent J. TI SARS and MERS: recent insights into emerging coronaviruses SO NATURE REVIEWS MICROBIOLOGY LA English DT Review ID RESPIRATORY SYNDROME-CORONAVIRUS; PAPAIN-LIKE PROTEASE; RECEPTOR-BINDING DOMAIN; HUMAN MONOCLONAL-ANTIBODY; SAUDI-ARABIA; COV INFECTION; DROMEDARY CAMELS; CLINICAL-FEATURES; SPIKE PROTEIN; VIRAL LOAD AB The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 marked the second introduction of a highly pathogenic coronavirus into the human population in the twenty-first century. The continuing introductions of MERS-CoV from dromedary camels, the subsequent travel-related viral spread, the unprecedented nosocomial outbreaks and the high case-fatality rates highlight the need for prophylactic and therapeutic measures. Scientific advancements since the 2002-2003 severe acute respiratory syndrome coronavirus (SARS-CoV) pandemic allowed for rapid progress in our understanding of the epidemiology and pathogenesis of MERS-CoV and the development of therapeutics. In this Review, we detail our present understanding of the transmission and pathogenesis of SARS-CoV and MERS-CoV, and discuss the current state of development of measures to combat emerging coronaviruses. C1 [de Wit, Emmie; van Doremalen, Neeltje; Munster, Vincent J.] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. [Falzarano, Darryl] Univ Saskatchewan, Vaccine & Infect Dis Org, Int Vaccine Ctr, 120 Vet Rd, Saskatoon, SK S7N 5E3, Canada. [Falzarano, Darryl] Univ Saskatchewan, Dept Vet Microbiol, 120 Vet Rd, Saskatoon, SK S7N 5E3, Canada. RP Munster, VJ (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. EM vincent.munster@nih.gov OI de Wit, Emmie/0000-0002-9763-7758 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health FX The work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health. NR 159 TC 9 Z9 9 U1 23 U2 45 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 EI 1740-1534 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD AUG PY 2016 VL 14 IS 8 BP 523 EP 534 DI 10.1038/nrmicro.2016.81 PG 12 WC Microbiology SC Microbiology GA DS1RV UT WOS:000380376300010 PM 27344959 ER PT J AU Amundsen, C Richter, H Menefee, S Komesu, Y Arya, L Gregory, WT Myers, D Zyczynski, H Vasavada, S Nolen, T Wallace, D Meikle, S AF Amundsen, C. Richter, H. Menefee, S. Komesu, Y. Arya, L. Gregory, W. T. Myers, D. Zyczynski, H. Vasavada, S. Nolen, T. Wallace, D. Meikle, S. TI THE REFRACTORY OVERACTIVE BLADDER: SACRAL NEUROMODULATION VS. BOTULINUM TOXIN ASSESSMENT (ROSETTA) SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Annual Meeting of the International-Continence-Society (ICS) CY SEP 13-16, 2016 CL Tokyo, JAPAN SP Int Continence Soc C1 [Amundsen, C.] Duke Univ, Durham, NC 27706 USA. [Richter, H.] Univ Alabama, Tuscaloosa, AL 35487 USA. [Menefee, S.] Kaiser Permanente San Diego, San Diego, CA USA. [Komesu, Y.] Univ New Mexico, Albuquerque, NM 87131 USA. [Arya, L.] Univ Penn, Philadelphia, PA 19104 USA. [Gregory, W. T.] Oregon Hlth & Sci Univ, Portland, OR USA. [Myers, D.] Brown Univ, Providence, RI 02912 USA. [Zyczynski, H.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Vasavada, S.] Cleveland Clin, Cleveland, OH 44106 USA. [Nolen, T.; Wallace, D.] RTI Int, Res Triangle Pk, NC USA. [Meikle, S.] NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD AUG PY 2016 VL 35 SU 4 MA 1 BP S23 EP S24 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA DR4XQ UT WOS:000379907200002 ER PT J AU Brubaker, L Thomas-White, K Kliethermes, S Rickey, L Lukacz, E Richter, H Moalli, P Zimmern, P Norton, P Kusek, J Wolfe, A AF Brubaker, L. Thomas-White, K. Kliethermes, S. Rickey, L. Lukacz, E. Richter, H. Moalli, P. Zimmern, P. Norton, P. Kusek, J. Wolfe, A. TI EVALUATION OF THE URINARY MICROBIOTA OF WOMEN WITH UNCOMPLICATED STRESS URINARY INCONTINENCE SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Annual Meeting of the International-Continence-Society (ICS) CY SEP 13-16, 2016 CL Tokyo, JAPAN SP Int Continence Soc C1 [Brubaker, L.] Loyola Univ, Dept OB Gyne & Urol, Chicago, IL 60611 USA. [Brubaker, L.] Loyola Univ, Dept Female Pelv Med & Reconstruct Surg, Chicago, IL 60611 USA. [Thomas-White, K.; Wolfe, A.] Loyola Univ, Dept Microimmuno, Chicago, IL 60611 USA. [Kliethermes, S.] Loyola Univ, Dept Publ Hlth Sci, Chicago, IL 60611 USA. [Rickey, L.] Yale Univ, Dept Urol, New Haven, CT 06520 USA. [Lukacz, E.] Univ Calif San Diego, Dept Reprod Med, La Jolla, CA 92093 USA. [Richter, H.] Univ Alabama Birmingham, Dept OB Gyne, Birmingham, AL USA. [Moalli, P.] Univ Pittsburgh, Dept OG Gyne, Pittsburgh, PA 15260 USA. [Zimmern, P.] Univ Texas Southwestern, Dept Urol, Dallas, TX USA. [Norton, P.] Univ Utah, Dept OB Gyne, Salt Lake City, UT 84112 USA. [Kusek, J.] NIDDK, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD AUG PY 2016 VL 35 SU 4 MA 14 BP S42 EP S43 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA DR4XQ UT WOS:000379907200015 ER PT J AU Li, Y McGreal, S Zhao, J Huang, RL Zhou, Y Zhong, H Xia, MH Ding, WX AF Li, Yuan McGreal, Steven Zhao, Jean Huang, Ruili Zhou, Yan Zhong, Hua Xia, Menghang Ding, Wen-Xing TI A cell-based quantitative high-throughput image screening identified novel autophagy modulators SO PHARMACOLOGICAL RESEARCH LA English DT Article DE Autophagy; High-throughput screening; GFP-LC3; mTOR; Dopamine receptor ID MICE; MACROAUTOPHAGY; MACHINERY; SURVIVAL; PATHWAY; DISEASE; INJURY; LIVER AB Macroautophagy is a major cellular degradation pathway for long-lived proteins and cellular organelles to maintain cellular homeostasis. Reduced autophagy has been implicated in neurodegenerative diseases, metabolic syndrome, and tumorigenesis. In contrast, increased autophagy has been shown to protect against tissue injury and aging. Here we employed a cell-based quantitative high-throughput image screening (qHTS) for autophagy modulators using mouse embryonic fibroblasts (MEFs) that are stably expressing GFP-LC3. The library of pharmacologically active compounds (LOPAC) was used to screen for the autophagy modulators in compounds alone or in combination with the lysosome inhibitor chloroquine (CQ). The GFP-LC3 puncta were then quantified to measure autophagic flux. The primary screening revealed 173 compounds with efficacy more than 40%. These compounds were cherry-picked and re-tested at multiple different concentrations using the same assay. A number of novel autophagy inducers, inhibitors, and modulators with dual-effects on autophagy were identified from the cherry-pick screening. Interestingly, we found a group of compounds that induce autophagy are related to dopamine receptors and are commonly used as clinical psychiatric drugs. Among them, indatraline hydrochloride (IND), a dopamine inhibitor, and chlorpromazine hydrochloride (CPZ) and fluphenazine dihydrochloride (FPZ), two dopamine receptor antagonists, were further evaluated. We found that FPZ-induced autophagy through mTOR inhibition but IND and CPZ induced autophagy in an mTOR-independent manner. Our data suggest that image-based autophagic flux qHTS can efficiently identify autophagy inducers and inhibitors. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Li, Yuan; McGreal, Steven; Ding, Wen-Xing] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, MS 1018 3901 Rainbow Blvd, Kansas City, KS 66160 USA. [Zhao, Jean; Huang, Ruili; Xia, Menghang] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Zhou, Yan; Zhong, Hua] Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Dept Pulm, Shanghai 200030, Peoples R China. RP Ding, WX (reprint author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, MS 1018 3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM wxding@kumc.edu FU NIAAA [R01 AA020518, R01 DK102142]; National Center for Research Resources [5P20RR021940]; National Institute of General Medical Sciences [8P20 GM103549]; Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P20 GM103418]; KUMC Research Institute; NIH Clinical and Translational Science Award [UL1TR000001]; National Center for Advancing Translational Sciences, National Institutes of Health; NIH COBRE [P20GM104936]; NIH [S10RR027564]; [T32 ES007079] FX The research was supported in part by the NIAAA funds R01 AA020518, R01 DK102142, National Center for Research Resources (5P20RR021940), the National Institute of General Medical Sciences (8P20 GM103549), T32 ES007079, an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (P20 GM103418) and an award received in an internal Lied basic science grant program of the KUMC Research Institute, with support from a NIH Clinical and Translational Science Award grant (UL1TR000001, formerly UL1RR033179), and the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health. The authors would like to thank Barbara Fegley from the electron microscopy core facility at the University of Kansas Medical Center for her excellent assistance for EM studies. The electron microscopy core facility is supported in part, by NIH COBRE grant P20GM104936. The JEOL JEM-1400 TEM used in the study was purchased with funds from NIH grant S10RR027564. NR 33 TC 0 Z9 0 U1 4 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD AUG PY 2016 VL 110 BP 35 EP 49 DI 10.1016/j.phrs.2016.05.004 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ9VQ UT WOS:000379557800004 PM 27168224 ER PT J AU Heissler, SM Sellers, JR AF Heissler, Sarah M. Sellers, James R. TI Kinetic Adaptations of Myosins for Their Diverse Cellular Functions SO TRAFFIC LA English DT Review DE actin; allostery; cation; cytoskeleton; mechanoenzymology; molecular motor; muscle; myosin; transporter ID SMOOTH-MUSCLE MYOSIN; DUTY RATIO MOTOR; CLASS-V MYOSIN; LOAD-DEPENDENT KINETICS; ACTIN-BASED MOTOR; HAND-OVER-HAND; MOLECULAR MOTOR; CARGO-BINDING; DICTYOSTELIUM-DISCOIDEUM; 3-DIMENSIONAL STRUCTURE AB Members of the myosin superfamily are involved in all aspects of eukaryotic life. Their function ranges from the transport of organelles and cargos to the generation of membrane tension, and the contraction of muscle. The diversity of physiological functions is remarkable, given that all enzymatically active myosins follow a conserved mechanoenzymatic cycle in which the hydrolysis of ATP to ADP and inorganic phosphate is coupled to either actin-based transport or tethering of actin to defined cellular compartments. Kinetic capacities and limitations of a myosin are determined by the extent to which actin can accelerate the hydrolysis of ATP and the release of the hydrolysis products and are indispensably linked to its physiological tasks. This review focuses on kinetic competencies that - together with structural adaptations - result in myosins with unique mechanoenzymatic properties targeted to their diverse cellular functions. C1 [Heissler, Sarah M.; Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, 50 South Dr,B50-3523, Bethesda, MD 20892 USA. RP Heissler, SM (reprint author), NHLBI, Lab Mol Physiol, NIH, 50 South Dr,B50-3523, Bethesda, MD 20892 USA. EM sarah.heissler@nih.gov FU National Heart, Lung, and Blood Institute FX We thank Dr Krishna Chinthalapudi, The Scripps Research Institute, for the contribution of Figure 1C. We apologize to all colleagues whose excellent work could not be included in the review due to space limitations. This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute. NR 197 TC 1 Z9 1 U1 13 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-9219 EI 1600-0854 J9 TRAFFIC JI Traffic PD AUG PY 2016 VL 17 IS 8 SI SI BP 839 EP 859 DI 10.1111/tra.12388 PG 21 WC Cell Biology SC Cell Biology GA DR5PU UT WOS:000379955700003 PM 26929436 ER PT J AU O'Brien, F Klauer, SG Ehsani, J Simons-Morton, BG AF O'Brien, Fearghal Klauer, Sheila G. Ehsani, Johnathon Simons-Morton, Bruce G. TI Changes over 12 months in eye glances during secondary task engagement among novice drivers SO ACCIDENT ANALYSIS AND PREVENTION LA English DT Article DE Young novice drivers; Eye glances; Secondary task engagement; Test track; Experience ID VISUAL-ATTENTION; EXPERIENCE; CRASHES; RISK; DISTRACTION AB During their first year of driving, crash rates among novice drivers are very high but decline rapidly. However, it is not clear what skills or knowledge they are acquiring in this period. Secondary task engagement while driving is a contributing factor to many traffic collisions and some of the elevated crash risk among novices could be explained by greater prevalence or longer periods of eyes off the road while engaging in these non-driving tasks. The current study looked at the eye glances of novice teen drivers engaging in secondary tasks on a test track at 0 and 12 months of licensure and compared their performance with their parents. Novices improved from 0 to 12 months on their longest single glance off the forward roadway and total percentage of time for eyes off the forward roadway, but parents remained stable. Compared with their parents, the longest single glance off the forward roadway was longer for novices at 0 months, but by 12 months there was no difference between the groups. However, for total percentage of time for eyes off the forward roadway, novices performed the same as their parents at 0 months and actually had shorter times at 12 months. These findings could reflect the combined development of driving skills over 12 months and the relative experience that modern teenagers have with portable electronic devices. The results suggest that novice drivers are particularly poor at engaging with secondary tasks while driving. Published by Elsevier Ltd. C1 [O'Brien, Fearghal; Ehsani, Johnathon; Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Bethesda, MD 20892 USA. [Klauer, Sheila G.] Virginia Tech, Transportat Inst, 3500 Transportat Res Plaza, Blacksburg, VA 24061 USA. RP O'Brien, F (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, 6100 Execut Blvd, Bethesda, MD 20892 USA. EM obrienfk@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-5-3405]; National Highway Traffic Safety Administration (NHTSA) FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, contract # N01-HD-5-3405 and the National Highway Traffic Safety Administration (NHTSA). NR 25 TC 1 Z9 1 U1 7 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0001-4575 EI 1879-2057 J9 ACCIDENT ANAL PREV JI Accid. Anal. Prev. PD AUG PY 2016 VL 93 BP 48 EP 54 DI 10.1016/j.aap.2016.04.022 PG 7 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA DQ9WB UT WOS:000379558900006 PM 27177392 ER PT J AU Jiraporn, P Leelalai, V Tong, SH AF Jiraporn, Pornsit Leelalai, Veeranuch Tong, Shenghui TI The effect of managerial ability on dividend policy: how do talented managers view dividend payouts? SO APPLIED ECONOMICS LETTERS LA English DT Article DE Dividends; dividend policy; dividend payouts; managerial ability; managerial talent; G34; G35 ID GEOGRAPHIC IDENTIFICATION; STOCK-PRICES; DAY BEHAVIOR; VALUATION; VARIABLES AB We contribute to the literature on dividend policy by relaxing Miller and Modigliani's (1961) perfect capital market assumptions and incorporating a factor that has not been investigated before, that is, variation in managerial ability. Based on more than 24000 observations across over 20years (1989-2011), our results show that firms with more talented executives are more likely to pay dividends and, among firms that pay dividends, pay significantly larger dividends. A rise in managerial ability by one SD raises the propensity to pay dividends by 27% and, for firms that pay dividends, increases dividend payouts by 29%. Our results are consistent with the notion that talented managers, confident in their ability to keep the firm profitable, are more willing to pay larger dividends because they are less concerned about having to reduce dividends in the future. Further analysis shows that our results are not likely vulnerable to endogeneity. C1 [Jiraporn, Pornsit] Penn State Univ, Sch Grad Profess Studies, Malvern, PA 19355 USA. [Jiraporn, Pornsit; Leelalai, Veeranuch] NIDA, Bangkok, Thailand. [Tong, Shenghui] CUFE, Beijing, Peoples R China. RP Jiraporn, P (reprint author), Penn State Univ, Sch Grad Profess Studies, Malvern, PA 19355 USA.; Jiraporn, P (reprint author), NIDA, Bangkok, Thailand. EM pxj11@psu.edu NR 22 TC 0 Z9 0 U1 5 U2 7 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1350-4851 EI 1466-4291 J9 APPL ECON LETT JI Appl. Econ. Lett. PD AUG PY 2016 VL 23 IS 12 BP 857 EP 862 DI 10.1080/13504851.2015.1114572 PG 6 WC Economics SC Business & Economics GA DQ7ZB UT WOS:000379427000008 ER PT J AU Badri, MK Zhang, HH Ohyama, Y Venkitapathi, S Alamoudi, A Kamiya, N Takeda, H Ray, M Scott, G Tsuji, T Kunieda, T Mishina, Y Mochida, Y AF Badri, Mohammed K. Zhang, Honghao Ohyama, Yoshio Venkitapathi, Sundharamani Alamoudi, Ahmed Kamiya, Nobuhiro Takeda, Haruko Ray, Manas Scott, Greg Tsuji, Takehito Kunieda, Tetsuo Mishina, Yuji Mochida, Yoshiyuki TI Expression of Evc2 in craniofacial tissues and craniofacial bone defects in Evc2 knockout mouse SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE Ellis-van Creveld syndrome; EVC2; Expression; Craniofacial bone; Development; Knockout (KO) mouse ID VAN-CREVELD-SYNDROME; WEYERS ACRODENTAL DYSOSTOSIS; HEDGEHOG SIGNAL; GROWTH-PLATE; CILIA; GENE; MUTATIONS; COMPLEX; PROTEIN; BASE AB Objective: Our objectives were to determine the expression of EVC2 in craniofacial tissues and investigate the effect of Evc2 deficiency on craniofacial bones using Evc2 knockout (KO) mouse model. Design: Evc2 KO mice were generated by introducing a premature stop codon followed by the Internal Ribosomal Entry Site fused to beta-galactosidase (LacZ). Samples from wild-type (WT), heterozygous (Het) and homozygous Evc2 KO mice were prepared. LacZ staining and immunohistochemistry (IHC) with anti-beta-galactosidase, anti-EVC2 and anti-SOX9 antibodies were performed. The craniofacial bones were stained with alcian blue and alizarin red. Results: The LacZ activity in KO was mainly observed in the anterior parts of viscerocranium. The Evc2-expressing cells were identified in many cartilageous regions by IHC with anti-beta-galactosidase antibody in KO and Het embryos. The endogenous EVC2 protein was observed in these areas in WT embryos. Double labeling with anti-SOX9 antibody showed that these cells were mainly chondrocytes. At adult stages, the expression of EVC2 was found in chondrocytes of nasal bones and spheno-occipital synchondrosis, and osteocytes and endothelial-like cells of the premaxilla and mandible. The skeletal double staining demonstrated that craniofacial bones, where the expression of EVC2 was observed, in KO had the morphological defects as compared to WT. Conclusion: To our knowledge, our study was the first to identify the types of Evc2-expressing cells in craniofacial tissues. Consistent with the expression pattern, abnormal craniofacial bone morphology was found in the Evc2 KO mice, suggesting that EVC2 may be important during craniofacial growth and development. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Badri, Mohammed K.; Ohyama, Yoshio; Venkitapathi, Sundharamani; Alamoudi, Ahmed; Mochida, Yoshiyuki] Boston Univ, Dept Mol & Cell Biol, Henry M Goldman Sch Dent Med, 700 Albany St, Boston, MA 02118 USA. [Badri, Mohammed K.] Taibah Univ, Coll Dent, Dept Pediat Dent & Orthodont, Al Madinah Al Munawarah, Saudi Arabia. [Zhang, Honghao; Kamiya, Nobuhiro; Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, 1011 N Univ Ave, Ann Arbor, MI 48109 USA. [Kamiya, Nobuhiro; Mishina, Yuji] NIEHS, Lab Reprod & Dev Toxicol, 111 TW Alexander Dr, Res Triangle Pk, NC 27009 USA. [Takeda, Haruko] Univ Liege, Unit Anim Genom, GIGA R, 1 Ave Hop, B-4000 Liege, Belgium. [Takeda, Haruko] Univ Liege, Fac Vet Med, 1 Ave Hop, B-4000 Liege, Belgium. [Ray, Manas; Scott, Greg; Mishina, Yuji] NIEHS, Knock Out Core, 111 TW Alexander Dr, Res Triangle Pk, NC 27009 USA. [Tsuji, Takehito; Kunieda, Tetsuo] Okayama Univ, Grad Sch Environm & Life Sci, Okayama, Japan. RP Mochida, Y (reprint author), Boston Univ, Dept Mol & Cell Biol, Henry M Goldman Sch Dent Med, 700 Albany St, Boston, MA 02118 USA. EM mochida@bu.edu FU NIDCR/NIH [DE019527, DE020843]; CTSA [UL1-TR000157]; Intramural Research Program of the NIEHS/NIH [ES071003-0] FX This study was supported by NIDCR/NIH grants DE019527 (Y. Mochida.), DE020843 (Y. Mishina) and in part by CTSA UL1-TR000157. This study was also supported by the Intramural Research Program of the NIEHS/NIH to Y. Mishina (ES071003-0). NR 30 TC 0 Z9 0 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 EI 1879-1506 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD AUG PY 2016 VL 68 BP 142 EP 152 DI 10.1016/j.archoralbio.2016.05.002 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DQ7EL UT WOS:000379369600020 PM 27164562 ER PT J AU Prenc, E Pulanic, D Pucic-Bakovic, M Pezer, M Desnica, L Vrhovac, R Nemet, D Pavletic, SZ AF Prenc, Ema Pulanic, Drazen Pucic-Bakovic, Maja Pezer, Marija Desnica, Lana Vrhovac, Radovan Nemet, Damir Pavletic, Steven Z. TI Potential of glycosylation research in graft versus host disease after allogeneic hematopoietic stem cell transplantation SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE Glycan; Glycosylation; Graft versus host disease; Hematopoietic stem cell transplantation ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; SYSTEMIC-LUPUS-ERYTHEMATOSUS; MEASURING THERAPEUTIC RESPONSE; CLINICAL-TRIALS; CHRONIC GVHD; SJOGRENS-SYNDROME; ACTIVATING FACTOR; B-CELLS; AUTOIMMUNE-DISEASES AB Background: Glycans, complex oligosaccharides, are directly involved in almost every biological process, have a fundamental role in the immune system, and are probably involved in nearly every human disease. However, glycosylation has been greatly ignored in the area of allogeneic hematopoietic stem cell transplantation (alloHSCT) and graft versus host disease (GVHD). Both acute and chronic GVHD are multisystemic debilitating immunological disturbances arising after alloHSCT. Scope of review: In this paper, we review the glycosylation research already done in the field of alloHSCT and GVHD and evaluate further potential of glycan analysis in GVHD by looking into resembling inflammatory and autoimmune conditions. Major Conclusions: Glycan research could bring significant improvement in alloHSCI. procedure with reduction in following complications, such as GVHD. Identifying glycan patterns that induce self-tolerance and the ones that cause the auto- and allo-immune response could lead to innovative and tissue-specific immunomodulative therapy instead of the current immunosuppressive treatment, enabling preservation of the graft-versus-tumor effect. Moreover, improved glycan pattern analyses could offer a more complete assessment and greatly needed dynamic biomarkers for GVHD. General significance: This review is written with a goal to encourage glycan research in the field of alloHSCT and GVHD as a perspective tool leading to improved engraftment, discovery of much needed biomarkers for GVHD, enabling an appropriate therapy and improved monitoring of therapeutic response. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. (C) 2016 Elsevier B.V. All rights reserved. C1 [Prenc, Ema] Croatian Cooperat Grp Hematol Dis, Zagreb, Croatia. [Pulanic, Drazen; Desnica, Lana; Vrhovac, Radovan; Nemet, Damir] Univ Hosp Ctr Zagreb, Dept Internal Med, Div Haematol, Zagreb, Croatia. [Pulanic, Drazen; Vrhovac, Radovan; Nemet, Damir] Univ Zagreb, Sch Med, Zagreb, Croatia. [Pulanic, Drazen; Nemet, Damir] JJ Strossmayer Univ Osijek, Fac Med Osijek, Osijek, Croatia. [Pucic-Bakovic, Maja; Pezer, Marija] Genos Glycosci Res Lab, Zagreb, Croatia. [Pavletic, Steven Z.] NCI, Graft Versus Host & Autoimmun Sect, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Pulanic, D (reprint author), Kispaticeva 12, Zagreb 10000, Croatia. EM dpulanic@yahoo.com FU Unity Through Knowledge Fund, Croatia; European Commission [278535, 305280, 324400, 315997]; intramural program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health, USA FX This work is supported in part by the Unity Through Knowledge Fund, Croatia (project "Clinical and biological factors determining severity and activity of chronic Graft-versus-Host Disease after allogeneic hematopoietic stem cell transplantion"), the European Commission HighGlycan (contract no. 278535), MIMOmics (contract no. 305280), HTP-GlycoMet (contract no. 324400), IntegraLife (contract no. 315997) grants, and in part by the intramural program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health, USA. NR 97 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 EI 1872-8006 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD AUG PY 2016 VL 1860 IS 8 SI SI BP 1615 EP 1622 DI 10.1016/j.bbagen.2016.02.015 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DQ5WB UT WOS:000379274800006 PM 26923767 ER PT J AU Kwako, LE Momenan, R Litten, RZ Koob, GF Goldman, D AF Kwako, Laura E. Momenan, Reza Litten, Raye Z. Koob, George F. Goldman, David TI Addictions Neuroclinical Assessment: A Neuroscience-Based Framework for Addictive Disorders SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Addiction; Assessment; Diagnosis; Neuroimaging; Nosology; Substance use ID DOMAIN CRITERIA RDOC; ALCOHOL-USE DISORDER; SELECTION WORKING-MEMORY; CLINICAL-IMPLICATIONS; SUBJECTIVE RESPONSES; COGNITIVE CONTROL; ATTENTIONAL BIAS; PHENX MEASURES; DRUG-USE; ABSTINENT ALCOHOLICS AB This article proposes a heuristic framework for the Addictions Neuroclinical Assessment that incorporates key functional domains derived from the neurocircuitry of addiction. We review how addictive disorders (ADs) are presently diagnosed and the need for new neuroclinical measures to differentiate patients who meet clinical criteria for addiction to the same agent while differing in etiology, prognosis, and treatment response. The need for a better understanding of the mechanisms provoking and maintaining addiction, as evidenced by the limitations of current treatments and within-diagnosis clinical heterogeneity, is articulated. In addition, recent changes in the nosology of ADs, challenges to current classification systems, and prior attempts to subtype individuals with ADs are described. Complementary initiatives, including the Research Domain Criteria project, that have established frameworks for the neuroscience of psychiatric disorders are discussed. Three domains-executive function, incentive salience, and negative emotionality-tied to different phases in the cycle of addiction form the core functional elements of ADs. Measurement of these domains in epidemiologic, genetic, clinical, and treatment studies will provide the underpinnings for an understanding of cross-population and temporal variation in addictions, shared mechanisms in addictive disorders, impact of changing environmental influences, and gene identification. Finally, we show that it is practical to implement such a deep neuroclinical assessment using a combination of neuroimaging and performance measures. Neuroclinical assessment is key to reconceptualizing the nosology of ADs on the basis of process and etiology, an advance that can lead to improved prevention and treatment. C1 [Kwako, Laura E.; Goldman, David] NIAAA, Off Clin Director, NIH, Bethesda, MD USA. [Momenan, Reza] NIAAA, Sect Brain Elect & Imaging, NIH, Bethesda, MD USA. [Litten, Raye Z.] NIAAA, Div Treatment & Recovery Res, NIH, Bethesda, MD USA. [Koob, George F.] NIAAA, Off Director, NIH, Bethesda, MD USA. [Goldman, David] NIAAA, Lab Neurogenet, NIH, Bethesda, MD USA. RP Kwako, LE (reprint author), NIAAA, NIH, 10 Ctr Dr,1-5340,MC 1108, Bethesda, MD 20892 USA. EM laura.kwako@nih.gov RI Goldman, David/F-9772-2010; koob, george/P-8791-2016 OI Goldman, David/0000-0002-1724-5405; FU Intramural NIH HHS [Z99 AA999999] NR 147 TC 7 Z9 7 U1 15 U2 36 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 1 PY 2016 VL 80 IS 3 BP 179 EP 189 DI 10.1016/j.biopsych.2015.10.024 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DR1UA UT WOS:000379689200006 PM 26772405 ER PT J AU Whitaker, LR de Oliveira, PEC McPherson, KB Fallon, RV Planeta, CS Bonci, A Hope, BT AF Whitaker, Leslie R. Carneiro de Oliveira, Paulo E. McPherson, Kylie B. Fallon, Rebecca V. Planeta, Cleopatra S. Bonci, Antonello Hope, Bruce T. TI Associative Learning Drives the Formation of Silent Synapses in Neuronal Ensembles of the Nucleus Accumbens SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Addiction; Electrophysiology; Glutamate; Memory; Psychostimulant; Transgenic ID VENTRAL TEGMENTAL AREA; CONTEXT-SPECIFIC SENSITIZATION; NMDA RECEPTOR PLASTICITY; LONG-TERM DEPRESSION; SYNAPTIC PLASTICITY; DOPAMINE NEURONS; BEHAVIORAL SENSITIZATION; COCAINE SENSITIZATION; PREFRONTAL CORTEX; AMPA RECEPTORS AB BACKGROUND: Learned associations between environmental stimuli and rewards play a critical role in addiction. Associative learning requires alterations in sparsely distributed populations of strongly activated neurons, or neuronal ensembles. Until recently, assessment of functional alterations underlying learned behavior was restricted to global neuroadaptations in a particular brain area or cell type, rendering it impossible to identify neuronal ensembles critically involved in learned behavior. METHODS: We used Fos-GFP transgenic mice that contained a transgene with a Fos promoter driving expression of green fluorescent protein (GFP) to detect neurons that were strongly activated during associative learning, in this case, context-independent and context-specific cocaine-induced locomotor sensitization. Whole-cell electrophysiological recordings were used to assess synaptic alterations in specifically activated GFP-positive (GFP+) neurons compared with surrounding nonactivated GFP-negative (GFP-) neurons 90 min after the sensitized locomotor response. RESULTS: After context-independent cocaine sensitization, cocaine-induced locomotion was equally sensitized by repeated cocaine injections in two different sensitization contexts. Correspondingly, silent synapses in these mice were induced in GFP+ neurons, but not GFP- neurons, after sensitization in both of these contexts. After context-specific cocaine sensitization, cocaine-induced locomotion was sensitized exclusively in mice trained and tested in the same context (paired group), but not in mice that were trained in one context and then tested in a different context (unpaired group). Silent synapses increased in GFP+ neurons, but not in GFP- neurons from mice in the paired group, but not from mice in the unpaired group. CONCLUSIONS: Our results indicate that silent synapses are formed only in neuronal ensembles of the nucleus accumbens shell that are related to associative learning. C1 [Whitaker, Leslie R.; McPherson, Kylie B.; Fallon, Rebecca V.; Bonci, Antonello; Hope, Bruce T.] NIDA, Behav Neurosci Branch, NIH, Intramural Res Program, Baltimore, MD USA. [Carneiro de Oliveira, Paulo E.; Planeta, Cleopatra S.] Univ Estadual Paulista, Fac Ciencias Farmaceut, Lab Neuropsicofarmacol, PANT, Araraquara, SP, Brazil. RP Hope, BT (reprint author), NIDA, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM bhope@intra.nida.nih.gov RI Hope, Bruce/A-9223-2010; OI Hope, Bruce/0000-0001-5804-7061; McPherson, Kylie/0000-0002-5196-098X FU National Institutes of Health National Institute on Drug Abuse Intramural Research Program; Brazil (PECO) FX This work was supported by the National Institutes of Health National Institute on Drug Abuse Intramural Research Program and a Capes fellowship from Brazil (PECO). NR 45 TC 1 Z9 1 U1 5 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 1 PY 2016 VL 80 IS 3 BP 246 EP 256 DI 10.1016/j.biopsych.2015.08.006 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DR1UA UT WOS:000379689200013 PM 26386479 ER PT J AU Bush, WS Crosslin, DR Owusu-Obeng, A Wallace, J Almoguera, B Basford, MA Bielinski, SJ Carrell, DS Connolly, JJ Crawford, D Doheny, KF Gallego, CJ Gordon, AS Keating, B Kirby, J Kitchner, T Manzi, S Mejia, AR Pan, V Perry, CL Peterson, JF Prows, CA Ralston, J Scott, SA Scrol, A Smith, M Stallings, SC Veldhuizen, T Wolf, W Volpi, S Wiley, K Li, R Manolio, T Bottinger, E Brilliant, MH Carey, D Chisholm, RL Chute, CG Haines, JL Hakonarson, H Harley, JB Holm, IA Kullo, IJ Jarvik, GP Larson, EB McCarty, CA Williams, MS Denny, JC Rasmussen-Torvik, LJ Roden, DM Ritchie, MD AF Bush, W. S. Crosslin, D. R. Owusu-Obeng, A. Wallace, J. Almoguera, B. Basford, M. A. Bielinski, S. J. Carrell, D. S. Connolly, J. J. Crawford, D. Doheny, K. F. Gallego, C. J. Gordon, A. S. Keating, B. Kirby, J. Kitchner, T. Manzi, S. Mejia, A. R. Pan, V. Perry, C. L. Peterson, J. F. Prows, C. A. Ralston, J. Scott, S. A. Scrol, A. Smith, M. Stallings, S. C. Veldhuizen, T. Wolf, W. Volpi, S. Wiley, K. Li, R. Manolio, T. Bottinger, E. Brilliant, M. H. Carey, D. Chisholm, R. L. Chute, C. G. Haines, J. L. Hakonarson, H. Harley, J. B. Holm, I. A. Kullo, I. J. Jarvik, G. P. Larson, E. B. McCarty, C. A. Williams, M. S. Denny, J. C. Rasmussen-Torvik, L. J. Roden, D. M. Ritchie, M. D. TI Genetic Variation Among 82 Pharmacogenes: The PGRNseq Data From the eMERGE Network SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ELECTRONIC MEDICAL-RECORDS; GENOME-WIDE ASSOCIATION; PERSONALIZED MEDICINE; IMPLEMENTATION CONSORTIUM; DRUG RESPONSE; VARIANTS; DEPRESSION; PROGRESS; DESIGN; UNIVERSITY AB Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from similar to 5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine. C1 [Bush, W. S.; Crawford, D.; Haines, J. L.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Crosslin, D. R.; Gallego, C. J.; Gordon, A. S.; Jarvik, G. P.] Univ Washington, Seattle, WA 98195 USA. [Owusu-Obeng, A.; Mejia, A. R.; Scott, S. A.; Bottinger, E.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Wallace, J.] Penn State Univ, University Pk, PA 16802 USA. [Almoguera, B.; Connolly, J. J.; Keating, B.; Hakonarson, H.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Basford, M. A.; Peterson, J. F.; Stallings, S. C.; Denny, J. C.; Roden, D. M.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Bielinski, S. J.; Veldhuizen, T.; Kullo, I. J.] Mayo Clin, Rochester, MN USA. [Carrell, D. S.; Ralston, J.; Larson, E. B.] Grp Hlth Res Inst, Seattle, WA USA. [Doheny, K. F.; Chute, C. G.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Kitchner, T.; Brilliant, M. H.; McCarty, C. A.] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI USA. [Manzi, S.; Perry, C. L.] Boston Childrens Hosp, Boston, MA USA. [Chisholm, R. L.; Rasmussen-Torvik, L. J.] Northwestern Univ, Feinberg Sch Med, Evanston, IL USA. [Prows, C. A.] Childrens Hosp Med Ctr, Cincinnati, OH USA. [Volpi, S.; Wiley, K.; Li, R.; Manolio, T.] Natl Human Genome Res Inst, Bethesda, MD USA. [Williams, M. S.; Ritchie, M. D.] Geisinger Hlth Syst, Danville, PA USA. [Harley, J. B.] Univ Cincinnati, US Dept Vet Affairs Med Ctr, Cincinnati, OH USA. [Holm, I. A.] Dept Pediat, Div Genet & Genom, Boston, MA USA. [Holm, I. A.] Manton Ctr Orphan Dis Res, Boston, MA USA. RP Ritchie, MD (reprint author), Geisinger Hlth Syst, Danville, PA USA. EM marylyn.ritchie@psu.edu RI Natarajan, Meena/J-9167-2012 OI Natarajan, Meena/0000-0001-5652-9681 FU NHGRI [U01HG006828, U01HG006830, U01HG006389, U01HG006382, U01HG006375, U01HG006379, U01HG006380, U01HG006388, U01HG006378, U01HG006385]; Mayo Clinic Center for Individualized Medicine, National Institutes of Health [U19 GM61388, R01 GM28157, U01 HG005137, R01 CA138461, R01 AG034676] FX The eMERGE Network was initiated and funded by NHGRI through the following grants: U01HG006828 (Cincinnati Children's Hospital Medical Center/Boston Children's Hospital); U01HG006830 (Children's Hospital of Philadelphia); U01HG006389 (Essential Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health Cooperative/University of Washington); U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center); and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center). The PGRNSeq dataset (eMERGE PGx), please also add U01HG004438 (CIDR) serving as a Sequencing Center. This work was also supported in part by the Mayo Clinic Center for Individualized Medicine, National Institutes of Health grants U19 GM61388 (the Pharmacogenomics Research Network), R01 GM28157, U01 HG005137, R01 CA138461, and R01 AG034676 (the Rochester Epidemiology Project). NR 44 TC 5 Z9 5 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD AUG PY 2016 VL 100 IS 2 BP 160 EP 169 DI 10.1002/cpt.350 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ6TA UT WOS:000379336900018 PM 26857349 ER PT J AU Emberson, LL Rubinstein, DY AF Emberson, Lauren L. Rubinstein, Dani Y. TI Statistical learning is constrained to less abstract patterns in complex sensory input (but not the least) SO COGNITION LA English DT Article DE Psychology; Learning; Statistical learning; Implicit learning; Cognitive development; Pattern recognition; Vision; Perception; Perceptual learning; Object perception; Categorization ID WORD SEGMENTATION; FMRI; INFORMATION; LANGUAGE; INFANTS; REGULARITIES; PERCEPTION; CATEGORIES; PREDICTION; EXEMPLARS AB The influence of statistical information on behavior (either through learning or adaptation) is quicldy becoming foundational to many domains of cognitive psychology and cognitive neuroscience, from language comprehension to visual development. We investigate a central problem impacting these diverse fields: when encountering input with rich statistical information, are there any constraints on teaming? This paper examines learning outcomes when adult learners are given statistical information across multiple levels of abstraction simultaneously: from abstract, semantic categories of everyday objects to individual viewpoints on these objects. After revealing statistical learning of abstract, semantic categories with scrambled individual exemplars (Exp. 1), participants viewed pictures where the categories as well as the individual objects predicted picture order (e.g., bird(1)-dog(1), bird(2)-dog(2)). Our findings suggest that participants preferentially encode the relationships between the individual objects, even in the presence of statistical regularities linking semantic categories (Exps. 2 and 3). In a final experiment we investigate whether learners are biased towards learning object-level regularities or simply construct the most detailed model given the data (and therefore best able to predict the specifics of the upcoming stimulus) by investigating whether participants preferentially learn from the statistical regularities linking individual snapshots of objects or the relationship between the objects themselves (e.g., bird_picture(1)-dog_picture(1), bird_picture(2)-dog_picture(2)). We find that participants fail to learn the relationships between individual snapshots, suggesting a bias towards object-level statistical regularities as opposed to merely constructing the most complete model of the input. This work moves beyond the previous existence proofs that statistical learning is possible at both very high and very low levels of abstraction (categories vs. individual objects) and suggests that, at least with the current categories and type of learner, there are biases to pick up on statistical regularities between individual objects even when robust statistical information is present at other levels of abstraction. These findings speak directly to emerging theories about how systems supporting statistical learning and prediction operate in our structure-rich environments. Moreover, the theoretical implications of the current work across multiple domains of study is already clear: statistical learning cannot be assumed to be unconstrained even if statistical learning has previously been established at a given level of abstraction when that information is presented in isolation. (C) 2016 Elsevier B.V. All rights reserved. C1 [Emberson, Lauren L.] Univ Rochester, Brain & Cognit Sci Dept, Rochester, NY 14627 USA. [Emberson, Lauren L.] Princeton Univ, Dept Psychol, Peretsman Scully Hall, Princeton, NJ 08540 USA. [Emberson, Lauren L.; Rubinstein, Dani Y.] Cornell Univ, Psychol Dept, Ithaca, NY 14853 USA. [Rubinstein, Dani Y.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Rubinstein, Dani Y.] NIMH, Sect Integrat Neuroimaging, Clin & Translat Neurosci Branch, NIH, Bethesda, MD 20892 USA. RP Emberson, LL (reprint author), Princeton Univ, Dept Psychol, Peretsman Scully Hall, Princeton, NJ 08540 USA. EM laurenle@princeton.edu FU Canadian Institution of Health Research post-doctoral fellowship [201210MFE-290131-231192]; NIH K99 award [HD076166-01A1] FX We'd like to thank Drs. Dima Amso, Rick Dale, Jordan DeLong, David Field, Thomas Farmer, Gary Lupyan, Adele Goldberg, Elika Bergelson, Toben Mintz and three anonymous Reviewers for helpful conversations and/or comments on the manuscript. We'd also like to thank Esteban Buz and Dave Kleinschmidt for their (statistical) support. Thank you to Claire Schmidt, Andrew Webb, Joey Ciufo, Mary Marchetti, Haley Weaver and Camila Rivero for help with data collection and, in particular, we thank Dr. Michael Spivey for his support during initial data collection at Cornell University. This work is supported by a Canadian Institution of Health Research post-doctoral fellowship (201210MFE-290131-231192) and an NIH K99 award (HD076166-01A1) to LLE. NR 54 TC 3 Z9 3 U1 7 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0010-0277 EI 1873-7838 J9 COGNITION JI Cognition PD AUG PY 2016 VL 153 BP 63 EP 78 DI 10.1016/j.cognition.2016.04.010 PG 16 WC Psychology, Experimental SC Psychology GA DQ9VZ UT WOS:000379558700007 PM 27139779 ER PT J AU deLemos, AS Ghabril, M Rockey, DC Gu, JZ Barnhart, HX Fontana, RJ Kleiner, DE Bonkovsky, HL AF deLemos, Andrew S. Ghabril, Marwan Rockey, Don C. Gu, Jiezhun Barnhart, Huiman X. Fontana, Robert J. Kleiner, David E. Bonkovsky, Herbert L. CA DILIN TI Amoxicillin-Clavulanate-Induced Liver Injury SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Allergy; Amoxicillin; Augmentin; Clavulanic acid; Drug-induced liver injury; Liver toxicity ID HEPATITIS; RISK; ACID; AMOXICILLIN/CLAVULANATE; COMBINATION; ASSOCIATION; FEATURES; JAUNDICE; OUTCOMES; FAILURE AB Amoxicillin-clavulanate (AC) is the most frequent cause of idiosyncratic drug-induced injury (DILI) in the US DILI Network (DILIN) registry. Here, we examined a large cohort of AC-DILI cases and compared features of AC-DILI to those of other drugs. Subjects with suspected DILI were enrolled prospectively, and cases were adjudicated as previously described. Clinical variables and outcomes of patients with AC-DILI were compared to the overall DILIN cohort and to DILI caused by other antimicrobials. One hundred and seventeen subjects with AC-DILI were identified from the cohort (n = 1038) representing 11 % of all cases and 24 % of those due to antimicrobial agents (n = 479). Those with AC-DILI were older (60 vs. 48 years, P < 0.001). AC-DILI was more frequent in men than women (62 vs. 39 %) compared to the overall cohort (40 vs. 60 %, P < 0.001). The mean time to symptom onset was 31 days. The Tb, ALT, and ALP were 7 mg/dL, 478, and 325 U/L at onset. Nearly all liver biopsies showed prominent cholestatic features. Resolution of AC-DILI, defined by return of Tb to < 2.5 mg/dL, occurred on average 55 days after the peak value. Three female subjects required liver transplantation, and none died due to DILI. AC-DILI causes a moderately severe, mixed hepatocellular-cholestatic injury, particularly in older men, unlike DILI in general, which predominates in women. Although often protracted, eventual apparent recovery is typical, particularly for men and usually in women, but three women required liver transplantation. C1 [deLemos, Andrew S.] Carolinas Med Ctr, Dept Med, 1025 Morehead Med Dr,Suite 600, Charlotte, NC 28204 USA. [Ghabril, Marwan] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Rockey, Don C.] Med Univ South Carolina, Dept Med, Charleston, SC USA. [Gu, Jiezhun; Barnhart, Huiman X.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Fontana, Robert J.] Univ Michigan, Sch Med, Dept Med, Ann Arbor, MI 48104 USA. [Kleiner, David E.] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. [Bonkovsky, Herbert L.] Wake Forest Baptist Med Ctr, Dept Med, Winston Salem, NC USA. RP deLemos, AS (reprint author), Carolinas Med Ctr, Dept Med, 1025 Morehead Med Dr,Suite 600, Charlotte, NC 28204 USA. EM Andrew.deLemos@carolinashealthcare.org OI Ghabril, Marwan/0000-0002-4784-3246 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [2U01-DK065176-06, 2U01-DK065201-06, 2U01-DK065184-06, 2U01-DK065211-06, 5U01DK065193-04, 5U01-DK065238-08, 1U01-DK083023-01, 1U01-DK083027-01, 1U01-DK082992-01, 1U01-DK083020-01]; CTSA [UL1 RR025761, UL1 RR025747, UL1 RR024134, UL1 RR024986, UL1 RR024982, UL1 RR024150]; Intramural Research Program of The NIH, National Cancer Institute FX The DILIN Network is structured as a U01 cooperative agreement with Funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grants: 2U01-DK065176-06 (Duke), 2U01-DK065201-06 (UNC), 2U01-DK065184-06 (Michigan), 2U01-DK065211-06 (Indiana), 5U01DK065193-04 (UConn), 5U01-DK065238-08 (UCSF/CPMC), 1U01-DK083023-01 (UTSW), 1U01-DK083027-01 (TJH/UPenn), 1U01-DK082992-01 (Mayo), 1U01-DK083020-01 (USC). Additional funding is provided by CTSA grants: UL1 RR025761 (Indiana), UL1 RR025747 (UNC), UL1 RR024134 (UPenn), UL1 RR024986 (Michigan), UL1 RR024982 (UTSW), UL1 RR024150 (Mayo) and in part by the Intramural Research Program of The NIH, National Cancer Institute. NR 28 TC 2 Z9 2 U1 3 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD AUG PY 2016 VL 61 IS 8 BP 2406 EP 2416 DI 10.1007/s10620-016-4121-6 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DR3FE UT WOS:000379787200033 PM 27003146 ER PT J AU Zheng, EX Rossi, S Fontana, RJ Vuppalanchi, R Hoofnagle, JH Khan, I Navarro, VJ AF Zheng, Elizabeth X. Rossi, Simona Fontana, Robert J. Vuppalanchi, Raj Hoofnagle, Jay H. Khan, Ikhlas Navarro, Victor J. TI Risk of Liver Injury Associated with Green Tea Extract in SLIMQUICK((R)) Weight Loss Products: Results from the DILIN Prospective Study SO DRUG SAFETY LA English DT Article ID HEPATOTOXICITY; ANTIOBESITY; SUPPLEMENTS; CATECHINS AB Introduction Herbal and dietary supplements (HDS) have been increasingly recognized as a cause for acute liver injury (Navarro et al. Hepatology 60(4):1399-1408, 2014; Bailey et al. J Nutr 141:261-266, 2011). HDS products frequently contain numerous ingredients, and are marketed under various product names. A perusal of marketed weight loss products indicates that green tea extract (GTE) is a common ingredient in many. We aimed to describe the course and outcome of six patients who developed liver injury attributed to SLIMQUICK(A (R)) weight loss products. Methods Patients with suspected drug-induced liver injury were enrolled in a prospective study of the Drug-Induced Liver Injury Network (DILIN) and causality was assessed by a panel of hepatologists. During the period under study, 6 of 1091 cases of liver injury were attributed to a SLIMQUICK(A (R)) product and were assigned causality scores of probable, highly likely, or definite. Results Six cases of acute liver injury attributed to SLIMQUICK(A (R)) products were enrolled in the DILIN prospective study between 2007 and 2011. All were women aged 22 to 58 years. Two had a normal body weight and four were mildly obese (body mass index 22.9-32.2 kg/m(2)). All were taking SLIMQUICK(A (R)) products for weight loss and no patient reported prior use. Laboratory tests revealed a hepatocellular pattern of injury, with initial alanine aminotransferase (ALT) levels above 1000 U/L in all but one patient. Three patients were hospitalized and one underwent successful liver transplantation. No patients died of liver injury. GTE and/or its component catechins were listed among the ingredients for five of the six products. Conclusions SLIMQUICK(A (R)) products can lead to severe acute hepatocellular liver injury, which may result in transplantation. Given the frequency of GTE as a component in weight loss products, this ingredient should be studied further as a possible cause for liver injury. C1 [Zheng, Elizabeth X.; Rossi, Simona; Navarro, Victor J.] Einstein Med Ctr, 5401 Old York Rd, Philadelphia, PA 19141 USA. [Fontana, Robert J.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Vuppalanchi, Raj] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Hoofnagle, Jay H.] NIDDK, NIH, Bethesda, MD 20892 USA. [Khan, Ikhlas] Univ Mississippi, Oxford, MS USA. RP Navarro, VJ (reprint author), Einstein Med Ctr, 5401 Old York Rd, Philadelphia, PA 19141 USA. EM navarrov@einstein.edu FU Indiana University [Purdue] [U01DK065211]; University of Michigan [Ann Arbor] [U01DK065184]; University of North Carolina [Chapel Hill] [U01DK065201]; Ashe-ville, Wake Forest Baptist Medical Center [U01DK065201]; University of Southern California [U01DK083020]; University of California-Los Angeles [Pfleger Liver Institute] [U01DK083020]; Albert Einstein Medical Center [U01DK083027]; Icahn School of Medicine at Mount Sinai [U01DK100928]; Duke Clinical Research Institute [U01DK065176]; Intramural Division of the National Cancer Institute (NCI), NIH; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institute of Health (NIH) FX The Drug-Induced Liver Injury Network (DILIN) is structured as a U01 cooperative agreement supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institute of Health (NIH) with funds provided by the following Grants: U01DK065211 (Indiana University [Purdue]), U01DK065184 (University of Michigan [Ann Arbor]), U01DK065201 (University of North Carolina [Chapel Hill], Ashe-ville, Wake Forest Baptist Medical Center), U01DK083020 (University of Southern California, University of California-Los Angeles [Pfleger Liver Institute]), U01DK083027 (Albert Einstein Medical Center), U01DK100928 (Icahn School of Medicine at Mount Sinai), U01DK065176 (Duke Clinical Research Institute). Additional support was provided by the Intramural Division of the National Cancer Institute (NCI), NIH. NR 22 TC 0 Z9 0 U1 1 U2 1 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0114-5916 EI 1179-1942 J9 DRUG SAFETY JI Drug Saf. PD AUG PY 2016 VL 39 IS 8 BP 749 EP 754 DI 10.1007/s40264-016-0428-7 PG 6 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA DQ8UG UT WOS:000379486100005 PM 27189593 ER PT J AU Aarhus, L Tambs, K Hoffman, HJ Engdahl, B AF Aarhus, Lisa Tambs, Kristian Hoffman, Howard J. Engdahl, Bo TI Childhood otitis media is associated with dizziness in adulthood: the HUNT cohort study SO EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY LA English DT Article DE Otitis media; Inner ear; Dizziness; Vertigo; Follow-up ID HIGH-FREQUENCY HEARING; NORD-TRONDELAG; CHILDREN; COMMUNITY; POPULATION; PREVALENCE; VERTIGO; HISTORY; NORWAY; EAR AB The objective of the study was to examine the association between otitis media in childhood and dizziness in adulthood. Longitudinal, population-based cohort study of 21,962 adults (aged 20-59 years, mean 40) who completed a health questionnaire in the Nord-Trondelag Hearing Loss Study was conducted. At 7, 10 and 13 years of age, the same individuals underwent screening audiometry in a longitudinal school hearing investigation. Children found with hearing loss underwent an ear, nose and throat specialist examination. Adults diagnosed with childhood chronic suppurative otitis media (n = 102) and childhood hearing loss after recurrent acute otitis media (n = 590) were significantly more likely to have increased risk of reported dizziness when compared to adults with normal hearing as children at the school investigation and also a negative history of recurrent otitis media (n = 21,270), p < 0.05. After adjusting for adult age, sex and socio-economic status, the odds ratios were 2.1 [95 % confidence interval (CI): 1.4-3.3] and 1.3 (95 % CI: 1.0-1.5), respectively. This longitudinal cohort study suggests that childhood chronic suppurative otitis media and childhood hearing loss after recurrent acute otitis media are associated with increased risk of dizziness in adulthood. This might reflect a permanent effect of inflammatory mediators or toxins on the vestibular system. The new finding stresses the importance of treatment and prevention of these otitis media conditions. C1 [Aarhus, Lisa; Tambs, Kristian; Engdahl, Bo] Norwegian Inst Publ Hlth, Div Mental Hlth, Dept Psychosomat & Hlth Behav, POB 4404, N-0403 Oslo, Norway. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders NIDCD, Epidemiol & Stat Program, Div Sci Programs, NIH, Bethesda, MD 20892 USA. RP Aarhus, L (reprint author), Norwegian Inst Publ Hlth, Div Mental Hlth, Dept Psychosomat & Hlth Behav, POB 4404, N-0403 Oslo, Norway. EM lisa.aarhus@fhi.no FU National Institute on Deafness and Other Communication Disorders (NIDCD), NIH [N01-DC-6-2104]; Extra Foundation: Health and Rehabilitation through the member organization The National Association of Hard of Hearing FX The NTHLS, which is a part of HUNT, was funded by the National Institute on Deafness and Other Communication Disorders (NIDCD), NIH, research contract No. N01-DC-6-2104. The present study was supported by a grant from The Extra Foundation: Health and Rehabilitation through the member organization The National Association of Hard of Hearing. The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. All funding had followed the guidelines on good publication practice. There was independence between researchers and funders/sponsors. All authors declare that they have no conflicts of interest. NR 26 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0937-4477 EI 1434-4726 J9 EUR ARCH OTO-RHINO-L JI Eur. Arch. Oto-Rhino-Laryn. PD AUG PY 2016 VL 273 IS 8 BP 2047 EP 2054 DI 10.1007/s00405-015-3764-9 PG 8 WC Otorhinolaryngology SC Otorhinolaryngology GA DQ5OV UT WOS:000379255600012 PM 26335289 ER PT J AU Johnston, AM Niemela, J Rosenzweig, SD Fried, AJ Delmonte, OM Fleisher, TA Kuehn, H AF Johnston, Alicia M. Niemela, Julie Rosenzweig, Sergio D. Fried, Ari J. Delmonte, Ottavia Maria Fleisher, Thomas A. Kuehn, Hyesun TI A Novel Mutation in IKBKG/NEMO Leads to Ectodermal Dysplasia with Severe Immunodeficiency (EDA-ID) SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Letter ID ESSENTIAL MODULATOR MUTATION; INCONTINENTIA PIGMENTI; NEMO C1 [Johnston, Alicia M.] Childrens Hosp, Baystate Med Ctr, Dept Pediat, Springfield, MA USA. [Niemela, Julie; Rosenzweig, Sergio D.; Fleisher, Thomas A.; Kuehn, Hyesun] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Fried, Ari J.; Delmonte, Ottavia Maria] Boston Childrens Hosp, Div Immunol, Boston, MA USA. RP Johnston, AM (reprint author), Childrens Hosp, Baystate Med Ctr, Dept Pediat, Springfield, MA USA. EM alicia.johnston@baystatehealth.org FU Intramural NIH HHS [Z01 CL010287-11] NR 7 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD AUG PY 2016 VL 36 IS 6 BP 541 EP 543 DI 10.1007/s10875-016-0309-y PG 3 WC Immunology SC Immunology GA DQ9NE UT WOS:000379535800003 PM 27368913 ER PT J AU Hampson, AJ Babalonis, S Lofwall, MR Nuzzo, PA Krieter, P Walsh, SL AF Hampson, Aidan J. Babalonis, Shanna Lofwall, Michelle R. Nuzzo, Paul A. Krieter, Phillip Walsh, Sharon L. TI A Pharmacokinetic Study Examining Acetazolamide as a Novel Adherence Marker for Clinical Trials SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE acetazolamide; adherence marker; ingestion marker; erythrocyte sequestration ID MEDICATION ADHERENCE; HUMAN-ERYTHROCYTES; ORAL OXYCODONE; HUMANS; RIBOFLAVIN; DEPENDENCE; LIABILITY; ALLERGY; TRACER AB Rationale: Accurate assessment of medication adherence is critical for determination of medication efficacy in clinical trials, but most current methods have significant limitations. This study tests a subtherapeutic (microdose) of acetazolamide as a medication ingestion marker because acetazolamide is rapidly absorbed and excreted without metabolism in urine and can be noninvasively sampled. Methods: In a double-blind, placebo-controlled, residential study, 10 volunteers received 15 mg oral acetazolamide for 4 consecutive days. Acetazolamide pharmacokinetics were assessed on day 3, and its pharmacokinetic and pharmacodynamic interactions with a model medication (30 mg oxycodone) were examined on day 4. The rate of acetazolamide elimination into urine was followed for several days after dosing cessation. Results: Erythrocyte sequestration (half-life = 50.2 +/- 18.5 h, mean +/- SD, n = 6), resulted in the acetazolamide microdose exhibiting a substantially longer plasma half-life (24.5 +/- 5.6 hours, n = 10) than previously reported for therapeutic doses (3-6 hours). After cessation of dosing, the rate of urinary elimination decreased significantly (F-3,F-23 = 247: P < 0.05, n = 6) in a predictable manner with low intersubject variability and a half-life of 16.1 +/- 3.8 h (n = 10). For each of 4 consecutive mornings after dosing cessation, the rates of urinary acetazolamide elimination remained quantifiable. There was no overall effect of acetazolamide on the pharmacodynamics, Cmax, Tmax, or elimination half-life of the model medication tested. Acetazolamide may have modestly increased overall oxycodone exposure (20%, P < 0.05) compared with one of the 2 days when oxycodone was given alone, but therewere no observed effects of acetazolamide on oxycodone pharmacodynamic responses. Conclusions: Coformulation of a once-daily trial medication with an acetazolamide microdose may allowestimation of the last time of medication consumption for up to 96 hours postdose. Inclusion of acetazolamide may therefore provide an inexpensive newmethod to improve estimates ofmedication adherence in clinical trials. C1 [Hampson, Aidan J.; Krieter, Phillip] NIDA, Div Therapies & Med Consequences, Rockville, MD 20852 USA. [Babalonis, Shanna; Lofwall, Michelle R.; Nuzzo, Paul A.; Walsh, Sharon L.] Univ Kentucky, Ctr Drug & Alcohol Res, Lexington, KY USA. RP Hampson, AJ (reprint author), NIDA, Div Therapies & Med Consequences, NIH, 6001 Execut Blvd, Rockville, MD 20852 USA. EM aidan.hampson@nih.gov FU National Institute on Drug Abuse [R01DA016718-08S1]; National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health [UL1TR000117] FX The authors thank the staff at the University of Kentucky (UK) Center on Drug and Alcohol Research for research support, the UK CCTS Laboratory for assistance with specimens, the UK Investigational Pharmacy for preparing study medication, UK CCTS Inpatient Unit nursing staff for patient care, and Dr Samy-Claude Elayi (UK Department of Cardiology, Gill Heart Institute) for patient support. The authors also thank Dr Nora Chiang at the National Institute on Drug Abuse for her pharmacokinetic expertise and support. Neither Dr Hampson nor Dr Krieter had Programmatic responsibility for R01DA016718-08S1 (S.L.W.), the National Institute on Drug Abuse grant that supported the conduct of this work. The authors also acknowledge nursing and inpatient support from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, UL1TR000117. NR 24 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD AUG PY 2016 VL 36 IS 4 BP 324 EP 332 DI 10.1097/JCP.0000000000000529 PG 9 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA DQ7HK UT WOS:000379377300005 PM 27300254 ER PT J AU Biesecker, BB AF Biesecker, Barbara Bowles TI The Greatest Priority for Genetic Counseling: Effectively Meeting Our Clients' Needs 2014 NSGC Natalie Weissberger Paul National Achievement Award SO JOURNAL OF GENETIC COUNSELING LA English DT Editorial Material DE Psychotherapeutic genetic counseling; Client centered care; Paradigm shift in genetic counseling ID ORAL LITERACY DEMAND; DIALOGUE AB Receipt of the 2014 Natalie Weissberger Paul (NWP) National Achievement Award was a highlight of my career. Thank you to all who nominated me for this prestigious NSGC recognition. I am humbled to join past NWP award winners many of whom are admired mentors, treasured colleagues and friends. I would like to express what a privilege it is to honor Natalie Weissberger Paul for whom this award is named. Twenty-nine years ago I co-edited a volume of the Birth Defects Original Article Series with Natalie summarizing a conference co-funded by the March of Dimes and NSGC (Biesecker et al., 1987). Natalie demonstrated her devotion to children with special needs through her work at the March of Dimes. As such I believe she would concur with the focus of my remarks on the partners in our work: our clients. C1 [Biesecker, Barbara Bowles] NHGRI, Social & Behav Res Branch, NIH, 31 Ctr Dr,Room B1B36, Bethesda, MD 20817 USA. RP Biesecker, BB (reprint author), NHGRI, Social & Behav Res Branch, NIH, 31 Ctr Dr,Room B1B36, Bethesda, MD 20817 USA. EM barbarab@mail.nih.gov FU Intramural NIH HHS [ZIA HG200317-13] NR 11 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 EI 1573-3599 J9 J GENET COUNS JI J. Genet. Couns. PD AUG PY 2016 VL 25 IS 4 BP 621 EP 624 DI 10.1007/s10897-016-9962-9 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA DQ8XR UT WOS:000379495500003 PM 27220742 ER PT J AU Baty, BJ Trepanier, A Bennett, RL Davis, C Erby, L Hippman, C Lerner, B Matthews, A Myers, MF Robbins, CB Singletary, CN AF Baty, Bonnie J. Trepanier, Angela Bennett, Robin L. Davis, Claire Erby, Lori Hippman, Catriona Lerner, Barbara Matthews, Anne Myers, Melanie F. Robbins, Carol B. Singletary, Claire N. TI Developing a Model of Advanced Training to Promote Career Advancement for Certified Genetic Counselors: An Investigation of Expanded Skills, Advanced Training Paths, and Professional Opportunities SO JOURNAL OF GENETIC COUNSELING LA English DT Article DE Advanced training; Genetic counselors; Career development; Career advancement ID EDUCATION; LADDERS AB There are currently multiple paths through which genetic counselors can acquire advanced knowledge and skills. However, outside of continuing education opportunities, there are few formal training programs designed specifically for the advanced training of genetic counselors. In the genetic counseling profession, there is currently considerable debate about the paths that should be available to attain advanced skills, as well as the skills that might be needed for practice in the future. The Association of Genetic Counseling Program Directors (AGCPD) convened a national committee, the Committee on Advanced Training for Certified Genetic Counselors (CATCGC), to investigate varied paths to post-master's training and career development. The committee began its work by developing three related grids that view career advancement from the viewpoints of the skills needed to advance (skills), ways to obtain these skills (paths), and existing genetic counselor positions that offer career change or advancement (positions). Here we describe previous work related to genetic counselor career advancement, the charge of the CATCGC, our preliminary work in developing a model through which to view genetic counselor advanced training and career advancement opportunities, and our next steps in further developing and disseminating the model. C1 [Baty, Bonnie J.] Univ Utah, Hlth Sci Ctr, Dept Pediat, Div Med Genet, SOM 2C454, Salt Lake City, UT 84132 USA. [Trepanier, Angela] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Bennett, Robin L.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Davis, Claire] Sarah Lawrence Coll, Joan H Marks Grad Program Human Genet, Bronxville, NY 10708 USA. [Erby, Lori] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Hippman, Catriona] Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. [Hippman, Catriona] BC Womens Hosp & Hlth Ctr, Womens Hlth Res Inst, Vancouver, BC, Canada. [Lerner, Barbara] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Matthews, Anne] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA. [Myers, Melanie F.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. [Robbins, Carol B.] Fac Dev & Adult Learning Consultant, New York, NY USA. [Singletary, Claire N.] Univ Texas Hlth, Dept Pediat & Obstet Gynecol & Reprod Sci, Houston, TX USA. RP Baty, BJ (reprint author), Univ Utah, Hlth Sci Ctr, Dept Pediat, Div Med Genet, SOM 2C454, Salt Lake City, UT 84132 USA. EM bonnie.baty@hsc.utah.edu FU Association of Genetic Counseling Program Directors FX The authors would like to acknowledge the help of Susan Manley, who is also a member of the CATCGC, and the Association of Genetic Counseling Program Directors, which provided the impetus to form the committee and paid for conference calls enabling the committee to meet. NR 22 TC 1 Z9 1 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 EI 1573-3599 J9 J GENET COUNS JI J. Genet. Couns. PD AUG PY 2016 VL 25 IS 4 BP 625 EP 634 DI 10.1007/s10897-015-9916-7 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DQ8XR UT WOS:000379495500004 PM 26739839 ER PT J AU Mitchell, GF Hwang, SJ Larson, MG Hamburg, NM Benjamin, EJ Vasan, RS Levy, D Vita, JA AF Mitchell, Gary F. Hwang, Shih-Jen Larson, Martin G. Hamburg, Naomi M. Benjamin, Emelia J. Vasan, Ramachandran S. Levy, Daniel Vita, Joseph A. TI Transfer function-derived central pressure and cardiovascular disease events: the Framingham Heart Study SO JOURNAL OF HYPERTENSION LA English DT Article DE aorta; augmentation index; cardiovascular disease; central pressure; prognosis; reflected wave ID AORTIC INPUT IMPEDANCE; BLOOD-PRESSURE; ARTERIAL STIFFNESS; WAVE-FORMS; CONSENSUS DOCUMENT; PULSE PRESSURE; VALIDATION; TONOMETRY; MORTALITY AB Background: Relations between central pulse pressure (PP) or pressure amplification and major cardiovascular disease (CVD) events are controversial. Estimates of central aortic pressure derived using radial artery tonometry and a generalized transfer function may better predict CVD risk beyond the predictive value of brachial SBP. Methods: Augmentation index, central SBP, central PP, and central-to-peripheral PP amplification were evaluated using radial artery tonometry and a generalized transfer function as implemented in the SphygmoCor device (AtCor Medical, Itasca, Illinois, USA). We used proportional hazards models to examine relations between central hemodynamics and first-onset major CVD events in 2183 participants (mean age 62 years, 58% women) in the Framingham Heart Study. Results: During median follow-up of 7.8 (limits 0.2-8.9) years, 149 participants (6.8%) had an incident event. Augmentation index (P = 0.6), central aortic systolic pressure (P = 0.20), central aortic PP (P = 0.24), and PP amplification (P = 0.15) were not related to CVD events in multivariable models that adjusted for age, sex, brachial cuff systolic pressure, use of antihypertensive therapy, total and high-density lipoprotein cholesterol concentrations, smoking, and presence of diabetes. In a model that included standard risk factors, model fit was improved (P = 0.03) when brachial systolic pressure was added after central, whereas model fit was not improved (P = 0.30) when central systolic pressure was added after brachial. Conclusion: After considering standard risk factors, including brachial cuff SBP, augmentation index, central PP and PP amplification derived using radial artery tonometry, and a generalized transfer function were not predictive of CVD risk. C1 [Mitchell, Gary F.] Cardiovasc Engn Inc, 1 Edgewater Dr,Suite 201A, Norwood, MA 02062 USA. [Hwang, Shih-Jen; Larson, Martin G.; Benjamin, Emelia J.; Vasan, Ramachandran S.; Levy, Daniel] Boston Univ, Framingham, MA USA. [Hwang, Shih-Jen; Larson, Martin G.; Benjamin, Emelia J.; Vasan, Ramachandran S.; Levy, Daniel] NHLBIs Framingham Study, Framingham, MA USA. [Hwang, Shih-Jen; Levy, Daniel] NHLBI, Populat Sci Branch, Bldg 10, Bethesda, MD 20892 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Hamburg, Naomi M.; Benjamin, Emelia J.; Vasan, Ramachandran S.; Vita, Joseph A.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. [Hamburg, Naomi M.; Benjamin, Emelia J.; Vasan, Ramachandran S.; Vita, Joseph A.] Boston Univ, Sch Med, Whitaker Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, 1 Edgewater Dr,Suite 201A, Norwood, MA 02062 USA. EM GaryFMitchell@mindspring.com OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung and Blood Institute [N01-HC-25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, 2-K24-HL04334, HL107385]; Donald W. Reynolds Foundation FX This study was supported by National Heart, Lung and Blood Institute N01-HC-25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, 2-K24-HL04334, HL107385 and a grant from the Donald W. Reynolds Foundation. NR 30 TC 4 Z9 4 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD AUG PY 2016 VL 34 IS 8 BP 1528 EP 1534 DI 10.1097/HJH.0000000000000968 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DQ8GW UT WOS:000379448100015 PM 27219486 ER PT J AU Eriksen, GS Andersen, JM Boix, F Bergh, MSS Vindenes, V Rice, KC Huestis, MA Morland, J AF Eriksen, Guro Soe Andersen, Jannike Morch Boix, Fernando Bergh, Marianne Skov-Skov Vindenes, Vigdis Rice, Kenner C. Huestis, Marilyn A. Morland, Jorg TI Comparison of (+)- and (-)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CONDITIONED PLACE PREFERENCE; MU-OPIOID RECEPTOR; LOCOMOTOR-ACTIVITY; ANTAGONIST; 6-MONOACETYLMORPHINE; METABOLITES; RATS; 3-METHOXYNALTREXONE; (+)-NALTREXONE; INVOLVEMENT AB Toll-like receptor 4 (TLR4) signaling is implied in opioid reinforcement, reward, and withdrawal. Here, we explored whether TLR4 signaling is involved in the acute psychomotor-stimulating effects of heroin, 6-acetylmorphine (6-AM), and morphine as well as whether there are differences between the three opioids regarding TLR4 signaling. To address this, we examined how pretreatment with (+)-naloxone, a TLR4 active but opioid receptor (OR) inactive antagonist, affected the acute increase in locomotor activity induced by heroin, 6-AM, or morphine in mice. We also assessed the effect of pretreatment with (-)-naloxone, a TLR4 and OR active antagonist, as well as the pharmacokinetic profiles of (+) and (-)-naloxone in the blood and brain. We found that (-)-naloxone reduced acute opioid-induced locomotor activity in a dose-dependent manner. By contrast, (+)-naloxone, administered in doses assumed to antagonize TLR4 but not ORs, did not affect acute locomotor activity induced by heroin, 6-AM, or morphine. Both naloxone isomers exhibited similar concentration versus time profiles in the blood and brain, but the brain concentrations of (-)-naloxone reached higher levels than those of (+)-naloxone. However, the discrepancies in their pharmacokinetic properties did not explain the marked difference between the two isomers' ability to affect opioid-induced locomotor activity. Our results underpin the importance of OR activation and do not indicate an apparent role of TLR4 signaling in acute opioid-induced psychomotor stimulation in mice. Furthermore, there were no marked differences between heroin, 6-AM, and morphine regarding involvement of OR or TLR4 signaling. C1 [Eriksen, Guro Soe; Andersen, Jannike Morch; Boix, Fernando; Bergh, Marianne Skov-Skov; Vindenes, Vigdis; Morland, Jorg] Norwegian Inst Publ Hlth, Div Forens Sci, Dept Drug Abuse Res, POB 4404 Nydalen, N-0403 Oslo, Norway. [Vindenes, Vigdis; Morland, Jorg] Univ Oslo, Inst Clin Med, Oslo, Norway. [Huestis, Marilyn A.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Rice, Kenner C.] NIDA, Sect Drug Design & Synth, Bethesda, MD 20892 USA. [Rice, Kenner C.] NIAAA, NIH, Bethesda, MD USA. RP Eriksen, GS (reprint author), Norwegian Inst Publ Hlth, Div Forens Sci, Dept Drug Abuse Res, POB 4404 Nydalen, N-0403 Oslo, Norway. EM guro.soe.eriksen@fhi.no FU Research Council of Norway [196621/V50]; Intramural Research Program of the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse FX This research was supported in part by the Research Council of Norway [Grant 196621/V50] and by the Intramural Research Program of the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse. NR 31 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2016 VL 358 IS 2 BP 209 EP 215 DI 10.1124/jpet.116.233544 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ7RW UT WOS:000379406400006 PM 27278234 ER PT J AU Bradbury, A Bagel, J Sampson, M Farhat, N Ding, WG Swain, G Prociuk, M O'Donnell, P Drobatz, K Gurda, B Wassif, C Remaley, A Porter, F Vite, C AF Bradbury, Allison Bagel, Jessica Sampson, Maureen Farhat, Nicole Ding, Wenge Swain, Gary Prociuk, Maria O'Donnell, Patricia Drobatz, Kenneth Gurda, Brittney Wassif, Christopher Remaley, Alan Porter, Forbes Vite, Charles TI Cerebrospinal Fluid Calbindin D Concentration as a Biomarker of Cerebellar Disease Progression in Niemann-Pick Type C1 Disease SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PURKINJE-CELLS; ALZHEIMERS-DISEASE; GENE-EXPRESSION; MOUSE; CHOLESTEROL; PROTEIN; IMMUNOREACTIVITY; MICE; 2-HYDROXYPROPYL-BETA-CYCLODEXTRIN; BRAIN AB Niemann-Pick type C (NPC) 1 disease is a rare, inherited, neurodegenerative disease. Clear evidence of the therapeutic efficacy of 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) in animal models resulted in the initiation of a phase I/IIa clinical trial in 2013 and a phase IIb/III trial in 2015. With clinical trials ongoing, validation of a biomarker to track disease progression and serve as a supporting outcome measure of therapeutic efficacy has become compulsory. In this study, we evaluated calcium-binding protein calbindin D-28K (calbindin) concentrations in the cerebrospinal fluid (CSF) as a biomarker of NPC1 disease. In the naturally occurring feline model, CSF calbindin was significantly elevated at 3 weeks of age, prior to the onset of cerebellar dysfunction, and steadily increased to >10-fold over normal at end-stage disease. Biweekly intrathecal administration of HP beta CD initiated prior to the onset of neurologic dysfunction completely normalized CSF calbindin in NPC1 cats at all time points analyzed when followed up to 78 weeks of age. Initiation of HP beta CD after the onset of clinical signs (16 weeks of age) resulted in a delayed reduction of calbindin levels in the CSF. Evaluation of CSF from patients with NPC1 revealed that calbindin concentrations were significantly elevated compared with CSF samples collected from unaffected patients. Off-label treatment of patients with NPC1 with miglustat, an inhibitor of glycosphingolipid biosynthesis, significantly decreased CSF calbindin compared with pretreatment concentrations. These data suggest that the CSF calbindin concentration is a sensitive biomarker of NPC1 disease that could be instrumental as an outcome measure of therapeutic efficacy in ongoing clinical trials. C1 [Bradbury, Allison; Bagel, Jessica; Ding, Wenge; Swain, Gary; Prociuk, Maria; O'Donnell, Patricia; Drobatz, Kenneth; Gurda, Brittney; Vite, Charles] Univ Penn, Sch Vet Med, Dept Clin Studies, 3800 Spruce St,208 Rosenthal Bldg, Philadelphia, PA 19104 USA. [Sampson, Maureen; Remaley, Alan] NHLBI, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Farhat, Nicole; Wassif, Christopher; Porter, Forbes] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Translat Res, NIH, Bethesda, MD USA. RP Bradbury, A (reprint author), Univ Penn, Sch Vet Med, Dept Clin Studies, 3800 Spruce St,208 Rosenthal Bldg, Philadelphia, PA 19104 USA. EM brada@vet.upenn.edu OI Gurda, Brittney /0000-0002-0174-9385 FU National Institutes of Health National Institute of Neurological Disorders and Stroke [R01-NS073661]; Support of Accelerated Research for NPC Disease; Race for Adam Foundation; National Niemann-Pick Disease Foundation; National Institutes of Health Office of the Director [OD P40-10939]; Ara Parseghian Medical Research Foundation; Dana's Angels Research Trust; Intramural Research Programs of the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute FX This research was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01-NS073661], Support of Accelerated Research for NPC Disease, the Race for Adam Foundation, the National Niemann-Pick Disease Foundation, and the National Institutes of Health Office of the Director [Grant OD P40-10939 (all to C.V.)]; the Ara Parseghian Medical Research Foundation and the Dana's Angels Research Trust [(to F.P. and C.V.)]; and the Intramural Research Programs of the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [(to F.P.)] and the National Heart, Lung, and Blood Institute [(to A.R.)]. NR 57 TC 1 Z9 1 U1 1 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2016 VL 358 IS 2 BP 254 EP 261 DI 10.1124/jpet.116.232975 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ7RW UT WOS:000379406400014 PM 27307499 ER PT J AU Kasper, N Peterson, KE Zhang, ZZ Ferguson, KK Sanchez, B Cantoral, A Meeker, JD Tellez-Rojo, MM Pawlowski, CM Ettinger, AS AF Kasper, Nicole Peterson, Karen E. Zhang, Zhenzhen Ferguson, Kelly K. Sanchez, Brisa N. Cantoral, Alejandra Meeker, John D. Tellez-Rojo, Maria M. Pawlowski, Carolyn M. Ettinger, Adrienne S. TI Association of Bisphenol A Exposure with Breastfeeding and Perceived Insufficient Milk Supply in Mexican Women SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Breastfeeding; Bisphenol A; Environmental exposure; Infant health ID CHILDREN; PHTHALATE; DIFFERENTIATION; ADOLESCENTS; PREVALENCE; PREDICTORS; INITIATION; LACTATION; OBESITY; RISK AB Introduction Estrogen inhibits lactation and bisphenol A (BPA) is a high production environmental estrogen. We hypothesize an inhibitory effect of BPA on lactation and aim to analyze the association between third trimester pregnancy urinary BPA and breastfeeding rates 1 month postpartum. Methods Odds ratios (OR) and 95 % confidence intervals (95 % CI) of breastfeeding and perceived insufficient milk supply (PIM) in relation to maternal peripartum urinary BPA concentrations were calculated in 216 mothers. Results 97.2 % of mothers in the lowest BPA tertile were breastfeeding at 1 month postpartum, compared to 89.9 % in highest (p = 0.01). Adjusted ORs (95 % CI) for not breastfeeding at 1 month were 1.9 (0.3, 10.7) and 4.3 (0.8, 21.6) for second and third BPA tertiles, respectively, compared to the lowest (p = 0.06, trend). 4.2 % reported PIM in the lowest BPA tertile, compared to 8.7 % in the highest (p = 0.03). Adjusted ORs (95 % CI) for PIM were 1.8 (0.4, 7.7) and 2.2 (0.5, 9.5), for the second and third BPA tertiles, respectively, compared to the lowest (p = 0.29, trend). Discussion These results suggest an association between maternal BPA exposure and decreased breastfeeding. C1 [Kasper, Nicole; Peterson, Karen E.; Zhang, Zhenzhen; Ettinger, Adrienne S.] Univ Michigan, Sch Publ Hlth, Dept Nutr Sci, 1415 Washington Hts, Ann Arbor, MI 48109 USA. [Kasper, Nicole] Univ Colorado, Sect Nutr, Dept Pediat, Anschutz Med Campus,13123 E 16th Ave, Aurora, CO 80045 USA. [Peterson, Karen E.] Harvard Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. [Peterson, Karen E.] Univ Michigan, Ctr Human Growth & Dev, 300 N Ingalls St, Ann Arbor, MI 48104 USA. [Zhang, Zhenzhen; Sanchez, Brisa N.] Univ Michigan, Sch Publ Hlth, Dept Biostat, 1415 Washington Hts, Ann Arbor, MI 48109 USA. [Ferguson, Kelly K.; Meeker, John D.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, 1415 Washington Hts, Ann Arbor, MI 48109 USA. [Ferguson, Kelly K.] NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. [Cantoral, Alejandra; Tellez-Rojo, Maria M.] Univ 655 Colonia Santa Maria Ahuacatitlan, Natl Inst Publ Hlth, Ctr Res Nutr & Hlth, Cuernavaca 62100, Morelos, Mexico. [Pawlowski, Carolyn M.] CS Mott Childrens Hosp, Brandon Newborn Intens Care Unit, 1540 E Hosp Dr, Ann Arbor, MI 48109 USA. RP Peterson, KE (reprint author), Univ Michigan, Sch Publ Hlth, Dept Nutr Sci, 1415 Washington Hts, Ann Arbor, MI 48109 USA.; Peterson, KE (reprint author), Harvard Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA.; Peterson, KE (reprint author), Univ Michigan, Ctr Human Growth & Dev, 300 N Ingalls St, Ann Arbor, MI 48104 USA. EM karenep@umich.edu OI Ferguson, Kelly/0000-0001-8467-3250 FU National Institute of Environmental Health Sciences (NIEHS); Environmental Protection Agency (EPA) [R01ES007821, P20 ES018171/RD83480001, P30 ES017885, P01 ES02284401/RD 83543601]; National Institute of Public Health, Ministry of Health, Mexico FX This research was supported in part by the National Institute of Environmental Health Sciences (NIEHS) and Environmental Protection Agency (EPA) Grants R01ES007821, P20 ES018171/RD83480001, P30 ES017885, P01 ES02284401/RD 83543601 and by the National Institute of Public Health, Ministry of Health, Mexico. The American British Cowdray Hospital provided the facilities used to conduct this research. NR 30 TC 1 Z9 1 U1 5 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD AUG PY 2016 VL 20 IS 8 BP 1713 EP 1719 DI 10.1007/s10995-016-1974-4 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DQ6WY UT WOS:000379347900016 PM 27150949 ER PT J AU Koster, A Shiroma, EJ Caserotti, P Matthews, CE Chen, KY Glynn, NW Harris, TB AF Koster, Annemarie Shiroma, Eric J. Caserotti, Paolo Matthews, Charles E. Chen, Kong Y. Glynn, Nancy W. Harris, Tamara B. TI Comparison of Sedentary Estimates between activPAL and Hip- and Wrist-Worn ActiGraph SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE ACCELEROMETRY; SITTING; SEDENTARY BEHAVIOR; VALIDATION STUDIES; SENSITIVITY AND SPECIFICITY; OLDER ADULTS ID PHYSICAL-ACTIVITY; UNITED-STATES; OLDER-ADULTS; ACCELEROMETER; CALIBRATION; VALIDATION; BEHAVIOR; MONITORS AB Purpose: Sedentary behavior is an emerging independent health risk factor. The accuracy of measuring sedentary time using accelerometers may depend on the wear location. This study in older adults evaluated the accuracy of various hip-and wrist-worn ActiGraph accelerometer cutoff points to define sedentary time using the activPAL as the reference method. Methods: Data from 62 adults (mean age, 78.4 yr) of the Aging Research Evaluating Accelerometry study were used. Participants simultaneously wore an activPAL accelerometer on the thigh and ActiGraph accelerometers on the hip, dominant, and nondominant wrist for 7 d in a free-living environment. Using the activPAL as the reference criteria, we compared classification of sedentary time to hip-worn and wrist-worn ActiGraph accelerometers over a range of cutoff points for both 60-s and 15-s epochs. Results: The optimal cutoff point for the hip vertical axis was <22 counts per minute with an area under the curve (AUC) of 0.85; the optimal hip vector magnitude cutoff point was <174 counts per minute with an AUC of 0.89. For the dominant wrist, the optimal vector magnitude cutoff point to define sedentary time was <2303 counts per minute (AUC, 0.86) and for the nondominant wrist <1853 counts per minute (AUC, 0.86). The optimal 15-s cutoff points resulted in lower agreements compared with activPAL. Conclusions: Hip-and wrist-worn ActiGraph data may be used to define sedentary time with a moderate to high accuracy when compared with activPAL. The observed optimal cutoff point for hip vertical axis <22 counts per minute is substantially lower than the standard <100 counts per minute. It is unknown how these optimal cutoff points perform in different populations. Results on an individual basis should therefore be interpreted with caution. C1 [Koster, Annemarie] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Social Med, Maastricht, Netherlands. [Shiroma, Eric J.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Caserotti, Paolo] Univ Southern Denmark, Dept Sports Sci & Clin Biomech, Odense, Denmark. [Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chen, Kong Y.] NIDDK, Diabet Endocrinol & Obes Branch, Bethesda, MD 20892 USA. [Glynn, Nancy W.] Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Aging & Populat Hlth, Pittsburgh, PA USA. RP Koster, A (reprint author), POB 616, NL-6200 MD Maastricht, Netherlands. EM a.koster@maastrichtuniversity.nl RI Koster, Annemarie/E-7438-2010; OI Glynn, Nancy/0000-0003-2265-0162; Chen, Kong/0000-0002-0306-1904 FU National Institutes of Health, National Institute on Aging; National Institutes of Health [AG024826, AG024827, AG036594, AG000181]; European Union [PCIG09-GA-2011-293621] FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging and by the research grants AG024826, AG024827, AG036594, and AG000181 from the National Institutes of Health. A Koster has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2011-CIG) under grant agreement PCIG09-GA-2011-293621. We are grateful to the staff of the AREA and DECO studies, particularly BS Lange-Maia, ME Garcia, MA Schepps, and JR Treinish. The results of the present study do not constitute endorsement by ACSM. NR 24 TC 2 Z9 2 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD AUG PY 2016 VL 48 IS 8 BP 1514 EP 1522 DI 10.1249/MSS.0000000000000924 PG 9 WC Sport Sciences SC Sport Sciences GA DR2TP UT WOS:000379757100011 PM 27031744 ER PT J AU Yang, L Yu, P Chen, X Cai, T AF Yang, Liu Yu, Ping Chen, Xiang Cai, Tao TI The de novo missense mutation N117S in skeletal muscle alpha-actin 1 causes a mild form of congenital nemaline myopathy SO MOLECULAR MEDICINE REPORTS LA English DT Article DE nemaline myopathy; target-capture sequencing; ACTA1; mutation; Chinese ID GENE; DISEASE AB Nemaline myopathy (NM) constitutes a spectrum of primary skeletal muscle disorders, the diagnosis of which is based on muscle weakness and the visualization of nemaline bodies in muscle biopsies. Mutations in several NM causal genes have been attributed to the majority of NM cases, particularly mutations in nebulin and skeletal muscle alpha-actin 1 (ACTA1), which are responsible for similar to 70% of cases; therefore, a genetic diagnostic strategy using targeted gene sequencing may potentially improve the diagnosis of suspected NM. The present study identified a de novo mutation in ACTA1 (c.350A>G; p.Asn117Ser) in a Chinese patient using target-capture sequencing of a panel containing 125 known causal genes for inherited muscle diseases. Clinical analyses revealed that the case described in the present study exhibited a relatively mild phenotype with regards to muscle weakness, as compared with more severe phenotypes reported in several other patients with the same mutation, thus suggesting the existence of genetic modifiers. In conclusion, this approach may be helpful for the identification of clinically undiagnosed patients with highly heterogeneous disorders. C1 [Yang, Liu; Chen, Xiang] Wenzhou Med Univ, Affiliated Hosp 2, Phys Med & Rehabil Ctr, 109 Xueyuan Western Rd, Wenzhou 325027, Zhejiang, Peoples R China. [Yang, Liu; Chen, Xiang] Wenzhou Med Univ, Yuying Childrens Hosp, 109 Xueyuan Western Rd, Wenzhou 325027, Zhejiang, Peoples R China. [Yu, Ping; Cai, Tao] Wenzhou Med Univ, Inst Genom Med, Wenzhou 325027, Zhejiang, Peoples R China. [Cai, Tao] Natl Inst Dent & Craniofacial Res, Expt Med Sect, NIH, 30 Convent Dr, Bethesda, MD 20892 USA. RP Chen, X (reprint author), Wenzhou Med Univ, Affiliated Hosp 2, Phys Med & Rehabil Ctr, 109 Xueyuan Western Rd, Wenzhou 325027, Zhejiang, Peoples R China.; Chen, X (reprint author), Wenzhou Med Univ, Yuying Childrens Hosp, 109 Xueyuan Western Rd, Wenzhou 325027, Zhejiang, Peoples R China.; Cai, T (reprint author), Natl Inst Dent & Craniofacial Res, Expt Med Sect, NIH, 30 Convent Dr, Bethesda, MD 20892 USA. EM chenxiangnj2005@aliyun.com.cn; tcai@mail.nih.gov FU Chinese Ministry of Health [201302002]; Wenzhou Medical University FX The present study was supported by research funding from the Chinese Ministry of Health Project (grant no. 201302002 to X.C) and Wenzhou Medical University Research Funding (to P.Y.). NR 22 TC 0 Z9 0 U1 1 U2 1 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1791-2997 EI 1791-3004 J9 MOL MED REP JI Mol. Med. Rep. PD AUG PY 2016 VL 14 IS 2 BP 1693 EP 1696 DI 10.3892/mmr.2016.5429 PG 4 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA DQ9UK UT WOS:000379554600085 PM 27357517 ER PT J AU Sharp, D Wasserman, D AF Sharp, Daniel Wasserman, David TI Deep Brain Stimulation, Historicism, and Moral Responsibility SO NEUROETHICS LA English DT Article DE Deep brain stimulation; Moral responsibility; Historicism; Manipulation argument; Compatibilism; Neuroethics AB Although philosophers have explored several connections between neuroscience and moral responsibility, the issue of how real-world neurological modifications, such as Deep Brain Stimulation (DBS), impact moral responsibility has received little attention. In this article, we draw on debates about the relevance of history and manipulation to moral responsibility to argue that certain kinds of neurological modification can diminish the responsibility of the agents so modified. We argue for a historicist position - a version of the history-sensitive reflection view - and defend that account against a rival, relational view of responsibility. We conclude that DBS can, under certain conditions, diminish responsibility, and explore the circumstances under which this might be so. We conclude by suggesting that philosophical debates about moral responsibility, manipulation, and history have greater practical relevance than is sometimes thought, and that attention to practical cases can help inform and deepen this body of scholarship. C1 [Sharp, Daniel] NYU, Dept Philosophy, 5 Washington Pl, New York, NY 10031 USA. [Wasserman, David] NIH, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. RP Sharp, D (reprint author), NYU, Dept Philosophy, 5 Washington Pl, New York, NY 10031 USA. EM des361@nyu.edu; david.wasserman@nih.gov NR 31 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1874-5490 EI 1874-5504 J9 NEUROETHICS-NETH JI Neuroethics PD AUG PY 2016 VL 9 IS 2 BP 173 EP 185 DI 10.1007/s12152-016-9260-0 PG 13 WC Ethics; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Biomedical Social Sciences GA DR1RZ UT WOS:000379683900029 ER PT J AU Mathur, MB Epel, E Kind, S Desai, M Parks, CG Sandler, DP Khazeni, N AF Mathur, Maya B. Epel, Elissa Kind, Shelley Desai, Manisha Parks, Christine G. Sandler, Dale P. Khazeni, Nayer TI Toward a mechanistic understanding of psychosocial factors in telomere degradation SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Letter C1 [Mathur, Maya B.; Desai, Manisha] Stanford Univ, Quantitat Sci Unit, Palo Alto, CA 94304 USA. [Mathur, Maya B.] Harvard Univ, Dept Biostat, Boston, MA 02115 USA. [Epel, Elissa] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Kind, Shelley] Suffolk Univ, Dept Psychol, Boston, MA 02114 USA. [Parks, Christine G.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Khazeni, Nayer] Stanford Univ, Div Pulm & Crit Care Med, Stanford, CA 94305 USA. [Khazeni, Nayer] Stanford Univ, Ctr Hlth Policy, Stanford, CA 94305 USA. [Khazeni, Nayer] Stanford Univ, Ctr Primary Care & Outcomes Res, Stanford, CA 94305 USA. RP Mathur, MB (reprint author), Care of Sayfer I, Stanford Univ, Quantitat Sci Unit, 1070 Arastradero Rd, Stanford, CA 94305 USA. EM mmathur@stanford.edu OI Parks, Christine/0000-0002-5734-3456 NR 5 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD AUG PY 2016 VL 56 BP 413 EP 413 DI 10.1016/j.bbi.2016.04.011 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DQ1UJ UT WOS:000378985600040 PM 27112382 ER PT J AU Levy, EB Krishnasamy, VP Lewis, AL Willis, S Macfarlane, C Anderson, V van der Bom, IMJ Radaelli, A Dreher, MR Sharma, KV Negussie, A Mikhail, AS Geschwind, JFH Wood, BJ AF Levy, Elliot B. Krishnasamy, Venkatesh P. Lewis, Andrew L. Willis, Sean Macfarlane, Chelsea Anderson, Victoria van der Bom, Imramsjah M. J. Radaelli, Alessandro Dreher, Matthew R. Sharma, Karun V. Negussie, Ayele Mikhail, Andrew S. Geschwind, Jean-Francois H. Wood, Bradford J. TI First Human Experience with Directly Image-able Iodinated Embolization Microbeads SO CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article DE Hepatic; Embolization; Image-able ID DRUG-ELUTING BEADS; TRANSCATHETER EMBOLOTHERAPY; CHEMOEMBOLIZATION AB To describe first clinical experience with a directly image-able, inherently radio-opaque microspherical embolic agent for transarterial embolization of liver tumors. LC Bead LUMI (TM) is a new product based upon sulfonate-modified polyvinyl alcohol hydrogel microbeads with covalently bound iodine (similar to 260 mg I/ml). 70-150 mu LC Bead LUMI (TM) iodinated microbeads were injected selectively via a 2.8 Fr microcatheter to near complete flow stasis into hepatic arteries in three patients with hepatocellular carcinoma, carcinoid, or neuroendocrine tumor. A custom imaging platform tuned for LC LUMI (TM) microbead conspicuity using a cone beam CT (CBCT)/angiographic C-arm system (Allura Clarity FD20, Philips) was used along with CBCT embolization treatment planning software (EmboGuide, Philips). LC Bead LUMI (TM) image-able microbeads were easily delivered and monitored during the procedure using fluoroscopy, single-shot radiography (SSD), digital subtraction angiography (DSA), dual-phase enhanced and unenhanced CBCT, and unenhanced conventional CT obtained 48 h after the procedure. Intra-procedural imaging demonstrated tumor at risk for potential under-treatment, defined as paucity of image-able microbeads within a portion of the tumor which was confirmed at 48 h CT imaging. Fusion of pre- and post-embolization CBCT identified vessels without beads that corresponded to enhancing tumor tissue in the same location on follow-up imaging (48 h post). LC Bead LUMI (TM) image-able microbeads provide real-time feedback and geographic localization of treatment in real time during treatment. The distribution and density of image-able beads within a tumor need further evaluation as an additional endpoint for embolization. C1 [Levy, Elliot B.; Krishnasamy, Venkatesh P.; Anderson, Victoria; Negussie, Ayele; Mikhail, Andrew S.; Wood, Bradford J.] NIH, Ctr Intervent Oncol, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lewis, Andrew L.; Willis, Sean; Macfarlane, Chelsea; Dreher, Matthew R.] UK Ltd, Biocompatibles, Watchmoor Pk, Camberley GU15 3YL, Surrey, England. [van der Bom, Imramsjah M. J.] Philips, Image Guided Intervent Clin Sci IGT Syst North &, 2 Canal Pk, Cambridge, MA 02141 USA. [Radaelli, Alessandro] Philips, Image Guided Intervent, Image Guided Therapy Syst, Veenpluis 4-6, NL-5680 DA Best, Netherlands. [Sharma, Karun V.] Childrens Natl Med Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. [Geschwind, Jean-Francois H.] Dept Radiol & Biomed Imaging, 330 Cedar St,POB 208042, New Haven, CT 06520 USA. RP Levy, EB (reprint author), NIH, Ctr Intervent Oncol, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM levyeb@cc.nih.gov OI Lewis, Andrew/0000-0001-5779-5631; Mikhail, Andrew/0000-0001-9206-5765 FU CRADA; Philips; Biocompatibles/BTG; Intramural Research Program of the NIH; Center of Interventional Oncology [ZID BC011242-08] FX The NIH authors are supported by CRADA's with Philips (B.W.) and with Biocompatibles/BTG (B.W). This work also supported by the Intramural Research Program of the NIH and the Center of Interventional Oncology, Grant/Z Number ZID BC011242-08. NIH may own intellectual property in the field. NR 12 TC 3 Z9 3 U1 5 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0174-1551 EI 1432-086X J9 CARDIOVASC INTER RAD JI Cardiovasc. Interv. Radiol. PD AUG PY 2016 VL 39 IS 8 BP 1177 EP 1186 DI 10.1007/s00270-016-1364-8 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DQ4KG UT WOS:000379172100014 PM 27206503 ER PT J AU Mungunsukh, O Lee, YH Bottaro, DP Day, RM AF Mungunsukh, Ognoon Lee, Young H. Bottaro, Donald P. Day, Regina M. TI The hepatocyte growth factor isoform NK2 activates motogenesis and survival but not proliferation due to lack of Akt activation SO CELLULAR SIGNALLING LA English DT Article DE Pulmonary; Tissue repair; HGF isoforms; Signal transduction; Fibrosis ID RECEPTOR TYROSINE KINASE; SCATTER FACTOR-RECEPTOR; EPITHELIAL-CELL LINES; INDUCED APOPTOSIS; MET RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE; ENDOTHELIAL-CELLS; SIGNALING PATHWAY; PROTEIN-KINASE; FACTOR GENE AB Hepatocyte growth factor (HGF) is a pleiotrophic factor involved in cellular proliferation, migration and morphogenesis. HGF is required for normal tissue and organ development during embryogenesis, but in the adult HGF has been demonstrated to drive normal tissue repair and inhibit fibrotic remodeling. HGF has two naturally occurring human isoforms as a result of alternative splicing, NK1 and NK2. While NK1 has been defined as an agonist for HGF receptor, Met, NK2 is defined as a partial Met antagonist. Furthermore, under conditions of fibrotic remodeling, NK2 is still expressed while full length HGF is suppressed. Furthermore, the mechanism by which NK2 partially signals through Met is not completely understood. Here, we investigated the mitogenic, motogenic, and anti-apoptotic activities of NK2 compared with full length HGF in primary human bronchial epithelial cells (BEpC) and bovine pulmonary artery endothelial cells (PAEC). In human BEpC, NK2 partial activated Met, inducing Met phosphorylation at Y1234/1235 in the tyrosine-kinase domain but not at Y1349 site in the multifunctional docking domain. Partial phosphorylation of Met by NK2 resulted in activation of MAPK and STAT3, but not AKT. This correlated with motogenesis and survival in a MAPK-dependent manner, but not cell proliferation. Overexpression of a constitutively active AKT complemented NK2 signaling, allowing NK2 to induce cell proliferation. These data indicate that NK2 and HGF drive motogenic and anti-apoptotic signaling but only HGF drives cell proliferation by activating AKT-pathway signaling. These results have implications for the biological consequences of differential regulation of the two isoforms under pro-fibrotic conditions. Published by Elsevier Inc. C1 [Mungunsukh, Ognoon; Day, Regina M.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bldg C Rm 2023,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Lee, Young H.; Bottaro, Donald P.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Day, RM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bldg C Rm 2023,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM Regina.day@usuhs.edu FU National Institutes of Health [HL-073939]; Uniformed Services University of the Health Sciences [C075QE]; American Heart Association FX This work was supported by National Institutes of Health grant HL-073939 and a Uniformed Services University of the Health Sciences grant (to R.M.D.) (C075QE) and by a predoctoral fellowship from the American Heart Association (to Y.H.L.). Some of the authors are employees of the U.S. Government, and this manuscript was prepared as part of their official duties. Title 17 U.S.C. 105 provides that 'Copyright protection under this title is not available for any work of the United States Government.' Title 17 U.S.C. 101 defined a U.S. Government work as a work prepared by a military service member or employees of the U.S. Government as part of that person's official duties. The views in this article are those of the authors and do not necessarily reflect the views, official policy, or position of the Uniformed Services University of the Health Sciences, Department of the Navy, Department of Defense, or the U.S. Federal Government. NR 80 TC 0 Z9 0 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD AUG PY 2016 VL 28 IS 8 BP 1114 EP 1123 DI 10.1016/j.cellsig.2016.05.012 PG 10 WC Cell Biology SC Cell Biology GA DP7HX UT WOS:000378670900033 PM 27224506 ER PT J AU Damiano, DL Zampieri, C Ge, J Acevedo, A Dsurney, J AF Damiano, Diane L. Zampieri, Cristiane Ge, Jie Acevedo, Ana Dsurney, John TI Effects of a rapid-resisted elliptical training program on motor, cognitive and neurobehavioral functioning in adults with chronic traumatic brain injury SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE Coordination; Motion; Cognition; TBI; Exercise ID OLDER-ADULTS; CONTROLLED-TRIAL; VIRTUAL-REALITY; EXERCISE; BALANCE; INDIVIDUALS; WALKING; IMPAIRMENT; BENEFITS; MOBILITY AB This small clinical trial utilized a novel rehabilitation strategy, rapid-resisted elliptical training, in an effort to increase motor, and thereby cognitive, processing speed in ambulatory individuals with traumatic brain injury (TBI). As an initial step, multimodal functional abilities were quantified and compared in 12 ambulatory adults with and 12 without TBI. After the baseline assessment, the group with TBI participated in an intensive 8-week daily exercise program using an elliptical trainer and was reassessed after completion and at an 8-week follow-up. The focus of training was on achieving a fast movement speed, and once the target was reached, resistance to motion was increased in small increments to increase intensity of muscle activation. Primary outcomes were: High-Level Mobility Assessment Tool (HiMAT), instrumented balance tests, dual-task (DT) performance and neurobehavioral questionnaires. The group with TBI had poorer movement excursion during balance tests and poorer dual-task (DT) performance. After training, balance reaction times improved and were correlated with gains in the HiMAT and DT. Sleep quality also improved and was correlated with improved depression and learning. This study illustrates how brain injury can affect multiple linked aspects of functioning and provides preliminary evidence that intensive rapid-resisted training has specific positive effects on dynamic balance and more generalized effects on sleep quality in TBI. C1 [Damiano, Diane L.; Zampieri, Cristiane] Dept Rehabil Med, Funct & Appl Biomech Sect, 10 Ctr Dr,Room 1-1468,MSC 1604, Bethesda, MD 20892 USA. [Ge, Jie] Univ Maryland, Sch Dent, 650 West Baltimore St, Baltimore, MD 21201 USA. [Acevedo, Ana] NIH, Dept Rehabil Med, Ctr Clin, 10 Ctr Dr,Room 1-1469,MSC 1604, Bethesda, MD 20892 USA. [Dsurney, John] NIH, Dept Rehabil Med, CNRM, Ctr Clin, 10 Ctr Dr,Room 1-1468,MSC 1604, Bethesda, MD 20892 USA. RP Damiano, DL (reprint author), Dept Rehabil Med, Funct & Appl Biomech Sect, 10 Ctr Dr,Room 1-1468,MSC 1604, Bethesda, MD 20892 USA. EM damianod@cc.nih.gov; zampierigallac@cc.nih.gov; jie.ge@umaryland.edu; acevedoat@cc.nih.gov; john.dsurney@nih.gov FU Intramural Research Program of the National Institutes of Health, Clinical Center, Rehabilitation Medicine Department [10-CC-0150]; Center for Neuroscience and Regenerative Medicine FX This research was supported by the Intramural Research Program of the National Institutes of Health, Clinical Center, Rehabilitation Medicine Department (Protocol #10-CC-0150), and by the Center for Neuroscience and Regenerative Medicine. NR 34 TC 0 Z9 0 U1 11 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 EI 1432-1106 J9 EXP BRAIN RES JI Exp. Brain Res. PD AUG PY 2016 VL 234 IS 8 BP 2245 EP 2252 DI 10.1007/s00221-016-4630-8 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DQ5RK UT WOS:000379262400013 PM 27025506 ER PT J AU Kim, Y Kim, WS Koh, K Yoon, B Damiano, DL Shim, JK AF Kim, Yushin Kim, Woo-Sub Koh, Kyung Yoon, BumChul Damiano, Diane L. Shim, Jae Kun TI Deficits in motor abilities for multi-finger force control in hemiparetic stroke survivors SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE Stroke; Motor activity; Fingers; Psychomotor performance; Nervous system; Functional capacity impairment ID JOINT COORDINATION; PRODUCTION TASKS; POSTSTROKE HEMIPARESIS; PREMOTOR CORTEX; ARM FUNCTION; POST-STROKE; BLOCK TEST; VARIABILITY; RELIABILITY; PERFORMANCE AB The ability to control redundant motor effectors is one of hallmarks in human motor control, and the topic has been studied extensively over several decades since the initial inquiries proposed by Nicholi Bernstein. However, our understanding of the influence of stroke on the control of redundant motor systems is very limited. This study aimed to investigate the effect of stroke-related constraints on multi-finger force control abilities in a visuomotor task. Impaired (IH) and less-impaired hands (LH) of 19 hemiparetic stroke survivors and 19 age-matched control subjects were examined. Each hand repeatedly produced isometric forces to match a target force of 5 N shown on a computer screen using all four fingers. The hierarchical variability decomposition (HVD) model was used to separate force-matching errors (motor performance) into task-relevant measures (accuracy, steadiness, and reproducibility). Task-irrelevant sources of variability in individual finger force profiles within and between trials (flexibility and multiformity) were also quantified. The IH in the stroke survivors showed deficits in motor performance attributed mainly to lower accuracy and reproducibility as compared to control hands (p < 0.05). The LH in stroke survivors showed lower reproducibility and both hands in stroke also had higher multiformity than the control hands (p < 0.05). The findings from our HVD model suggest that accuracy, reproducibility, and multiformity were mainly impaired during force-matching task in the stroke survivors. The specific motor deficits identified through the HVD model with the new conceptual framework may be considered as critical factors for scientific investigation on stroke and evidence-based rehabilitation of this population. C1 [Kim, Yushin; Damiano, Diane L.] NIH, Funct Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA. [Kim, Woo-Sub] Korea Univ, Dept Rehabil Med, Guro Hosp, Seoul 08308, South Korea. [Koh, Kyung; Shim, Jae Kun] Univ Maryland, Sch Publ Hlth 0110F, Dept Kinesiol, 4200 Valley Dr, College Pk, MD 20742 USA. [Yoon, BumChul] Korea Univ, Dept Phys Therapy, Seoul, South Korea. [Shim, Jae Kun] Kyung Hee Univ, Dept Mech Engn, Coll Engn, Yongin, South Korea. RP Kim, WS (reprint author), Korea Univ, Dept Rehabil Med, Guro Hosp, Seoul 08308, South Korea.; Shim, JK (reprint author), Univ Maryland, Sch Publ Hlth 0110F, Dept Kinesiol, 4200 Valley Dr, College Pk, MD 20742 USA.; Shim, JK (reprint author), Kyung Hee Univ, Dept Mech Engn, Coll Engn, Yongin, South Korea. EM Jelmanoo@naver.com; jkshim@umd.edu OI Kim, Woo-Sub/0000-0002-3185-0062 FU National Research Foundation of Korea [NRF-2013004812]; Translational Research Center for Rehabilitation Robots, Korea National Rehabilitation Center, Ministry of Health Welfare, Korea [NRCTR-EX15007]; Intramural Research Program at the National Institutes of Health (NIH) Clinical Center; Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI); Ministry of Health & Welfare, Republic of Korea [HI14C1155] FX We thank Taeyoung Kim, PT, M.Sc. for assistance with data collection. The research was funded in part by National Research Foundation (NRF-2013004812) of Korea and the Translational Research Center for Rehabilitation Robots, Korea National Rehabilitation Center, Ministry of Health & Welfare, Korea (NRCTR-EX15007) and by the Intramural Research Program at the National Institutes of Health (NIH) Clinical Center. This research was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1155). NR 51 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 EI 1432-1106 J9 EXP BRAIN RES JI Exp. Brain Res. PD AUG PY 2016 VL 234 IS 8 BP 2391 EP 2402 DI 10.1007/s00221-016-4644-2 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DQ5RK UT WOS:000379262400026 PM 27071926 ER PT J AU Chan, A Singh, AJ Northcote, PT Miller, JH AF Chan, Ariane Singh, A. Jonathan Northcote, Peter T. Miller, John H. TI Peloruside A, a microtubule-stabilizing agent, induces aneuploidy in ovarian cancer cells SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE BUBR1; p55CDC; Peloruside A; MAD2; Microtubule; Aneuploidy; Mitosis; Spindle checkpoint ID SPINDLE-ASSEMBLY CHECKPOINT; MEROTELIC KINETOCHORE ORIENTATION; MAMMALIAN TISSUE-CELLS; MITOTIC CHECKPOINT; SACCHAROMYCES-CEREVISIAE; CHROMOSOMAL INSTABILITY; PROMOTING COMPLEX; TAXOID SITE; CYCLIN-B; BUBR1 AB To ensure proper chromosome segregation, mitosis is tightly regulated by the spindle assembly checkpoint (SAC). Low concentrations of microtubule-stabilizing agents can induce aneuploid populations of cells in the absence of G(2)/M block, suggesting pertubation of the spindle checkpoint. We investigated the effects of peloruside A, a microtubule-stabilizing agent, on expression levels of several key cell cycle proteins, MAD2, BUBR1, p55CDC and cyclin B1. Synchronized 1A9 ovarian carcinoma cells were allowed to progress through the cell cycle in the presence or absence of peloruside A. Co-immunoprecipitation and Western blotting were used to probe the cell cycle kinetics of MAD2 and BUBR1 dissociation from p55CDC. Using confocal microscopy, we investigated whether premature dissociation of MAD2 and BUBR1 at low (40 nM) but not high (100 nM) concentrations of peloruside A was caused by defects in the attachment of chromosomes to the mitotic spindle. An increased frequency of polar chromosomes was observed at low concentrations of peloruside A, suggesting that an increased frequency of pseudo-metaphase cells, which are not detected by the spindle assembly checkpoint, may be underlying the induction of aneuploidy. C1 [Chan, Ariane; Miller, John H.] Victoria Univ Wellington, Sch Biol Sci, POB 600, Wellington 6140, New Zealand. [Chan, Ariane; Singh, A. Jonathan; Northcote, Peter T.; Miller, John H.] Victoria Univ Wellington, Ctr Biodiscovery, POB 600, Wellington 6140, New Zealand. [Chan, Ariane] Volpara Solut Ltd, Level 12,86 Victoria St, Wellington 6011, New Zealand. [Singh, A. Jonathan; Northcote, Peter T.] Victoria Univ Wellington, Sch Chem & Phys Sci, POB 600, Wellington 6140, New Zealand. [Singh, A. Jonathan] Natl Canc Inst Frederick, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Miller, JH (reprint author), Victoria Univ Wellington, Sch Biol Sci, POB 600, Wellington 6140, New Zealand.; Miller, JH (reprint author), Victoria Univ Wellington, Ctr Biodiscovery, POB 600, Wellington 6140, New Zealand. EM john.h.miller@vuw.ac.nz FU Cancer Society of New Zealand; Wellington Medical Research Foundation; Victoria University of Wellington; Genesis Oncology Trust of New Zealand FX This work was supported by grants from the Cancer Society of New Zealand (JHM), Wellington Medical Research Foundation (JHM, PTN), and Victoria University of Wellington (JHM, AC) and a PhD scholarship from the Genesis Oncology Trust of New Zealand (AC). NR 50 TC 0 Z9 0 U1 2 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD AUG PY 2016 VL 34 IS 4 BP 424 EP 438 DI 10.1007/s10637-016-0355-6 PG 15 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DQ2EP UT WOS:000379015000004 PM 27155614 ER PT J AU Rosen, D Patel, N Pavletic, N Grillon, C Pine, DS Ernst, M AF Rosen, Dana Patel, Nilam Pavletic, Nevia Grillon, Christian Pine, Daniel S. Ernst, Monique TI Age and Social Context Modulate the Effect of Anxiety on Risk-taking in Pediatric Samples SO JOURNAL OF ABNORMAL CHILD PSYCHOLOGY LA English DT Article DE Peer judgement; Adolescents; Children; Clinical anxiety ID ADOLESCENT BRAIN; DECISION-MAKING; MOTIVATED BEHAVIOR; PEER INFLUENCE; TRIADIC MODEL; DISORDERS; PERSPECTIVE; AVOIDANCE; CHILDREN; MATURATION AB Although risk-taking has been studied from a developmental perspective, no study has examined how anxiety, age, risk-valence and social context interact to modulate decision-making in youths. This study probes this question using a risk-taking task, the Stunt Task, in clinically anxious children (n = 17, 10 F, age = 8.3-12.1 years), healthy children (n = 13, 4 F, age = 9.3-12.2 years), clinically anxious adolescents (n = 18, 6 F, age = 12.3-17.7 years), and healthy adolescents (n =14, 10 F, age = 12.5-17.3 years). Social context was manipulated: in one condition, participants were led to believe that a group of peers were observing and judging their performance (peer-judge), while, in the other condition, they were led to believe that peers were not observing them (control). Only anxious children showed an influence of social context on their risk-taking behavior. Specifically, anxious children bet significantly less and had slower reaction times (RT) during the peer-judge than control condition. However, across social conditions, risk-valence modulated RT differently in function of age and diagnosis. Anxious children were slower on the positive-valence risky trial, whereas anxious adolescents were slower on the negative-valence risky trials relative to their respective healthy peers. In conclusion, clinically anxious children were the only group that was sensitive (risk-averse) to the effect of a negative peer-judge context. The negative peer-judge context did not affect risky decision-making in adolescents, whether they were anxious or healthy. Future work using a stronger aversive social context might be more effective at influencing risky behavior in this age group. C1 [Rosen, Dana; Patel, Nilam; Pavletic, Nevia; Grillon, Christian; Pine, Daniel S.; Ernst, Monique] NIMH, NIH, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. RP Ernst, M (reprint author), NIMH, NIH, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health FX This study was funded by the Intramural Research Program of the National Institute of Mental Health. NR 44 TC 0 Z9 0 U1 11 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0627 EI 1573-2835 J9 J ABNORM CHILD PSYCH JI J. Abnorm. Child Psychol. PD AUG PY 2016 VL 44 IS 6 BP 1161 EP 1171 DI 10.1007/s10802-015-0098-4 PG 11 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA DQ5CH UT WOS:000379221500011 PM 26659306 ER PT J AU Kalb, LG Vasa, RA Ballard, ED Woods, S Goldstein, M Wilcox, HC AF Kalb, Luther G. Vasa, Roma A. Ballard, Elizabeth D. Woods, Steven Goldstein, Mitchell Wilcox, Holly C. TI Epidemiology of Injury-Related Emergency Department Visits in the US Among Youth with Autism Spectrum Disorder SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autistic disorder; Injury; Epidemiology; Intellectual disability; Emergency medicine ID CHILDREN; RISK; PSYCHOPATHOLOGY; DISABILITIES; ADOLESCENTS AB Several reports suggest children with autism spectrum disorder (ASD) are more likely to be seen for injury-related ED visits; however, no nationally representative study has examined this question. Using data from the 2008 Nationwide Emergency Department Sample, over a quarter of all visits among those with ASD were related to injury. In the multivariate analyses, the odds of an injury-related visit was 54 % greater among those with ASD compared to youth with intellectual disability (ID), but 48 % less compared to youth without ID or ASD. Compared to all other pediatric injury-visits in the US, visits among children with ASD were more likely to be due to self-inflicted injury and poisoning and were more likely to result in hospitalization (all p < 0.001). C1 [Kalb, Luther G.; Vasa, Roma A.] Kennedy Krieger Inst, Ctr Autism & Related Disorders, Baltimore, MD 21205 USA. [Kalb, Luther G.; Wilcox, Holly C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA. [Vasa, Roma A.; Woods, Steven; Wilcox, Holly C.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Ballard, Elizabeth D.] NIMH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. [Goldstein, Mitchell] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. RP Kalb, LG (reprint author), Kennedy Krieger Inst, Ctr Autism & Related Disorders, Baltimore, MD 21205 USA.; Kalb, LG (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA. EM lkalb2@jhu.edu FU NICHD NIH HHS [F31 HD085755] NR 26 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD AUG PY 2016 VL 46 IS 8 BP 2756 EP 2763 DI 10.1007/s10803-016-2820-7 PG 8 WC Psychology, Developmental SC Psychology GA DQ9SC UT WOS:000379548600015 PM 27241347 ER PT J AU Arem, H Sorkin, M Cartmel, B Fiellin, M Capozza, S Harrigan, M Ercolano, E Zhou, Y Sanft, T Gross, C Schmitz, K Neogi, T Hershman, D Ligibel, J Irwin, ML AF Arem, Hannah Sorkin, Mia Cartmel, Brenda Fiellin, Martha Capozza, Scott Harrigan, Maura Ercolano, Elizabeth Zhou, Yang Sanft, Tara Gross, Cary Schmitz, Kathryn Neogi, Tuhina Hershman, Dawn Ligibel, Jennifer Irwin, Melinda L. TI Exercise adherence in a randomized trial of exercise on aromatase inhibitor arthralgias in breast cancer survivors: the Hormones and Physical Exercise (HOPE) study SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Physical activity; Exercise; Breast cancer; Aromatase inhibitors; Arthralgia ID POSTMENOPAUSAL WOMEN; AMERICAN-COLLEGE; SPORTS-MEDICINE; RECOMMENDATIONS; PREDICTORS; THERAPY; HEALTH AB Up to 50 % of postmenopausal breast cancer survivors taking aromatase inhibitors (AIs) experience AI-associated arthralgias, or joint pain, which causes many to stop taking AIs and may inhibit exercise, despite known health benefits. We thus evaluated exercise adherence and factors associated with better exercise adherence in breast cancer survivors experiencing AI-induced arthralgia in the (HOPE) year long randomized controlled trial. We included 61 HOPE women randomized to exercise (150 min/week of moderate-intensity aerobic exercise and twice-weekly supervised strength training). Our main outcomes were aerobic exercise measured with daily activity logs, attendance at supervised exercise sessions, and changes in cardiorespiratory fitness, measured maximal oxygen consumption (VO(2)max). We examined means and standard deviations (SDs) for exercise adherence by demographic and medical characteristics and used the t test for mean differences. We also examined predictors of adherence using linear regression. On average, at the end of the year long trial, women reported 119 (SD 78) min/week of moderate-intensity aerobic exercise and participated in 70 % of supervised exercise training sessions. After adjustment for other factors that influence adherence, at 6 months postrandomization, only baseline VO(2)max was associated with higher aerobic exercise levels and at 12 months, only older age predicted better supervised exercise training attendance. Breast cancer survivors taking AIs and experiencing arthralgia are able to initiate and maintain a year long exercise program, regardless of other factors that influence activity levels. Breast cancer survivors can exercise at levels that have been shown to improve AI-associated arthralgia. C1 [Arem, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sorkin, Mia; Cartmel, Brenda; Fiellin, Martha; Capozza, Scott; Harrigan, Maura; Ercolano, Elizabeth; Irwin, Melinda L.] Yale Sch Publ Hlth, New Haven, CT 06510 USA. [Cartmel, Brenda; Ercolano, Elizabeth; Zhou, Yang; Sanft, Tara; Gross, Cary; Irwin, Melinda L.] Yale Canc Ctr, New Haven, CT 06510 USA. [Schmitz, Kathryn] Univ Penn, Philadelphia, PA 19104 USA. [Neogi, Tuhina] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hershman, Dawn] Columbia Univ, New York, NY USA. [Ligibel, Jennifer] Dana Farber Canc Inst, Boston, MA 02115 USA. [Irwin, Melinda L.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, POB 208034, New Haven, CT 06520 USA. RP Irwin, ML (reprint author), Yale Sch Publ Hlth, New Haven, CT 06510 USA.; Irwin, ML (reprint author), Yale Canc Ctr, New Haven, CT 06510 USA.; Irwin, ML (reprint author), Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, POB 208034, New Haven, CT 06520 USA. EM melinda.irwin@yale.edu FU intramural research program at the National Cancer Institute; NCI [R01 CA132931]; Breast Cancer Research Foundation; Yale Cancer Center Support Grant (CCSG) [P30 CA016359]; CTSA from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH) [UL1 TR000142] FX HA is supported by the intramural research program at the National Cancer Institute. HOPE was supported by NCI R01 CA132931 and in part by a grant from the Breast Cancer Research Foundation. This study was also supported in part by the Yale Cancer Center Support Grant (CCSG) P30 CA016359 and the CTSA Grant Number UL1 TR000142 from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH). Certain data used in this study were obtained from the Connecticut Tumor Registry located in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data. NR 23 TC 1 Z9 1 U1 3 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD AUG PY 2016 VL 10 IS 4 BP 654 EP 662 DI 10.1007/s11764-015-0511-6 PG 9 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA DP7WS UT WOS:000378710500005 PM 26782031 ER PT J AU Robertson, K Jiang, H Evans, SR Marra, CM Berzins, B Hakim, J Sacktor, N Silva, MT Campbell, TB Nair, A Schouten, J Kumwenda, J Supparatpinyo, K Tripathy, S Kumarasamy, N la Rosa, A Montano, S Mwafongo, A Firnhaber, C Sanne, I Naini, L Amod, F Walawander, A AF Robertson, K. Jiang, H. Evans, S. R. Marra, C. M. Berzins, B. Hakim, J. Sacktor, N. Tulius Silva, M. Campbell, T. B. Nair, A. Schouten, J. Kumwenda, J. Supparatpinyo, K. Tripathy, S. Kumarasamy, N. la Rosa, A. Montano, S. Mwafongo, A. Firnhaber, C. Sanne, I. Naini, L. Amod, F. Walawander, A. CA 5271 Study Team AIDS Clinical Trials Grp TI International neurocognitive normative study: neurocognitive comparison data in diverse resource-limited settings: AIDS Clinical Trials Group A5271 SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE Neurocognitive assessment; Normative comparison data; Resource limited; Cognitive impairment; Neuropsychological functioning ID INFECTED INDIVIDUALS; HIV AB Infrastructure for conducting neurological research in resource-limited settings (RLS) is limited. The lack of neurological and neuropsychological (NP) assessment and normative data needed for clinical interpretation impedes research and clinical care. Here, we report on ACTG 5271, which provided neurological training of clinical site personnel and collected neurocognitive normative comparison data in diverse settings. At ten sites in seven RLS countries, we provided training for NP assessments. We collected normative comparison data on HIV- participants from Brazil (n = 240), India (n = 480), Malawi (n = 481), Peru (n = 239), South Africa (480), Thailand (n = 240), and Zimbabwe (n = 240). Participants had a negative HIV test within 30 days before standardized NP exams were administered at baseline and 770 at 6 months. Participants were enrolled in eight strata, gender (female and male), education (< 10 and a parts per thousand yen10 years), and age (< 35 and a parts per thousand yen35 years). Of 2400 enrolled, 770 completed the 6-month follow-up. As expected, significant between-country differences were evident in all the neurocognitive test scores (p < 0.0001). There was variation between the age, gender, and education strata on the neurocognitive tests. Age and education were important variables for all tests; older participants had poorer performance, and those with higher education had better performance. Women had better performance on verbal learning/memory and speed of processing tests, while men performed better on motor tests. This study provides the necessary neurocognitive normative data needed to build infrastructure for future neurological and neurocognitive studies in diverse RLS. These normative data are a much-needed resource for both clinicians and researchers. C1 [Robertson, K.] Univ N Carolina, Dept Neurol, 2127 Phys Off Bldg,170 Manning Dr, Chapel Hill, NC 27599 USA. [Jiang, H.; Evans, S. R.] Harvard Univ, Boston, MA 02115 USA. [Marra, C. M.; Schouten, J.] Univ Washington, Seattle, WA 98195 USA. [Berzins, B.] Northwestern Univ, Chicago, IL 60611 USA. [Hakim, J.] Univ Zimbabwe, Harare, Zimbabwe. [Sacktor, N.] Johns Hopkins Univ, Baltimore, MD USA. [Tulius Silva, M.] Fiocruz MS, Rio De Janeiro, Brazil. [Campbell, T. B.] Univ Colorado Denver, Aurora, CO USA. [Nair, A.; Walawander, A.] Frontier Sci, Buffalo, NY USA. NIAID, AIDS Clin Trials Grp, Div AIDS, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kumwenda, J.] Queen Elizabeth, Blantyre, Malawi. [Supparatpinyo, K.] Chiang Mai Univ, Chiang Mai, Thailand. [Tripathy, S.] NARI, Pune, Maharashtra, India. [Kumarasamy, N.] YRGCARE, Madras, Tamil Nadu, India. [la Rosa, A.; Montano, S.] Asociac Civil Impacta Salud & Educ, Lima, Peru. [Montano, S.] Naval Med Res Unit Six NAMRU 6, Lima, Peru. [Mwafongo, A.] UNC Project, Lilongwe, Malawi. [Firnhaber, C.; Sanne, I.] Univ Witwatersrand, Johannesburg, South Africa. [Naini, L.] Social Sci Syst, Silver Spring, MD USA. [Amod, F.] Univ KwaZulu Natal, Durban, South Africa. RP Robertson, K (reprint author), Univ N Carolina, Dept Neurol, 2127 Phys Off Bldg,170 Manning Dr, Chapel Hill, NC 27599 USA. EM kevinr@neurology.unc.edu FU NIAID ACTU [AI069450]; Rio de Janeiro, Brazil, CTU [AI69476]; CTU Grant [5U01AI069426-03]; YRGCARE Medical Centre Chennai, India [AI069432]; University of North Carolina Project, Kamuzu Central Hospital, Lilongwe, Malawi [AI069518]; Harare, Zimbabwe, CTU Grant [BRS-ACURE-Q-08-00173-TOOI-OOO]; Johannesburg, South Africa, CTU Grant [AI069463, BRS-ACURE-Q-07-00143 T006]; Research Institute for Health Sciences-Chiang Mai University, Thailand [AI069399, AACTG.27.5199.06]; NARI Pune, India CRS [5U01AI069417-03]; NARI-NIV Clinic, Pune, India [5U01AI069417-03]; NARI, Pune, India [5U01AI06941703]; Blantyre College of Medicine, Malawi-Johns Hopkins Project [U01A1069518]; INMENSA-Lince CRS Lima, Peru [5U01 AI069438-03, BRS-ACURE-Q-07-00141-T001-001]; Asociacion Civil Impacta Salud y Educacion, Lima, Peru [AI069438, BRS-ACURE-Q-08-00007-T-002]; Statistical and Data Management Center of the Adult AIDS Clinical Trials Group [1 U01 068634]; National Institute of Allergy and Infectious Diseases [U01AI068636]; National Institute of Mental Health (NIMH); National Institute of Dental and Craniofacial Research (NIDCR); National Institute of Mental Health; AIDS Clinical Trials Group (ACTG) - National Institute of Allergy and Infectious Diseases (NIAID) [U01AI068636]; Statistical and Data Analysis Center (SDAC) Grant [AI-068634]; [UM1 AI069481-08] FX Thomas Campbell, M.D., grant support from NIAID ACTU # AI069450.; Deise Vieira, M.D., and Marcus Tulius T Silva, M.D.-PhD-IPEC-FIOCRUZ (Site 12101) Rio de Janeiro, Brazil, CTU Grant # AI69476; Umesh Lalloo, M.D., F.R.C.P., and Rosie Mngqibisa, MB ChB, Durban, South Africa, Adult HIV CRS (Site 11201) CTU Grant # 5U01AI069426-03; Nagalingeshwaran Kumarasamy, M.B.B.S., Ph.D., and Jabin Sharma-YRGCARE Medical Centre Chennai, India (Site 11701), CTU Grant # AI069432; Mitch Matoga MBBS, Mina Hosseinipour, M.D., University of North Carolina Project, Kamuzu Central Hospital, Lilongwe, Malawi (Site 12001), CTU Grant # AI069518; Mauleen Waison and Rachel Mahachi-Parirenyatwa CRS (Site 30313), Harare, Zimbabwe, CTU Grant # BRS-ACURE-Q-08-00173-TOOI-OOO; Cynthia Firnhaber, M.D. Sharla Faesen and Daphne S. Radebe, B.A.-Wits HIV Clinical Research Site (Helen Joseph Hosp) (Site 11101) Johannesburg, South Africa, CTU Grant# AI069463; BRS-ACURE-Q-07-00143 T006; Thira Sirisanthana, M.D. and Daralak Tavornprasit-Research Institute for Health Sciences-Chiang Mai University, Thailand (Site 11501), CTU Grant # AI069399; AACTG.27.5199.06; Anjali A. Joglekar, M.B.B.S. and Srikanth Prasad Tripathy, M.D., M.B.B.S.-NARI Pune, India CRS (Site 11601), CTU Grant # 5U01AI069417-03; Manisha V. Ghate, M.B.B.S., D.C.H. and Madhura Nene, M.B.B.S.-NARI-NIV Clinic, Pune, India (Site 11603), CTU Grant # 5U01AI069417-03; Dr. Raman Gnagakhedkar and Usha Katti, M.B.B.S.-Dr. Kotnis Dispensary, NARI, Pune, India (Site 11602), CTU Grant # 5U01AI06941703; Ben Kalonga and Henry Chamba-Blantyre College of Medicine, Malawi-Johns Hopkins Project (Site 30301) CTU Grant # U01A1069518; Carlos Mosquera, M.D., and Rosa Infante, M. D.-INMENSA-Lince CRS Lima, Peru (Site 11302), CTU Grant # 5U01 AI069438-03; BRS-ACURE-Q-07-00141-T001-001; Jorge Sanchez, MD, MPH, and Juan Carlos Hurtado, M.D.-Asociacion Civil Impacta Salud y Educacion (Site 11301) Lima, Peru, CTU Grant # AI069438; BRS-ACURE-Q-08-00007-T-002; Dr. Scott R Evans and Hongyu Jiang were funded in part by the Statistical and Data Management Center of the Adult AIDS Clinical Trials Group grant 1 U01 068634.; Jeffrey Schouten, MD CTU Grant# UM1 AI069481-08.; The project described was supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases and supported by the National Institute of Mental Health (NIMH) and National Institute of Dental and Craniofacial Research (NIDCR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. This work was supported by the National Institute of Mental Health and the AIDS Clinical Trials Group (ACTG) funded by The National Institute of Allergy and Infectious Diseases (NIAID) Award Number U01AI068636 and Statistical and Data Analysis Center (SDAC) Grant Number AI-068634. Portions of this work were previously presented as WEPEB327 at the 8th International AIDS Conference, July 19-22, 2015, Vancouver, BC, CAN. NR 11 TC 1 Z9 1 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD AUG PY 2016 VL 22 IS 4 BP 472 EP 478 DI 10.1007/s13365-015-0415-2 PG 7 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA DQ1YA UT WOS:000378995700007 PM 26733457 ER PT J AU Shah, PH Moreira, DM Okhunov, Z Patel, VR Chopra, S Razmaria, AA Alom, M George, AK Yaskiv, O Schwartz, MJ Desai, M Vira, MA Richstone, L Landman, J Shalhav, AL Gill, I Kavoussi, LR AF Shah, Paras H. Moreira, Daniel M. Okhunov, Zhamshid Patel, Vinay R. Chopra, Sameer Razmaria, Aria A. Alom, Manaf George, Arvin K. Yaskiv, Oksana Schwartz, Michael J. Desai, Mihir Vira, Manish A. Richstone, Lee Landman, Jaime Shalhav, Arieh L. Gill, Inderbir Kavoussi, Louis R. TI Positive Surgical Margins Increase Risk of Recurrence after Partial Nephrectomy for High Risk Renal Tumors SO JOURNAL OF UROLOGY LA English DT Article DE nephrectomy; laparoscopy; carcinoma; renal cell; kidney neoplasms ID LAPAROSCOPIC PARTIAL NEPHRECTOMY; ASSISTED PARTIAL NEPHRECTOMY; NEPHRON-SPARING SURGERY; CELL CARCINOMA; ONCOLOGICAL OUTCOMES; ACTIVE-SURVEILLANCE; LOCAL RECURRENCE; PROSTATE-CANCER; SURVIVAL; IMPACT AB Purpose: The clinical significance of a positive surgical margin after partial nephrectomy remains controversial. The association between positive margin and risk of disease recurrence in patients with clinically localized renal neoplasms undergoing partial nephrectomy was evaluated. Materials and Methods: A retrospective multi-institutional review of 1,240 patients undergoing partial nephrectomy for clinically localized renal cell carcinoma between 2006 and 2013 was performed. Recurrence-free survival was estimated using the Kaplan-Meier method and evaluated as a function of positive surgical margin with the log rank test and Cox models adjusting for tumor size, grade, histology, pathological stage, focality and laterality. The relationship between positive margin and risk of relapse was evaluated independently for pathological high risk (pT2-3a or Fuhrman grades III-IV) and low risk (pT1 and Fuhrman grades I-II) groups. Results: A positive surgical margin was encountered in 97 (7.8%) patients. Recurrence developed in 69 (5.6%) patients during a median followup of 33 months, including 37 (10.3%) with high risk disease (eg pT2-pT3a or Fuhrman grade III-IV). A positive margin was associated with an increased risk of relapse on multivariable analysis (HR 2.08, 95% CI 1.09-3.97, p = 0.03) but not with site of recurrence. In a stratified analysis based on pathological features, a positive surgical margin was significantly associated with a higher risk of recurrence in cases considered high risk (HR 7.48, 95% CI 2.75-20.34, p < 0.001) but not low risk (HR 0.62, 95% CI 0.08-4.75, p = 0.647). Conclusions: Positive surgical margins after partial nephrectomy increase the risk of disease recurrence, primarily in patients with adverse pathological features. C1 [Shah, Paras H.; Patel, Vinay R.; Alom, Manaf; Yaskiv, Oksana; Schwartz, Michael J.; Vira, Manish A.; Richstone, Lee; Kavoussi, Louis R.] North Shore LIJ, Smith Inst Urol, Dept Urol, New Hyde Pk, New York, NY USA. [Moreira, Daniel M.] Mayo Clin, Dept Urol, Rochester, MN USA. [Okhunov, Zhamshid; Landman, Jaime] Univ Calif Irvine, Dept Urol, Irvine, CA USA. [Chopra, Sameer; Desai, Mihir; Gill, Inderbir] Univ So Calif, USC Inst Urol, Los Angeles, CA USA. [Razmaria, Aria A.; Shalhav, Arieh L.] Univ Chicago, Dept Urol, Chicago, IL 60637 USA. [George, Arvin K.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Shah, PH (reprint author), Smith Inst Urol, 405 Lakeville Rd,Suite M41,New Hyde Pk, New York, NY 11040 USA. EM pshah1023@gmail.com NR 30 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD AUG PY 2016 VL 196 IS 2 BP 327 EP 333 DI 10.1016/j.juro.2016.02.075 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DQ5SX UT WOS:000379266400009 PM 26907508 ER PT J AU Turkbey, B George, AK Choyke, PL Pinto, PA AF Turkbey, Baris George, Arvin K. Choyke, Peter L. Pinto, Peter A. TI The Efficacy of Multiparametric Magnetic Resonance Imaging and Magnetic Resonance Imaging Targeted Biopsy in Risk Classification for Patients with Prostate Cancer on Active Surveillance EDITORIAL COMMENT SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Turkbey, Baris; George, Arvin K.; Choyke, Peter L.; Pinto, Peter A.] NCI, NIH, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD AUG PY 2016 VL 196 IS 2 BP 381 EP 381 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DQ5SX UT WOS:000379266400034 PM 27154560 ER PT J AU Deligiannidis, KM Kroll-Desrosiers, AR Mo, SY Nguyen, HP Svenson, A Jaitly, N Hall, JE Barton, BA Rothschild, AJ Shaffer, SA AF Deligiannidis, Kristina M. Kroll-Desrosiers, Aimee R. Mo, Shunyan Nguyen, Hien P. Svenson, Abby Jaitly, Nina Hall, Janet E. Barton, Bruce A. Rothschild, Anthony J. Shaffer, Scott A. TI Peripartum neuroactive steroid and gamma-aminobutyric acid profiles in women at-risk for postpartum depression SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Neuroactive steroid; gamma-aminobutyric acid; Pregnancy; Postpartum; Depression; Anxiety ID PREMENSTRUAL DYSPHORIC DISORDER; MAGNETIC-RESONANCE SPECTROSCOPY; STRUCTURED INTERVIEW GUIDE; CEREBROSPINAL-FLUID; POSTNATAL DEPRESSION; PREGNANOLONE ISOMERS; RAT-BRAIN; PERINATAL DEPRESSION; GABA CONCENTRATIONS; UMBILICAL BLOOD AB Neuroactive steroids (NAS) are allosteric modulators of the gamma-aminobutyric acid (GABA) system. NAS and GABA are implicated in depression. The peripartum period involves physiologic changes in NAS which may be associated with peripartum depression and anxiety. We measured peripartum plasma NAS and GABA in healthy comparison subjects (HCS) and those at-risk for postpartum depression (AR-PPD) due to current mild depressive or anxiety symptoms or a history of depression. We evaluated 56 peripartum medication-free subjects. We measured symptoms with the Hamilton Depression Rating Scale (HAM-D-17), Hamilton Anxiety Rating Scale (HAM-A) and Spielberger State-Trait Anxiety Inventory-State (STAI-S). Plasma NAS and GABA were quantified by liquid chromatography-mass spectrometry. We examined the associations between longitudinal changes in NAS, GABA and depressive and anxiety symptoms using generalized estimating equation methods. Peripartum GABA concentration was 1.9 +/- 0.7 ng/mL (p = 0.004) lower and progesterone and pregnanolone were 15.8 +/- 1 7.5 (p = 0.04) and 1.5 +/- 0.7 ng/mL (p = 0.03) higher in AR-PPD versus HCS, respectively. HAM-D-17 was negatively associated with GABA (beta = -0.14 +/- 0.05, p = 0.01) and positively associated with pregnanolone (beta = 0.16 +/- 0.06, p = 0.01). STAI-S was positively associated with pregnanolone (beta = 0.11 +/- 0.04, p = 0.004), allopregnanolone (beta = 0.13 +/- 0.05, p = 0.006) and pregnenolone (beta = 0.02 +/- 0.01, p = 0.04). HAM-A was negatively associated with GABA (beta = 0.121 +/- 0.04, p =0.004) and positively associated with pregnanolone (beta = 0.11 +/- 0.05, p = 0.05). Altered peripartum NAS and GABA profiles in AR-PPD women suggest that their interaction may play an important role in the pathophysiology of peripartum depression and anxiety. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Deligiannidis, Kristina M.; Svenson, Abby; Jaitly, Nina; Rothschild, Anthony J.] Univ Massachusetts, Sch Med, Dept Psychiat, Ctr Psychopharmacol Res & Treatment, Worcester, MA 01655 USA. [Deligiannidis, Kristina M.] Univ Massachusetts, Sch Med, UMass Mem Med Ctr, Womens Mental Hlth Program,Dept Psychiat, Worcester, MA 01655 USA. [Deligiannidis, Kristina M.] Univ Massachusetts, Sch Med, UMass Mem Med Ctr, Womens Mental Hlth Program,Dept Obstet & Gynecol, Worcester, MA 01655 USA. [Kroll-Desrosiers, Aimee R.; Barton, Bruce A.] Univ Massachusetts, Dept Quantitat Hlth Sci, Sch Med, Worcester, MA 01655 USA. [Mo, Shunyan; Nguyen, Hien P.; Shaffer, Scott A.] Univ Massachusetts, Sch Med, Prote & Mass Spectrometry Facil, Worcester, MA 01655 USA. [Mo, Shunyan; Nguyen, Hien P.; Shaffer, Scott A.] Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01655 USA. [Jaitly, Nina; Hall, Janet E.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Deligiannidis, KM (reprint author), Univ Massachusetts, Ctr Psychopharmacol Res & Treatment, UMass Mem Med Ctr, Womens Mental Hlth Program,Med Sch, 55 Lake Ave North, Worcester, MA 01655 USA. EM kristina.deligiannidis@umassmemorial.org; aimee.kroll@umassmed.edu; shunyan.mo@umassmed.edu; hien.nguyen@umassmed.edu; abbysve@gmail.com; nina.jaitly@nih.gov; janet.hall@nih.gov; bruce.barton@umassmed.edu; anthony.rothschild@umassmemorial.org; scott.shaffer@umassmed.edu RI Deligiannidis, Kristina/C-3654-2014; OI Deligiannidis, Kristina/0000-0001-7439-2236; Hall, Janet/0000-0003-4644-3061 FU National Center for Advancing Translational Sciences, National Institutes of Health [UL1TR000161]; National Institutes of Health [5K23MH097794]; NIH [1S10RR027107] FX This study was supported by National Center for Advancing Translational Sciences, National Institutes of Health Grant (UL1TR000161) and National Institutes of Health Grant (5K23MH097794). Mass spectrometry instrumentation was supported by funding from an NIH Shared Instrumentation Grant (1S10RR027107). The work described in this paper was presented, in part, as a poster presentation at the Society of Biological Psychiatry (SOBP) 70th Annual Meeting, Toronto, Canada on May 12, 2015 and in part, at the American College of Neuropsychopharmacology (ACNP) 54th Annual Meeting, Hollywood, Florida on December 7, 2015. NR 69 TC 1 Z9 1 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD AUG PY 2016 VL 70 BP 98 EP 107 DI 10.1016/j.psyneuen.2016.05.010 PG 10 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA DQ1MP UT WOS:000378965400011 PM 27209438 ER PT J AU Brotherton, JML Jit, M Gravitt, PE Brisson, M Kreimer, AR Pai, SI Fakhry, C Monsonego, J Franceschi, S AF Brotherton, Julia M. L. Jit, Mark Gravitt, Patti E. Brisson, Marc Kreimer, Aimee R. Pai, Sara I. Fakhry, Carole Monsonego, Joseph Franceschi, Silvia TI Eurogin Roadmap 2015: How has HPV knowledge changed our practice: Vaccines SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE HPV; vaccine; cervical cancer; oropharyngeal cancer ID HUMAN-PAPILLOMAVIRUS VACCINATION; HPV-16/18 AS04-ADJUVANTED VACCINE; SQUAMOUS-CELL CARCINOMA; OF-STUDY ANALYSIS; P16-POSITIVE OROPHARYNGEAL CANCER; INCOMPLETELY ADDRESSES ISSUES; CROSS-PROTECTIVE EFFICACY; LONG-TERM IMMUNOGENICITY; POPULATION-LEVEL IMPACT; BLIND PATRICIA TRIAL AB This review is one of two complementary reviews that have been prepared in the framework of the Eurogin Roadmap 2015 to evaluate how knowledge about HPV is changing practices in HPV infection and disease control through vaccination and screening. In this review of HPV vaccine knowledge, we present the most significant findings of the past year which have contributed to our knowledge of the two HPV prophylactic vaccines currently in widespread use and about the recently licensed nonavalent HPV vaccine. Whereas anal cancer is dealt with in the companion mini-review on screening, we also review here the rapidly evolving evidence regarding HPV-associated head and neck cancer and priority research areas. C1 [Brotherton, Julia M. L.] VCS Registries, Natl HPV Vaccinat Program, East Melbourne, Vic, Australia. [Brotherton, Julia M. L.] Univ Melbourne, Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Jit, Mark] Publ Hlth England, Modelling & Econ Unit, London, England. [Jit, Mark] London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London WC1, England. [Gravitt, Patti E.] Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Albuquerque, NM 87131 USA. [Brisson, Marc] Univ Laval, Dept Med Sociale & Prevent, Quebec City, PQ, Canada. [Kreimer, Aimee R.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pai, Sara I.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Fakhry, Carole] Johns Hopkins Outpatient Ctr, Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. [Monsonego, Joseph] Inst Col, 174 Rue Courcelles, F-75017 Paris, France. [Franceschi, Silvia] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon 08, France. RP Brotherton, JML (reprint author), POB 310, East Melbourne, Vic 8002, Australia. EM jbrother@vcs.org.au FU bioCSL/Merck; Merck Frosst FX JMLB has been an investigator on investigator designed unrestricted epidemiological research grants partially funded through bioCSL/Merck but has received no personal financial benefits. In the past 3 years, MB received an unrestricted grant from Merck Frosst related to Zoster burden of illness (no grants ongoing). JM reports having received honorarium as a member of the scientific advisory board of Sanofi Pasteur MSD, Merck, Roche Diagnostics, Gen-Probe and Genticel and compensation from Merck and Glaxo Smith Kline to conduct vaccine trials. NR 110 TC 4 Z9 4 U1 10 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD AUG 1 PY 2016 VL 139 IS 3 BP 510 EP 517 DI 10.1002/ijc.30063 PG 8 WC Oncology SC Oncology GA DP3TK UT WOS:000378418100003 PM 26916230 ER PT J AU Sung, H Rosenberg, PS Chen, WQ Hartman, M Lim, WY Chia, KS Mang, OWK Lapah, TSE Anderson, WF Yang, XHR AF Sung, Hyuna Rosenberg, Philip S. Chen, Wan-Qing Hartman, Mikael Lim, Wei-yen Chia, Kee Seng Mang, Oscar Wai-Kong Lapah, T. S. E. Anderson, William F. Yang, Xiaohong R. TI The impact of breast cancer-specific birth cohort effects among younger and older Chinese populations SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast cancer; China; birth cohort effect; westernization; age group ID AGE; PERIOD; TRENDS; RATES; RISK; DIAGNOSIS; SINGAPORE; MODELS; TIME AB Historically low breast cancer incidence rates among Asian women have risen worldwide; purportedly due to the adoption of a " Western" life style among younger generations (i.e., the more recent birth cohorts). However, no study has simultaneously compared birth cohort effects between both younger and older women in different Asian and Western populations. Using cancer registry data from rural and urban China, Singapore and the United States (1990-2008), we estimated age-standardized incidence rates (ASR), annual percentage change (EAPC) in the ASR, net drifts, birth cohort specific incidence rates and cohort rate ratios (CRR). Younger (30-49 years, 1943-1977 birth cohorts) and older women (50-79 years; 1913-1957 birth cohorts) were assessed separately. CRRs among Chinese populations were estimated using birth cohort specific rates with US nonHispanic white women (NHW) serving as the reference population with an assigned CRR of 1.0. We observed higher EAPCs and net drifts among those Chinese populations with lower ASRs. Similarly, we observed the most rapidly increasing cohortspecific incidence rates among those Chinese populations with the lowest baseline CRRs. Both trends were more significant among older than younger women. Average CRRs were 0.06-0.44 among older and 0.18-0.81 among younger women. Rapidly rising cohort specific rates have narrowed the historic disparity between Chinese and US NHW breast cancer populations particularly in regions with the lowest baseline rates and among older women. Future analytic studies are needed to investigate risk factors accounting for the rapid increase of breast cancer among older and younger women separately in Asian populations. C1 [Sung, Hyuna; Rosenberg, Philip S.; Anderson, William F.; Yang, Xiaohong R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Chen, Wan-Qing] Natl Canc Ctr, Natl Off Canc Prevent & Control, Beijing, Peoples R China. [Chen, Wan-Qing] Natl Canc Ctr, Natl Cent Canc Registry, Beijing, Peoples R China. [Hartman, Mikael] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Hartman, Mikael; Lim, Wei-yen; Chia, Kee Seng] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Hartman, Mikael] Natl Univ Singapore, Dept Surg, Singapore 117548, Singapore. [Mang, Oscar Wai-Kong] Hosp Author, Hong Kong Canc Registry, Hong Kong, Hong Kong, Peoples R China. [Lapah, T. S. E.] Chinese Univ Hong Kong, JC Sch Publ Hlth & Primary Care, Div Occupat & Environm Hlth, Hong Kong, Hong Kong, Peoples R China. RP Sung, H (reprint author), NCI, NIH, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Rm 6E512,9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM hyuna.sung@nih.gov FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics NR 28 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD AUG 1 PY 2016 VL 139 IS 3 BP 527 EP 534 DI 10.1002/ijc.30095 PG 8 WC Oncology SC Oncology GA DP3TK UT WOS:000378418100005 PM 26992019 ER PT J AU Karami, S Daughtery, SE Schwartz, K Davis, FG Ruterbusch, JJ Wacholder, S Graubard, BI Berndt, SI Hofmann, JN Purdue, MP Moore, LE Colt, JS AF Karami, Sara Daughtery, Sarah E. Schwartz, Kendra Davis, Faith G. Ruterbusch, Julie J. Wacholder, Sholom Graubard, Barry I. Berndt, Sonja I. Hofmann, Jonathan N. Purdue, Mark P. Moore, Lee E. Colt, Joanne S. TI Analgesic use and risk of renal cell carcinoma: A case-control, cohort and meta-analytic assessment SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE renal cell carcinoma; kidney cancer; acetaminophen; analgesics; meta-analysis ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CANCER-RISK; BLADDER-CANCER; UNITED-STATES; ACETAMINOPHEN; PARACETAMOL; POPULATION; MEDICATION; ASPIRIN; KIDNEY AB Analgesics are the most commonly consumed drugs worldwide. Evidence that analgesics increase kidney cancer risk has been mixed. We investigated the association between renal cell carcinoma (RCC) and analgesic use in a large population-based case-control study and a post-trial observational cohort study. Findings were used to update a recent meta-analytic review. We analyzed data from 1,217 RCC cases and 1,235 controls in the US Kidney Cancer Study and 98,807 participants in the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO: n = 137 RCCs). Self-reported acetaminophen, aspirin and nonsteroid anti-inflammatory drug (NSAID) use and duration information was assessed in relation to RCC. For the US Kidney Cancer Study, we calculated odds ratios (ORs) and 95% confidence intervals (as) using unconditional logistic regression. For PLCO, we computed hazard ratios (HRs) and 95%Cls using Cox regression. Among case-control participants, RCC risk was associated with over-the-counter acetaminophen use (OR = 1.35, 95%CI = 1.01-1.83). There was a positive trend with increasing duration (p-trend = 0.01), with a two-fold risk for use >= 10 years (OR= 2.01, 95%Cl = 1.30-3.12). No association with prescription acetaminophen use was detected. In PLCO, acetaminophen use was also associated with increased RCC risk (HR =1.68, 95%CI = 1.19-2.39), although elevated risk was absent among the few long-term users. No association with RCC risk was detected for aspirin or NSAIDs use in either study. An association between acetaminophen use and kidney cancer was supported by meta-analytic cohort (n = 4; summary relative risk = 1.34; 95`10C1 =- qg 1 11 1;-heterogeneity = 0.40) and case-control (n= 9, summary OR = 1.20; 95%Cl = 1.01-1.42; n 'heterogeneity = 0.05) findings. In brief, acetaminophen use may increase the risk of developing RCC. C1 [Karami, Sara; Wacholder, Sholom; Graubard, Barry I.; Berndt, Sonja I.; Hofmann, Jonathan N.; Purdue, Mark P.; Moore, Lee E.; Colt, Joanne S.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20850 USA. [Daughtery, Sarah E.] Patient Ctr Outcome Res Inst, Washington, DC USA. [Schwartz, Kendra; Ruterbusch, Julie J.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA. [Schwartz, Kendra; Ruterbusch, Julie J.] NCI, Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Davis, Faith G.] Univ Illinois, Chicago, IL 60612 USA. RP Karami, S (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20850 USA.; Karami, S (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,6E624, Rockville, MD 20850 USA. EM karamis@mail.nih.gov FU NCI (Intramural Research Program), Division of Cancer Epidemiology and Genetics, National Institutes of Health; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS (PLCO research) FX Grant sponsor: NCI (Intramural Research Program), Division of Cancer Epidemiology and Genetics, National Institutes of Health and Division of Cancer Prevention, National Cancer Institute, NIH, DHHS (PLCO research) NR 40 TC 0 Z9 0 U1 5 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD AUG 1 PY 2016 VL 139 IS 3 BP 584 EP 592 DI 10.1002/ijc.30108 PG 9 WC Oncology SC Oncology GA DP3TK UT WOS:000378418100010 PM 27009534 ER PT J AU Lavysh, D Sokolova, M Minakhin, L Yakunina, M Artamonova, T Kozyavkin, S Makarova, KS Koonin, EV Severinov, K AF Lavysh, Dania Sokolova, Maria Minakhin, Leonid Yakunina, Maria Artamonova, Tatjana Kozyavkin, Sergei Makarova, Kira S. Koonin, Eugene V. Severinov, Konstantin TI The genome of AR9, a giant transducing Bacillus phage encoding two multisubunit RNA polymerases SO VIROLOGY LA English DT Article DE Bacteriophage; Genome; Bacillus subtilis; Introns; RNA polymerase; Transcription; Evolution AB Bacteriophage AR9 and its close relative PBS1 have been extensively used to construct early Bacillus subtilis genetic maps. Here, we present the 251,042 bp AR9 genome, a linear, terminally redundant double-stranded DNA containing deoxyuridine instead of thymine. Multiple AR9 genes are interrupted by non-coding sequences or sequences encoding putative endonucleases. We show that these sequences are group I and group II self-splicing introns. Eight AR9 proteins are homologous to fragments of bacterial RNA polymerase (RNAP) subunits beta/beta. These proteins comprise two sets of paralogs of RNAP largest subunits, with each paralog encoded by two disjoint phage genes. Thus, AR9 is a phiKZ-related giant phage that relies on two multisubunit viral RNAPs to transcribe its genome independently of host transcription apparatus. Purification of one of PBS1/AR9 RNAPs has been reported previously, which makes AR9 a promising object for further studies of RNAP evolution, assembly and mechanism. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lavysh, Dania; Severinov, Konstantin] Russian Acad Sci, Inst Mol Genet & Gene Biol, Moscow, Russia. [Sokolova, Maria; Yakunina, Maria; Artamonova, Tatjana; Severinov, Konstantin] Peter Great St Petersburg Polytech Univ, St Petersburg, Russia. [Sokolova, Maria; Severinov, Konstantin] Skolkovo Inst Sci & Technol, Skolkovo, Russia. [Minakhin, Leonid; Severinov, Konstantin] Rutgers State Univ, Waksman Inst, Piscataway, NJ 08854 USA. [Kozyavkin, Sergei] Fidel Syst Inc, Gaithersburg, MD 20879 USA. [Makarova, Kira S.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Severinov, K (reprint author), Rutgers State Univ, Waksman Inst, Piscataway, NJ 08854 USA. EM daria.lavysh@img.ras.ru; maria.sokolova@skolkovotech.ru; minakhin@waksman.rutgers.edu; yakuninam@gmail.com; artamonova@nanobio.spbstu.ru; serg@fidelitysystems.com; makarova@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gov; severik@waksman.rutgers.edu RI Yakunina, Maria Vyacheslavovna/A-5842-2014; Sokolova, Maria /A-7068-2014; OI Sokolova, Maria/0000-0001-7251-6952 FU NIH [GM RO159295]; Russian Academy of Sciences Molecular and Cellular Biology program; Ministry of Education and Science of the Russian Federation [14. B25.31.0004]; US Department of Health and Human Services FX This work was supported by NIH (GM RO159295), by the Russian Academy of Sciences Molecular and Cellular Biology program Grant to KS and by the Ministry of Education and Science of the Russian Federation, Grant 14. B25.31.0004. EVK and KSM are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 64 TC 3 Z9 3 U1 2 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD AUG PY 2016 VL 495 BP 185 EP 196 DI 10.1016/j.viro1.2016.04.030 PG 12 WC Virology SC Virology GA DP7DR UT WOS:000378659900020 PM 27236306 ER PT J AU Rueda, CB Llorente-Folch, I Traba, J Amigo, I Gonzalez-Sanchez, P Contreras, L Juaristi, I Martinez-Valero, P Pardo, B del Arco, A Satrustegui, J AF Rueda, Carlos B. Llorente-Folch, Irene Traba, Javier Amigo, Ignacio Gonzalez-Sanchez, Paloma Contreras, Laura Juaristi, Ines Martinez-Valero, Paula Pardo, Beatriz del Arco, Araceli Satrustegui, Jorgina TI Glutamate excitotoxicity and Ca2+-regulation of respiration: Role of the Ca2+ activated mitochondrial transporters (CaMCs) SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Article; Proceedings Paper CT 19th European Bioenergetics Conference (EBEC) CY 2016 CL Riva del Garda, ITALY DE ATP-Mg/Pi carrier; Aspartate/glutamate carrier; Aralar; Calcium; Excitotoxicity; Mitochondria; PARP-1; SCaMC-3 ID PERMEABILITY TRANSITION PORE; EXTRASYNAPTIC NMDA RECEPTORS; PENTOSE-PHOSPHATE PATHWAY; APOPTOSIS-INDUCING FACTOR; MG/P-I CARRIER; NEURONAL DEATH; ATP SYNTHASE; CALCIUM UNIPORTER; CELL-DEATH; MOLECULAR-MECHANISMS AB Glutamate elicits Ca2+ signals and workloads that regulate neuronal fate both in physiological and pathological circumstances. Oxidative phosphorylation is required in order to respond to the metabolic challenge caused by glutamate. In response to physiological glutamate signals, cytosolic Ca2+ activates respiration by stimulation of the NADH malate-aspartate shuttle through Ca2+-binding to the mitochondrial aspartate/glutamate carrier (Aralar/AGC1/Slc25a12), and by stimulation of adenine nucleotide uptake through Ca2+ binding to the mitochondria( ATP-Mg/Pi carrier (SCaMC-3/S1c25a23). In addition, after Ca2+ entry into the matrix through the mitochondrial Ca2+ uniporter (MCU), it activates mitochondria( dehydrogenases. In response to pathological glutamate stimulation during excitotoxicity, Ca2+ overload, reactive oxygen species (ROS), mitochondria( dysfunction and delayed Ca2+ deregulation (DCD) lead to neuronal death. Glutamate-induced respiratory stimulation is rapidly inactivated through a mechanism involving Poly (ADP-ribose) Polymerase-1 (PARP-1) activation, consumption of cytosolic NAD+, a decrease in matrix ATP and restricted substrate supply. Glutamate-induced Ca2+-activation of SCaMC-3 imports adenine nucleotides into mitochondria, counteracting the depletion of matrix ATP and the impaired respiration, while Aralar-dependent lactate metabolism prevents substrate exhaustion. A second mechanism induced by excitotoxic glutamate is permeability transition pore (PTP) opening, which critically depends on ROS production and matrix Ca2+ entry through the MCU. By increasing matrix content of adenine nucleotides, SCaMC-3 activity protects against glutamate-induced PTP opening and lowers matrix free Ca2+, resulting in protracted appearance of DCD and protection against excitotoxicity in vitro and in vivo, while the lack of lactate protection during in vivo excitotoxicity explains increased vulnerability to kainite-induced toxicity in Aralar +/ mice. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. (C) 2016 Elsevier B.V. All rights reserved. C1 [Rueda, Carlos B.; Llorente-Folch, Irene; Gonzalez-Sanchez, Paloma; Contreras, Laura; Juaristi, Ines; Martinez-Valero, Paula; Pardo, Beatriz; del Arco, Araceli; Satrustegui, Jorgina] Univ Autonoma Madrid, CSIC, Ctr Biol Mol Severo Ochoa, Dept Biol Mol, E-28049 Madrid, Spain. [Rueda, Carlos B.; Llorente-Folch, Irene; Gonzalez-Sanchez, Paloma; Contreras, Laura; Juaristi, Ines; Martinez-Valero, Paula; Pardo, Beatriz; del Arco, Araceli; Satrustegui, Jorgina] CIBER Enfermedades Raras CIBERER, Barcelona, Spain. [Rueda, Carlos B.; Llorente-Folch, Irene; Gonzalez-Sanchez, Paloma; Contreras, Laura; Juaristi, Ines; Martinez-Valero, Paula; Pardo, Beatriz; del Arco, Araceli; Satrustegui, Jorgina] Fdn Jimenez Diaz, Inst Invest Sanitarias, Madrid, Spain. [Traba, Javier] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Amigo, Ignacio] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-13560970 Sao Paulo, Brazil. [del Arco, Araceli] Univ Castilla La Mancha, Fac Ciencias Ambientals & Bioquim, Toledo 45071, Spain. [Rueda, Carlos B.] Columbia Univ, Dept Neurol, New York, NY USA. [Rueda, Carlos B.] Columbia Univ, Ctr Motor Neuron Biol & Dis, New York, NY USA. [Llorente-Folch, Irene] Royal Coll Surgeons Ireland, Dept Physiol & Med Phys, Ctr Study Neurol Disorders, Dublin 2, Ireland. RP Satrustegui, J (reprint author), UAM, Ctr Biol Mol Severo Ochoa, Dept Biol Mol, C Nicolas Cabrera 1, Madrid 28049, Spain. NR 118 TC 1 Z9 1 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 EI 0006-3002 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD AUG PY 2016 VL 1857 IS 8 SI SI BP 1158 EP 1166 DI 10.1016/j.bbabio.2016.04.003 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DP0KS UT WOS:000378179300014 PM 27060251 ER PT J AU Patel, KD Glancy, B Balaban, RS AF Patel, Keval D. Glancy, Brian Balaban, Robert S. TI The electrochemical transmission in I-Band segments of the mitochondrial reticulum SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Article; Proceedings Paper CT 19th European Bioenergetics Conference (EBEC) CY 2016 CL Riva del Garda, ITALY DE Mitochondria; Antiporters; Diffusion; Mitochondria reticulum; Protons; Cations ID NA+/H+ EXCHANGER; MEMBRANE-SURFACE; CATION-TRANSPORT; MUSCLE; HOMEOSTASIS; CHANNELS; MATRIX; ENERGY AB Within the mitochondrial reticulum of skeletal muscle, the I-Band segments (IBS) traverse the cell and form a contiguous matrix with the mitochondria( segments at the periphery (PS) of the cell. A tight electrical coupling via the matrix between the PS and IBS has been demonstrated. In addition, oxidative phosphorylation complexes that generate the proton motive force (PMF) are preferentially located in the PS, while Complex V, which utilizes the PMF, is primarily located along the IBS. This has led to the hypothesis that PS can support the production of ATP in the IBS by maintaining the potential energy available to produce ATP deep in the muscle cell via conduction of the PMF down the IBS. However, the mechanism of transmitting the PMF down the IBS is poorly understood. This theoretical study was undertaken to establish the physical limits governing IBS conduction as well as potential mechanisms for balancing the protons entering the matrix along the IBS with the ejection of protons in the PS. The IBS was modeled as a 300 nm diameter, water-filled tube, with an insulated circumferential wall. Two mechanisms were considered to drive ion transport along the IBS: the electrical potential and/or concentration gradients between the PS to the end of the IBS. The magnitude of the flux was estimated from the maximum ATP production rate for skeletal muscle. The major transport ions in consideration were H+, Na+, and K+ using diffusion coefficients from the literature. The simulations were run using COMSOL Multiphysics simulator. These simulations suggest conduction along the IBS via H+ alone is unlikely requiring un-physiological gradients, while Na+ or K+ could carry the current with minor gradients in concentration or electrical potential along the IBS. The majority of conduction down the IBS is likely dependent on these abundant ions; however, this presents a question as to how H+ is recycled from the matrix of the IBS to the PS for active extrusion. We propose that the abundant cation-proton antiporter in skeletal muscle mitochondria operates in opposite directions in the IBS and PS to permit local recycling of H+ at each site driven by cooperative gradients in H+ and Na+/K+ which favor H+ entry in the PS and H+ efflux in the IBS. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016; edited by Prof. Paolo Bernardi. (C) Published by Elsevier B.V. C1 [Patel, Keval D.; Glancy, Brian; Balaban, Robert S.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Balaban, RS (reprint author), NHLBI, NIH, 9000 Rockville Pike,Bldg 10 Room B1D161, Bethesda, MD 20892 USA. EM RSB@nih.gov RI Glancy, Brian/P-3163-2016 OI Glancy, Brian/0000-0002-8571-244X FU Intramural NIH HHS [Z01 HL004601-21]; NHLBI NIH HHS [HL004601-27] NR 24 TC 1 Z9 1 U1 3 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 EI 0006-3002 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD AUG PY 2016 VL 1857 IS 8 SI SI BP 1284 EP 1289 DI 10.1016/j.bbabio.2016.02.014 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DP0KS UT WOS:000378179300028 PM 26921810 ER PT J AU Mortensen, ME Birch, R Wong, LY Valentin-Blasini, L Boyle, EB Caldwell, KL Merrill, LS Moye, J Blount, BC AF Mortensen, Mary E. Birch, Rebecca Wong, Lee Yang Valentin-Blasini, Liza Boyle, Elizabeth B. Caldwell, Kathleen L. Merrill, Lori S. Moye, John, Jr. Blount, Benjamin C. TI Thyroid antagonists and thyroid indicators in US pregnant women in the Vanguard Study of the National Children's Study SO ENVIRONMENTAL RESEARCH LA English DT Article DE National Children's Study; Perchlorate; Biomonitoring; NHANES; Pregnancy ID NUTRITION EXAMINATION SURVEY; TANDEM MASS-SPECTROMETRY; SODIUM-IODIDE SYMPORTER; UNITED-STATES; DRINKING-WATER; THIOCYANATE EXPOSURE; HORMONE LEVELS; PERCHLORATE EXPOSURE; URINARY PERCHLORATE; DIETARY-INTAKE AB The sodium iodide-symporter (NIS) mediates uptake of iodide into thyroid follicular cells. This key step in thyroid hormone synthesis is inhibited by perchlorate, thiocyanate (SCN) and nitrate (NO3) anions. When these exposures occur during pregnancy the resulting decreases in thyroid hormones may adversely affect neurodevelopment of the human fetus. Our objectives were to describe and examine the relationship of these anions to the serum thyroid indicators, thyroid stimulating hormone (TSH) and free thyroxine (FT4), in third trimester women from the initial Vanguard Study of the National Children's Study (NCS); and to compare urine perchlorate results with those in pregnant women from the National Health and Nutritional Examination Survey (NHANES). Urinary perchlorate, SCN, NO3, and iodine, serum TSH, FT4, and cotinine were measured and a food frequency questionnaire (FFQ) was administered to pregnant women enrolled in the initial Vanguard Study. We used multiple regression models of FT4 and TSH that included perchlorate equivalent concentration (PEC, which estimates combined inhibitory effects of the anions perchlorate, SCN, and NO3 on the NIS). We used multiple regression to model predictors of each urinary anion, using FFQ results, drinking water source, season of year, smoking status, and demographic characteristics. Descriptive statistics were calculated for pregnant women in NHANES 2001-2012. The geometric mean (GM) for urinary perchlorate was 4.04 mu g/L, for TSH 1.46 mIU/L, and the arithmetic mean for FT4 1.11 ng/dL in 359 NCS women. In 330 women with completed FFQs, consumption of leafy greens, winter season, and Hispanic ethnicity were significant predictors of higher urinary perchlorate, which differed significantly by study site and primary drinking water source, and bottled water was associated with higher urinary perchlorate compared to filtered tap water. Leafy greens consumption was associated with higher urinary NO3 and higher urinary SCN. There was no association between urinary perchlorate or PEC and TSH or FT4, even for women with urinary iodine < 100 mu g/L. GM urinary perchlorate concentrations in the full sample (n=494) of third trimester NCS women (4.03 mu g/L) were similar to pregnant women in NHANES (3.58 mu g/L). Published by Elsevier Inc. C1 [Mortensen, Mary E.; Wong, Lee Yang; Valentin-Blasini, Liza; Caldwell, Kathleen L.; Blount, Benjamin C.] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA USA. [Birch, Rebecca; Boyle, Elizabeth B.; Merrill, Lori S.] Westat Corp, Rockville, MD USA. [Moye, John, Jr.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NCS Program Off, NIH, Bethesda, MD USA. RP Mortensen, ME (reprint author), Div Sci Lab, MS F-20,4770 Buford Highway, Atlanta, GA 30341 USA. EM MMortensen@cdc.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of the Director of the National Institutes of Health [HHSN275200503414C, HHSN275200503411C, HHSN275200603416C, HHSN275200503415C, HHSN275200503413C, HHSN275200503410C, HHSN275200503396C]; National Center for Environmental Health, Centers for Disease Control and Prevention FX This analysis was conducted as part of the National Children's Study, supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and funded, through its appropriation, by the Office of the Director of the National Institutes of Health under Contract nos. HHSN275200503414C, HHSN275200503411C, HHSN275200603416C, HHSN275200503415C, HHSN275200503413C, HHSN275200503410C, and HHSN275200503396C. Funding for the biospecimen analyses was provided by the National Center for Environmental Health, Centers for Disease Control and Prevention. The manuscript was developed by a Writing Team identified by the National Children's Study Publications Committee for the purpose of timely sharing of centrally collected NCS data. We acknowledge the contributions of the following Vanguard Centers and Principal Investigators: Children's Hospital of Philadelphia, Jennifer Culhane; Mt. Sinai Medical School, Phil Landrigan; South Dakota State University, Bonny Specker; University of California at Irvine, James Swanson and Dean Baker; University of North Carolina at Chapel Hill, Barbara Entwisle and Nancy Dole; University of Utah School of Medicine, Ed Clark; University of Wisconsin, Maureen Durkin. Dr. Michael Varner provided invaluable editorial review and insightful suggestions that sharpened our focus on thyroid measurement methods and issues. We are grateful to the NHANES staff for the quality and completeness of their efforts conducting this complex survey and specimen collection. We appreciate the dedication and diligence of the NCEH laboratory staff that performed the pilot study measurements. NR 57 TC 1 Z9 1 U1 3 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD AUG PY 2016 VL 149 BP 179 EP 188 DI 10.1016/j.envres.2016.05.017 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DP3AY UT WOS:000378366000020 PM 27208469 ER PT J AU Kreisl, WC Lyoo, CH Liow, JS Wei, M Snow, J Page, E Jenko, KJ Morse, CL Zoghbi, SS Pike, VW Turner, RS Innis, RB AF Kreisl, William C. Lyoo, Chul Hyoung Liow, Jeih-San Wei, Monica Snow, Joseph Page, Emily Jenko, Kimberly J. Morse, Cheryl L. Zoghbi, Sami S. Pike, Victor W. Turner, R. Scott Innis, Robert B. TI C-11-PBR28 binding to translocator protein increases with progression of Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; Neuroinflammation; PET imaging ID MILD COGNITIVE IMPAIRMENT; VIVO RADIOLIGAND BINDING; PITTSBURGH COMPOUND-B; HUMAN BRAIN; MICROGLIAL ACTIVATION; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; MOUSE MODEL; 18 KDA AB This longitudinal study sought to determine whether the 18 kDa translocator protein (TSPO), a marker of neuroinflammation, increases over time in Alzheimer's disease. Positron emission tomography imaging with the TSPO radioligand C-11-PBR28 was performed at baseline and after a median follow-up of 2.7 years in 14 amyloid-positive patients and 8 amyloid-negative controls. Patients had a greater increase in TSPO binding than controls in inferior parietal lobule, precuneus, occipital cortex, hippocampus, entorhinal cortex, and combined middle and inferior temporal cortex. TSPO binding in temporoparietal regions increased from 3.9% to 6.3% per annum in patients, but ranged from -0.5% to 1% per annum in controls. The change in TSPO binding correlated with cognitive worsening on clinical dementia rating scale-sum of boxes and reduced cortical volume. The annual rate of increased TSPO binding in temporoparietal regions was about 5-fold higher in patients with clinical progression (n = 9) compared with those who did not progress (n = 5). TSPO may serve as a biomarker of Alzheimer's progression and response to anti-inflammatory therapies. Published by Elsevier Inc. C1 [Kreisl, William C.; Lyoo, Chul Hyoung; Liow, Jeih-San; Wei, Monica; Page, Emily; Jenko, Kimberly J.; Morse, Cheryl L.; Zoghbi, Sami S.; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Snow, Joseph] NIMH, Off Clin Director, Bethesda, MD 20892 USA. [Turner, R. Scott] Georgetown Univ, Memory Disorders Program, Washington, DC USA. [Kreisl, William C.] Columbia Univ, Taub Inst, Med Ctr, 622 W 168th St,PH 19th Floor, New York, NY 10032 USA. [Lyoo, Chul Hyoung] Yonsei Univ, Dept Neurol, Gangnam Severance Hosp, Coll Med, Seoul 120749, South Korea. RP Kreisl, WC (reprint author), Columbia Univ, Taub Inst, Med Ctr, 622 W 168th St,PH 19th Floor, New York, NY 10032 USA. EM wck2107@cumc.columbia.edu RI Turner, Raymond/G-2263-2011 OI Turner, Raymond/0000-0001-7534-2935 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health [IRP-NIMH-NIH, ZIAMH002852, ZIAMH0022793, NCT00955422, NCT00613119] FX This work was funded by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002852 and ZIAMH0022793 under clinicaltrials.gov identifiers NCT00955422 and NCT00613119). The NIMH had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the article for publication. NR 34 TC 5 Z9 5 U1 2 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD AUG PY 2016 VL 44 BP 53 EP 61 DI 10.1016/j.neurobiolaging.2016.04.011 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DO8UD UT WOS:000378058500005 PM 27318133 ER PT J AU White, LK Britton, JC Sequeira, S Ronkin, EG Chen, G Bar-Haim, Y Shechner, T Ernst, M Fox, NA Leibenluft, E Pine, DS AF White, Lauren K. Britton, Jennifer C. Sequeira, Stefanie Ronkin, Emily G. Chen, Gang Bar-Haim, Yair Shechner, Tomer Ernst, Monique Fox, Nathan A. Leibenluft, Ellen Pine, Daniel S. TI Behavioral and neural stability of attention bias to threat in healthy adolescents SO NEUROIMAGE LA English DT Article DE Attention bias; fMRI; Reliability; Anxiety; vlPFC; Fronto-amygdala connectivity ID GENERALIZED ANXIETY DISORDER; POSTTRAUMATIC-STRESS-DISORDER; PREFRONTAL CORTEX ACTIVATION; TEST-RETEST RELIABILITY; DOT-PROBE TASK; ANGRY FACES; CORRELATION-COEFFICIENT; FMRI; AMYGDALA; CHILDREN AB Considerable translational research on anxiety examines attention bias to threat and the efficacy of attention training in reducing symptoms. Imaging research on the stability of brain functions engaged by attention bias tasks could inform such research. Perturbed fronto-amygdala function consistently arises in attention bias research on adolescent anxiety. The current report examines the stability of the activation and functional connectivity of these regions on the dot-probe task. Functional magnetic resonance imaging (fMRI) activation and connectivity data were acquired with the dot-probe task in 39 healthy youth (f = 18, Mean Age = 13.71 years, SD = 2.31) at two time points, separated by approximately nine weeks. Intraclass-correlations demonstrate good reliability in both neural activation for the ventrolateral PFC and task-specific connectivity for fronto-amygdala circuitry. Behavioral measures showed generally poor test-retest reliability. These findings suggest potential avenues for future brain imaging work by highlighting brain circuitry manifesting stable functioning on the dot-probe attention bias task. Published by Elsevier Inc. C1 [White, Lauren K.; Sequeira, Stefanie; Ernst, Monique; Leibenluft, Ellen; Pine, Daniel S.] NIMH, Bethesda, MD 20892 USA. [Britton, Jennifer C.] Univ Miami, Coral Gables, FL 33124 USA. [Ronkin, Emily G.] Georgia State Univ, Atlanta, GA 30303 USA. [Chen, Gang] NIH, Bethesda, MD USA. [Bar-Haim, Yair] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. [Shechner, Tomer] Univ Haifa, IL-31999 Haifa, Israel. [Fox, Nathan A.] Univ Maryland, Baltimore, MD USA. RP White, LK (reprint author), NIMH, Bethesda, MD 20892 USA. EM Lauren.white@nih.gov; j.britton@miami.edu; stefanie.sequeira@nih.gov; emily.ronkin@gmail.com; gangchen@mail.nih.gov; yair1@post.tau.ac.il; tshechner@psy.haifa.ac.il; ernstm@mail.nih.gov; Fox@umd.edu; leibs@mail.nih.gov; pined@mail.nih.gov FU Intramural NIH HHS [Z01 MH002781-06] NR 44 TC 1 Z9 1 U1 10 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2016 VL 136 BP 84 EP 93 DI 10.1016/j.neuroimage.2016.04.058 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DO8QI UT WOS:000378048000008 PM 27129757 ER PT J AU Oliveira-Paula, GH Pinheiro, LC Guimaraes, DA Tella, SOC Blanco, ALF Angelis, CD Schechter, AN Tanus-Santos, JE AF Oliveira-Paula, Gustavo H. Pinheiro, Lucas C. Guimaraes, Danielle A. Conde Tella, Sandra O. Furlan Blanco, Ana L. Angelis, Celio D. Schechter, Alan N. Tanus-Santos, Jose E. TI Tempol improves xanthine oxidoreductase-mediated vascular responses to nitrite in experimental renovascular hypertension SO REDOX BIOLOGY LA English DT Article DE Hypertension; Nitric Oxide; Nitrite; Oxidative stress; Xanthine oxidoreductase ID ORAL SODIUM-NITRITE; ENDOTHELIAL DYSFUNCTION; BLOOD-PRESSURE; DIETARY NITRATE; OXIDE PATHWAY; RATS; MECHANISMS; DISEASE; ENZYME; ANION AB Upregulation of xanthine oxidoreductase (XOR) increases vascular reactive oxygen species (ROS) levels and contributes to nitroso-redox imbalance. However, XOR can generate nitric oxide (NO) from nitrite, and increased superoxide could inactivate NO formed from nitrite. This study tested the hypothesis that XOR contributes to the cardiovascular effects of nitrite in renovascular hypertension, and that treatment with the antioxidant tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) improves XOR-mediated effects of nitrite. Blood pressure was assessed weekly in two-kidney one-clip (2K1C) and control rats. After six weeks of hypertension, the relaxing responses to nitrite were assessed in aortic rings in the presence of the XOR inhibitor oxypurinol (or vehicle), either in the absence or in the presence of tempol. Moreover, in vivo hypotensive responses to nitrite were also examined in the presence of oxypurinol (or vehicle) and tempol (or vehicle). Aortic XOR activity and expression were evaluated by fluorescence and Western blot, respectively. Vascular ROS production was assessed by the dihydroethidium assay. 2K1C hypertensive rats showed increased aortic XOR activity and vascular ROS production compared with control rats. Oxypurinol shifted the nitrite concentration response curve to the right in aortic rings from 2K1C rats (but not in controls). Oxypurinol also attenuated the hypotensive responses to nitrite in 2K1C rats (but not in controls). These functional findings agree with increased aortic and plasma XOR activity found in 2K1C rats. Tempol treatment enhanced oxypurinol-induced shift of the nitrite concentration response curve to the right. However, antioxidant treatment did not affect XOR-mediated hypotensive effects of nitrite. Our results show that XOR is important to the cardiovascular responses to nitrite in 2K1C hypertension, and XOR inhibitors commonly used by patients may cancel this effect. This finding suggests that nitrite treatment may not be effective in patients being treated with XOR inhibitors. Moreover, while tempol may improve the vascular responses to nitrite, antihypertensive responses are not affected. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Oliveira-Paula, Gustavo H.; Pinheiro, Lucas C.; Guimaraes, Danielle A.; Conde Tella, Sandra O.; Furlan Blanco, Ana L.; Tanus-Santos, Jose E.] Univ Sao Paulo, Dept Pharmacol, Ribeirao Preto Med Sch, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP, Brazil. [Angelis, Celio D.] Univ Estadual Campinas, Dept Pharmacol, Campinas, SP, Brazil. [Schechter, Alan N.] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Tanus-Santos, JE (reprint author), Univ Sao Paulo, Dept Pharmacol, Ribeirao Preto Med Sch, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP, Brazil. EM tanus@fmrp.usp.br RI Tanus-Santos, Jose/A-4451-2008; pinheiro, lucas/F-6917-2015; Oliveira-Paula, Gustavo H./J-4895-2014 OI Oliveira-Paula, Gustavo H./0000-0002-8248-9713 FU Fundacao de Aparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2014-23946-0]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); CAPES (Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior) FX This work was supported by Fundacao de Aparo a Pesquisa do Estado de Sao Paulo (FAPESP Grant number 2014-23946-0), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), and CAPES (Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior). NR 42 TC 3 Z9 3 U1 3 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2317 J9 REDOX BIOL JI Redox Biol. PD AUG PY 2016 VL 8 BP 398 EP 406 DI 10.1016/j.redox.2016.04.001 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN9UU UT WOS:000377427000043 PM 27078869 ER PT J AU Mason, RP AF Mason, Ronald Paul TI Imaging free radicals in organelles, cells, tissue, and in vivo with immuno-spin trapping SO REDOX BIOLOGY LA English DT Review DE Immuno-spin trapping; Free radical detection; Spin trap; Mass spectrometry; Confocal microscopy; Molecular resonance imaging ID HYDROGEN-PEROXIDE; DNA RADICALS; MASS-SPECTROMETRY; MOLECULAR MRI; MOUSE MODEL; PROTEIN; HEMOGLOBIN; ADDUCTS; DMPO; IDENTIFICATION AB The accurate and sensitive detection of biological free radicals in a reliable manner is required to define the mechanistic roles of such species in biochemistry, medicine and toxicology. Most of the techniques currently available are either not appropriate to detect free radicals in cells and tissues due to sensitivity limitations (electron spin resonance, ESR) or subject to artifacts that make the validity of the results questionable (fluorescent probe-based analysis). The development of the immuno-spin trapping technique overcomes all these difficulties. This technique is based on the reaction of amino acid- and DNA base-derived radicals with the spin trap 5,5-dimethyl-l-pyrroline N-oxide (DMPO) to form protein- and DNA-DMPO nitroxide radical adducts, respectively. These adducts have limited stability and decay to produce the very stable macromolecule-DMPO-nitrone product. This stable product can be detected by mass spectrometry, NMR or immunochemistry by the use of anti-DMPO nitrone antibodies. The formation of macromolecule-DMPO-nitrone adducts is based on the selective reaction of free radical addition to the spin trap and is thus not subject to artifacts frequently encountered with other methods for free radical detection. The selectivity of spin trapping for free radicals in biological systems has been proven by ESR. Immuno-spin trapping is proving to be a potent, sensitive (a million times higher sensitivity than ESR), and easy (not quantum mechanical) method to detect low levels of macromolecule derived radicals produced in vitro and in vivo. Anti-DMPO antibodies have been used to determine the distribution of free radicals in cells and tissues and even in living animals. In summary, the invention of the immuno-spin trapping technique has had a major impact on the ability to accurately and sensitively detect biological free radicals and, subsequently, on our understanding of the role of free radicals in biochemistry, medicine and toxicology. Published by Elsevier B.V. C1 [Mason, Ronald Paul] NIEHS, Immun Inflammat & Dis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Mason, RP (reprint author), NIEHS, Immun Inflammat & Dis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM mason4@niehs.nih.gov FU Intramural Research Program, National Institutes of Health; National Institute of Environmental Health Sciences FX The author gratefully acknowledges Jean Corbett, Dr. Ann Motten, and Mary Mason for their editorial expertise. The author also wishes to thank Dr. Douglas Ganini and Dr. Kumar Ashutosh for helpful suggestions. This work was supported by the Intramural Research Program, National Institutes of Health, and National Institute of Environmental Health Sciences. NR 30 TC 0 Z9 0 U1 17 U2 44 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2317 J9 REDOX BIOL JI Redox Biol. PD AUG PY 2016 VL 8 BP 422 EP 429 DI 10.1016/j.redox.2016.04.003 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN9UU UT WOS:000377427000046 PM 27203617 ER PT J AU Gradstein, L Zolotushko, J Sergeev, YV Lavy, I Narkis, G Perez, Y Guigui, S Sharon, D Banin, E Walter, E Lifshitz, T Birk, OS AF Gradstein, Libe Zolotushko, Jenny Sergeev, Yuri V. Lavy, Itay Narkis, Ginat Perez, Yonatan Guigui, Sarah Sharon, Dror Banin, Eyal Walter, Eyal Lifshitz, Tova Birk, Ohad S. TI Novel GUCY2D mutation causes phenotypic variability of Leber congenital amaurosis in a large kindred SO BMC Medical Genetics LA English DT Article DE Blindness; Guanylate cyclase; GUCY2D; Leber Congenital Amaurosis ID MEMBRANE GUANYLYL CYCLASE; LONG-TERM PRESERVATION; GENE-THERAPY; RETGC1 DEFICIENCY; ACTIVATOR; PROTEINS; DISEASE; RPE65; MOUSE AB Background: Leber congenital amaurosis (LCA) is a severe retinal degenerative disease that manifests as blindness or poor vision in infancy. The purpose of this study was to clinically characterize and identify the cause of disease in a large inbred Bedouin Israeli tribe with LCA. Methods: Thirty individuals of a single kindred, including eight affected with LCA, were recruited for this study. Patients' clinical data and electroretinography (ERG) findings were collected. Molecular analysis included homozygosity mapping with polymorphic markers and Sanger sequencing of candidate genes. Results: Of the eight affected individuals of the kindred, nystagmus was documented in five subjects and keratoconus in three. Cataract was found in 5 of 16 eyes. Photopic and scotopic ERG performed in 5 patients were extinguished. All affected subjects were nearly blind, their visual acuity ranged between finger counting and uncertain light perception. Assuming autosomal recessive heredity of a founder mutation, studies using polymorphic markers excluded homozygosity of affected individuals at the genomic loci of all previously known genes associated with LCA, except GUCY2D. Sequencing of GUCY2D identified a novel missense mutation (c.2129C>T; p.Ala710Val) resulting in substitution of alanine by valine at position 710 within the protein kinase domain of the retina-specific enzyme guanylate cyclase 1 (GC1) encoded by GUCY2D. Molecular modeling implied that the mutation changes the conformation of the regulatory segment within the kinase styk-domain of GC1 and causes loss of its helical structure, likely inhibiting phosphorylation of threonine residue within this segment, which is needed to activate the catalytic domain of the protein. Conclusions: This is the first documentation of the p. Ala710Val mutation in GC1 and the second ever described mutation in its protein kinase domain. Our findings enlarge the scope of genetic variability of LCA, highlight the phenotypic heterogeneity found amongst individuals harboring an identical LCA mutation, and possibly provide hope for gene therapy in patients with this congenital blinding disease. As the Bedouin kindred studied originates from Saudi Arabia, the mutation found might be an ancient founder mutation in that large community. C1 [Gradstein, Libe; Lavy, Itay; Guigui, Sarah; Walter, Eyal; Lifshitz, Tova] Ben Gurion Univ Negev, Soroka Med Ctr, Dept Ophthalmol, Fac Hlth Sci, IL-84101 Beer Sheva, Israel. [Gradstein, Libe; Lavy, Itay; Guigui, Sarah; Walter, Eyal; Lifshitz, Tova] Ben Gurion Univ Negev, Fac Hlth Sci, Clalit Hlth Serv, IL-84101 Beer Sheva, Israel. [Zolotushko, Jenny; Narkis, Ginat; Perez, Yonatan; Birk, Ohad S.] Ben Gurion Univ Negev, Natl Inst Biotechnol Negev, Morris Kahn Lab Human Genet, IL-84105 Beer Sheva, Israel. [Zolotushko, Jenny; Narkis, Ginat; Perez, Yonatan; Birk, Ohad S.] Ben Gurion Univ Negev, Fac Hlth Sci, IL-84105 Beer Sheva, Israel. [Sergeev, Yuri V.] NEI, NIH, Bethesda, MD 20892 USA. [Sharon, Dror; Banin, Eyal] Hadassah Hebrew Univ, Dept Ophthalmol, Med Ctr, Jerusalem, Israel. [Birk, Ohad S.] Ben Gurion Univ Negev, Fac Hlth Sci, Soroka Med Ctr, Genet Inst, IL-84101 Beer Sheva, Israel. RP Birk, OS (reprint author), Ben Gurion Univ Negev, Natl Inst Biotechnol Negev, Morris Kahn Lab Human Genet, IL-84105 Beer Sheva, Israel.; Birk, OS (reprint author), Ben Gurion Univ Negev, Fac Hlth Sci, IL-84105 Beer Sheva, Israel.; Birk, OS (reprint author), Ben Gurion Univ Negev, Fac Hlth Sci, Soroka Med Ctr, Genet Inst, IL-84101 Beer Sheva, Israel. EM obirk@bgu.ac.il OI Birk, Ohad/0000-0003-1430-1296 FU Israeli ministry of health [3-11799] FX The study was supported by the Israeli ministry of health grant 3-11799. NR 18 TC 1 Z9 1 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JUL 30 PY 2016 VL 17 AR 52 DI 10.1186/s12881-016-0314-2 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA DS5ND UT WOS:000380828100001 PM 27475985 ER PT J AU Maoz, K Eldar, S Stoddard, J Pine, DS Leibenluft, E Bar-Haim, Y AF Maoz, Keren Eldar, Sharon Stoddard, Joel Pine, Daniel S. Leibenluft, Ellen Bar-Haim, Yair TI Angry-happy interpretations of ambiguous faces in social anxiety disorder SO PSYCHIATRY RESEARCH LA English DT Article DE Social phobia; Interpretation bias; Ambiguous facial expressions; Emotion; Anger ID SELF-REPORT VERSION; FACIAL EXPRESSIONS; INTERPRETATION BIAS; PSYCHOMETRIC PROPERTIES; RESPONSE BIAS; PHOBIA; EMOTION; SCALE; ACTIVATION; SENSITIVITY AB Social Anxiety Disorder (SAD) is characterized by a tendency to interpret ambiguous social cues as negative. Here we tested whether interpretation of ambiguous faces differs between participants with SAD and non-anxious controls. Twenty-seven individuals with SAD and 21 non-anxious control participants completed an emotion recognition task in which they judged ambiguous morphed faces as happy or angry. Participants with SAD judged a higher proportion of the faces as angry compared to non-anxious participants, and were slower to judge faces as angry compared to happy, while no such reaction time bias manifested in the control group. Finally, happy judgments were slower in the SAD group compared to the control group, while angry judgments were faster in the SAD group compared to the control group. These findings provide evidence for a negative bias in resolving emotional ambiguity in facial expressions among individuals with SAD. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Maoz, Keren; Eldar, Sharon; Bar-Haim, Yair] Tel Aviv Univ, Sch Psychol Sci, IL-69987 Tel Aviv, Israel. [Stoddard, Joel; Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Emot & Dev Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bar-Haim, Yair] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. RP Maoz, K (reprint author), Tel Aviv Univ, Sch Psychol Sci, IL-69987 Tel Aviv, Israel. OI Stoddard, Joel/0000-0003-4070-4566 FU US Department of Defense [W81XWH-13-2-0001] FX This study was partially supported by US Department of Defense Grant number W81XWH-13-2-0001. This sponsor was not involved and did not influence study design, data collection, analysis, interpretation, writing or decision regarding submission for publication. NR 42 TC 2 Z9 2 U1 12 U2 19 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUL 30 PY 2016 VL 241 BP 122 EP 127 DI 10.1016/j.psychres.2016.04.100 PG 6 WC Psychiatry SC Psychiatry GA DQ7EY UT WOS:000379370900021 PM 27173656 ER PT J AU Zigler, JS Hodgkinson, CA Wright, M Klise, A Sundin, O Broman, KW Hejtmancik, F Huang, H Patek, B Sergeev, Y Hose, S Brayton, C Jiao, XD Vasquez, D Maragakis, N Mori, S Goldman, D Hoke, A Sinha, D AF Zigler, J. Samuel, Jr. Hodgkinson, Colin A. Wright, Megan Klise, Andrew Sundin, Olof Broman, Karl W. Hejtmancik, Fielding Huang, Hao Patek, Bonnie Sergeev, Yuri Hose, Stacey Brayton, Cory Jiao Xaiodong Vasquez, David Maragakis, Nicholas Mori, Susumu Goldman, David Hoke, Ahmet Sinha, Debasish TI A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems SO PLOS ONE LA English DT Article ID MICE; BETA-A3/A1-CRYSTALLIN; PROTEIN AB A novel mutation, causing a phenotype we named frogleg because its most obvious characteristic is a severe splaying of the hind limbs, arose spontaneously in a colony of Sprague-Dawley rats. Frogleg is a complex phenotype that includes abnormalities in hind limb function, reduced brain weight with dilated ventricles and infertility. Using micro-satellite markers spanning the entire rat genome, the mutation was mapped to a region of rat chromosome 1 between D1Rat131 and D1Rat287. Analysis of whole genome sequencing data within the linkage interval, identified a missense mutation in the branched-chain alpha-keto dehydrogenase kinase (Bckdk) gene. The protein encoded by Bckdk is an integral part of an enzyme complex located in the mitochondrial matrix of many tissues which regulates the levels of the branched-chain amino acids (BCAAs), leucine, isoleucine and valine. BCAAs are essential amino acids (not synthesized by the body), and circulating levels must be tightly regulated; levels that are too high or too low are both deleterious. BCKDK phosphorylates Ser293 of the E1a subunit of the BCKDH protein, which catalyzes the rate-limiting step in the catabolism of the BCAAs, inhibiting BCKDH and thereby, limiting breakdown of the BCAAs. In contrast, when Ser293 is not phosphorylated, BCKDH activity is unchecked and the levels of the BCAAs will decrease dramatically. The mutation is located within the kinase domain of Bckdk and is predicted to be damaging. Consistent with this, we show that in rats homozygous for the mutation, phosphorylation of BCKDH in the brain is markedly decreased relative to wild type or heterozygous littermates. Further, circulating levels of the BCAAs are reduced by 70-80% in animals homozygous for the mutation. The frogleg phenotype shares important characteristics with a previously described Bckdk knockout mouse and with human subjects with Bckdk mutations. In addition, we report novel data regarding peripheral neuropathy of the hind limbs. C1 [Zigler, J. Samuel, Jr.; Klise, Andrew; Patek, Bonnie; Hose, Stacey; Sinha, Debasish] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Hodgkinson, Colin A.; Goldman, David] NIAAA, NIH, Rockville, MD 20852 USA. [Wright, Megan; Maragakis, Nicholas; Hoke, Ahmet] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Sundin, Olof] Texas Tech Univ, Hlth Sci Ctr, Dept Biomed Sci, El Paso, TX USA. [Broman, Karl W.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biostat & Informat, Madison, WI USA. [Huang, Hao; Sergeev, Yuri; Jiao Xaiodong] NEI, NIH, Bethesda, MD 20892 USA. [Huang, Hao] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Dept Radiol, Philadelphia, PA 19104 USA. [Brayton, Cory] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Vasquez, David] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21205 USA. [Mori, Susumu] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. RP Sinha, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. EM Debasish@jhmi.edu OI Hejtmancik, James/0000-0002-4788-0362 FU National Institutes of Health, National Institutes of Child Health and Human Disease [R21HD059008]; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation FX DS received support from National Institutes of Health, National Institutes of Child Health and Human Disease, R21HD059008, https://www.nichd.nih.gov/Pages/index.aspx. AH received support from Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, http://www.adelsonfoundation.org/amrfphil.html. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 29 PY 2016 VL 11 IS 7 AR e0160447 DI 10.1371/journal.pone.0160447 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5IM UT WOS:000381516300052 PM 27472223 ER PT J AU Miura, K Swihart, BJ Deng, BB Zhou, LW Pham, TP Diouf, A Burton, T Fay, MP Long, CA AF Miura, Kazutoyo Swihart, Bruce J. Deng, Bingbing Zhou, Luwen Pham, Thao P. Diouf, Ababacar Burton, Timothy Fay, Michael P. Long, Carole A. TI Transmission-blocking activity is determined by transmission-reducing activity and number of control oocysts in Plasmodium falciparum standard membrane-feeding assay SO VACCINE LA English DT Article DE Malaria; Transmission-blocking vaccine; Standard membrane-feeding assay ID MALARIA TRANSMISSION; VACCINE CANDIDATES; PROTEIN; PREVALENCE; ANTIBODIES; TARGET; DRUGS; AREA AB Malaria transmission-blocking vaccines (TBVs) are potentially helpful tools for malaria eradication. The standard membrane-feeding assay (SMFA) is considered one of the "gold standard" assays for TBV development. However, lack of consensus in reporting results from SMFA has made it very challenging to compare results from different studies. Two main readouts, % inhibition in mean oocyst count per mosquito (TRA) and % inhibition in prevalence of infected mosquitoes (TBA), have been used widely. In this study, we statistically modeled the oocyst data in SMFA using data from 105 independent feeding experiments including 9804 mosquitoes. The model was validated using an independent data set that included 10,790 mosquitoes from 110 feeding studies. The model delineates a relationship between TRA, the mean oocyst count in the control mosquitoes (m(o)-contl), and TBA. While TRA was independent from mo-contl, TBA values changed depending on m(o)-contl. Regardless of monoclonal or polyclonal antibodies tested, there were strong concordances between observed TBA and predicted TBA based on the model using mo-contl and observed TRA. Simulations showed that SMFA with lower true control means had increased uncertainty in TRA estimates. The strong linkage between TBA, TRA and mo-contl inspired creation of a standardized TBA, a model-based TBA standardized to a target control mean, which allows comparison across multiple feeds regardless of mo-contl. This is the first study showing that the observed TBA can be reasonably predicted by mo-contl and the TRA of the test antibody using independent experimental data. This study indicates that TRA should be used to compare results from multiple feeds with different levels of m(o)-contl. If a measure of TBA is desired, it is better to report standardized TBA rather than observed TBA. These recommendations support rational comparisons of results from different studies, thus benefiting future TBV development. Published by Elsevier Ltd. C1 [Miura, Kazutoyo; Deng, Bingbing; Zhou, Luwen; Pham, Thao P.; Diouf, Ababacar; Burton, Timothy; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. [Swihart, Bruce J.; Fay, Michael P.] NIAID, Biostat Res Branch, NIH, 5601 Fishers Lane, Rockville, MD 20852 USA. RP Miura, K (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM kmiura@niaid.nih.gov; bruce.swihart@nih.gov; bingbing.deng@nih.gov; luwen.zhou@nih.gov; Phuong.pham2@nih.gov; dioufa@niaid.nih.gov; timothy.burton@nih.gov; mfay@niaid.nih.gov; clong@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; PATH Malaria Vaccine Initiative FX We thank Jetsumon Sattabongkot for the direct membrane feeding data. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). This study was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH and also by the PATH Malaria Vaccine Initiative. NR 30 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUL 29 PY 2016 VL 34 IS 35 BP 4145 EP 4151 DI 10.1016/j.vaccine.2016.06.066 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DT0JR UT WOS:000381170300009 PM 27372156 ER PT J AU Amador-Molina, JC Valerdi-Madrigal, ED Dominguez-Castillo, RI Sirota, LA Arciniega, JL AF Amador-Molina, Juan C. Valerdi-Madrigal, Esther D. Dominguez-Castillo, Rocio I. Sirota, Lev A. Arciniega, Juan L. TI Temperature-mediated recombinant anthrax protective antigen aggregate development: Implications for toxin formation and immunogenicity SO VACCINE LA English DT Article DE Anthrax; Vaccine; Stability; Protective antigen; Aggregation ID BACILLUS-ANTHRACIS; LETHAL TOXIN; ALUMINUM-HYDROXIDE; THERMAL INACTIVATION; NEUTRALIZATION ASSAY; GUINEA-PIGS; VACCINE; DEAMIDATION; PROTEIN; INFECTION AB Anthrax vaccines containing recombinant PA (rPA) as the only antigen face a stability issue: rPA forms aggregates in solution after exposure to temperatures >= 40 degrees C, thus losing its ability to form lethal toxin (LeTx) with Lethal Factor. To study rPA aggregation's impact on immune response, we subjected rPA to several time and temperature combinations. rPA treated at 50 degrees C for 30 min formed high mass aggregates when analyzed by gel electrophoresis and failed to form LeTx as measured by a macrophage lysis assay (MLA). Aggregated rPA-formed LeTx was about 30 times less active than LeTx containing native rPA. Mice immunized with heat-treated rPA combined with Al(OH)(3) developed antibody titers about 49 times lower than mice immunized with native rPA, as measured by a Toxicity Neutralization Assay (TNA). Enzyme Linked Immunosorbent Assay (ELISA) of the same immune sera showed anti-rPA titers only 2-7 times lower than titers elicited by native rPA. Thus, rPA's ability to form LeTx correlates with its production of neutralizing antibodies, and aggregation significantly impairs the protein's antibody response. However, while these findings suggest MLA has some value as an in-process quality test for rPA in new anthrax vaccines, they also confirm the superiority of TNA for use in vaccine potency. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Amador-Molina, Juan C.; Valerdi-Madrigal, Esther D.; Dominguez-Castillo, Rocio I.; Sirota, Lev A.; Arciniega, Juan L.] US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. Tecnol Monterrey, Campus Estado Mexico,Carretera Lago Guadalupe Km, Atizapan De Zaragoza 52926, Estado De Mexic, Mexico. [Dominguez-Castillo, Rocio I.] IPN, Ctr Invest & Estudios Avanzados, Av Inst Politecn Nacl 2508, Mexico City 07360, DF, Mexico. [Sirota, Lev A.] NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. RP Amador-Molina, JC (reprint author), Tecnol Monterrey, Campus Estado Mexico,Carretera Lago Guadalupe Km, Atizapan De Zaragoza 52926, Estado De Mexic, Mexico. EM jc.amador@itesm.mx FU Biomedical Advanced Research and Development Authority; Research Participation Program at the Center for Biologics Evaluation and Research FX This project was supported in part by the Biomedical Advanced Research and Development Authority and by an appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 65 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUL 29 PY 2016 VL 34 IS 35 BP 4188 EP 4195 DI 10.1016/j.vaccine.2016.06.057 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DT0JR UT WOS:000381170300015 PM 27364097 ER PT J AU Zhou, XY Liu, Z Zhang, J Adelsberger, JW Yang, J Burton, GF AF Zhou, Xueyuan Liu, Zhu Zhang, Jun Adelsberger, Joseph W. Yang, Jun Burton, Gregory F. TI Alpha-1-antitrypsin interacts with gp41 to block HIV-1 entry into CD4+T lymphocytes SO BMC MICROBIOLOGY LA English DT Article DE HIV-1; Alpha-1-antitrypsin; Reverse transcriptase; Integrase; gp41 ID HUMAN-IMMUNODEFICIENCY-VIRUS; LEUKOCYTE PROTEASE INHIBITOR; RAT PERITONEAL-MACROPHAGES; REVERSE-TRANSCRIPTASE; SERPIN A1; INFECTION; EXPRESSION; TYPE-1; DEFICIENCY; PEPTIDE AB Background: Study of a clinic case reveals that alpha-1-antitrypsin (AAT) deficiency is related to CD4+ T cell count decline and AIDS progression, suggesting that AAT might be an endogenous inhibitor of HIV/AIDS. Previous study shows that AAT inhibits HIV-1 replication in infected host cells and the C-terminus fragment of AAT, VIRIP, interferes with HIV-1 infection. However, it is still unclear whether and how intact AAT inhibits HIV-1 infection. It is also unknown what the mechanism of AAT is and which critical step(s) are involved. Results: In the present study, the C-terminus of AAT (C) was synthesized. C terminus-truncated AAT (Delta AAT) was also prepared by digesting AAT with metalloproteinase. Primary CD4+ T cells were then co-cultured with HIV-1 with the presence or absence of AAT/C/Delta AAT to detect cis-infection of HIV-1. The interaction between AAT/C/Delta AAT and gp120/gp41 was also measured. Meanwhile, HIV-1 reverse transcriptase activity and viral DNA integration were also detected in these lymphocytes. The results demonstrated that AAT and C, not Delta AAT, inhibited HIV-1 entry by directly interacting with gp41. Meanwhile, AAT, C and Delta AAT could not directly interfere with the steps of viral RNA reverse transcription and viral DNA integration. Conclusion: AAT inhibits HIV-1 entry by directly interacting with gp41 through its C-terminus and thereby inhibits HIV-1 infection. C1 [Zhou, Xueyuan; Adelsberger, Joseph W.; Yang, Jun] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Clin Serv Program, Frederick, MD 21702 USA. [Liu, Zhu] Hainan Univ, Coll Agr, Hainan Key Lab Sustainable Utilizat Trop Bioresou, Haikou 570228, Hainan, Peoples R China. [Zhang, Jun] Univ Alabama Birmingham, Dept Chem, Birmingham, AL 35294 USA. [Burton, Gregory F.] Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA. RP Zhou, XY (reprint author), Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Clin Serv Program, Frederick, MD 21702 USA.; Liu, Z (reprint author), Hainan Univ, Coll Agr, Hainan Key Lab Sustainable Utilizat Trop Bioresou, Haikou 570228, Hainan, Peoples R China. EM xueyuan.zhou@nih.gov; zhuliu@hainu.edu.cn RI Zhang, Jun/R-1502-2016 OI Zhang, Jun/0000-0002-5842-7424 FU Public Health Service grants from the National Institute of Allergy and Infectious Disease [AI91517]; Brigham Young University Grant from the College of Physical and Mathematical Sciences; National Natural Science Foundation of China [31560021, 31100052]; Science and Technology Program of Hainan Province [KJHZ2015-24]; Startup Fund for Distinguished Scholars of Hainan University [KYQD1515] FX This work was supported by Public Health Service grants AI91517 from the National Institute of Allergy and Infectious Disease (G.F.B.) and by a Brigham Young University Grant from the College of Physical and Mathematical Sciences (G.F.B.). This work was also partially supported by grants from National Natural Science Foundation of China (Nos. 31560021 and 31100052) (Z.L.), Science and Technology Program of Hainan Province (No. KJHZ2015-24) (Z.L.) and the Startup Fund for Distinguished Scholars of Hainan University (No. KYQD1515) (Z.L.). NR 37 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD JUL 29 PY 2016 VL 16 AR 172 DI 10.1186/s12866-016-0751-2 PG 12 WC Microbiology SC Microbiology GA DS4WW UT WOS:000380783300005 PM 27473095 ER PT J AU Gebert, C Rong, Q Jeong, S Iben, J Pfeifer, K AF Gebert, Claudia Rong, Qi Jeong, Sangkyun Iben, James Pfeifer, Karl TI H19ICR mediated transcriptional silencing does not require target promoter methylation SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Genomic imprinting; Gene silencing; H19; DNA methylation ID IMPRINTED H19/IGF2 LOCUS; DNA METHYLATION; ALLELIC EXPRESSION; IGF2/H19 LOCUS; GENE; REGION; DELETION; MECHANISMS; INSULATOR; MARKS AB Transcription of the reciprocally imprinted genes Insulin-like growth factor 2 (Igf2) and H19 is orchestrated by the 2.4-kb H19 Imprinting Control Region (H19ICR) located upstream of H19. Three known functions are associated with the H19ICR: (1) it is a germline differentially methylated region, (2) it is a transcriptional insulator, and (3) it is a transcriptional silencer. The molecular mechanisms of the DMR and insulator functions have been well characterized but the basis for the ICR's silencer function is less well understood. In order to study the role the H19ICR intrinsically plays in gene silencing, we transferred the 2.4-kb H19ICR to a heterologous non-imprinted location on chromosome 5, upstream of the alpha fetoprotein (Afp) promoter. Independent of its orientation, the 2.4-kb H19ICR silences transcription from the paternal Afp promoter. Thus silencing is a function intrinsic to this DNA element. Further, ICR mediated silencing is a developmental process that, unexpectedly, does not occur through DNA methylation at the target promoter. Published by Elsevier Inc. C1 [Gebert, Claudia; Rong, Qi; Jeong, Sangkyun; Iben, James; Pfeifer, Karl] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Jeong, Sangkyun] Korea Inst Oriental Med, Div Med Res, Daejeon 305811, South Korea. RP Pfeifer, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM pfeiferk@mail.nih.gov OI Pfeifer, Karl/0000-0002-0254-682X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Research [ZIA HD 001804] FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Research (ZIA HD 001804). Steve Coon and Tianwei Li generated the deep sequencing. NR 29 TC 0 Z9 0 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 29 PY 2016 VL 476 IS 3 BP 121 EP 126 DI 10.1016/j.bbrc.2016.05.042 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DP8PD UT WOS:000378759200002 PM 27178213 ER PT J AU Cramer, SD Aplan, PD Durum, SK AF Cramer, Sarah D. Aplan, Peter D. Durum, Scott K. TI Therapeutic targeting of IL-7R alpha signaling pathways in ALL treatment SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; B-CELL PRECURSOR; CHILDRENS ONCOLOGY GROUP; THYMIC STROMAL LYMPHOPOIETIN; MURINE XENOGRAFT MODELS; OF-FUNCTION MUTATIONS; T-ALL; CYTOTOXIC ACTIVITY; CRLF2 EXPRESSION; MTOR INHIBITORS AB Increased understanding of pediatric acute lymphoblastic leukemia (ALL) pathobiology has led to dramatic improvements in patient survival. However, there is still a needto developtargeted therapies toenable reduced chemotherapy intensity and to treat relapsed patients. The interleukin-7 receptor alpha ( IL-7R alpha) signaling pathways areprime therapeutic targetsbecause these pathways harbor genetic aberrations in both T-cell ALL and B-cell precursor ALL. Therapeutic targeting of the IL-7R alpha signaling pathways may lead to improved outcomes in a subset of patients. C1 [Cramer, Sarah D.; Durum, Scott K.] NCI, Cytokines & Immun Sect, Canc & Inflammat Program, NIH, Bldg 560,Room 31-71, Frederick, MD 21702 USA. [Cramer, Sarah D.] NIH, Comparat Biomed Scientist Training Program, Bldg 10, Bethesda, MD 20892 USA. [Cramer, Sarah D.] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. [Aplan, Peter D.] NCI, Leukemia Biol Sect, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Durum, SK (reprint author), NCI, Ctr Canc Res, Bldg 560,Room 31-71, Frederick, MD 21702 USA. EM durums@mail.nih.gov FU Children's Cancer Foundation, Inc.; National Multiple Sclerosis Society [PP1882]; Comparative Biomedical Scientist Training Program [Z01 BC 010931]; National Institutes of Health; Intramural Research Program of the National Cancer Institute, National Institutes of Health [ZIA SC 010378, ZIA BC 009287] FX This work was supported by grants from the Children's Cancer Foundation, Inc.; the National Multiple Sclerosis Society (PP1882) (S.K.D.), the Comparative Biomedical Scientist Training Program (Z01 BC 010931), National Institutes of Health (S.D.C.); and the Intramural Research Program of the National Cancer Institute, National Institutes of Health (ZIA SC 010378 [P.D.A.] and ZIA BC 009287 [S.K.D.]). NR 94 TC 3 Z9 4 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 28 PY 2016 VL 128 IS 4 BP 473 EP 478 DI 10.1182/blood-2016-03-679209 PG 6 WC Hematology SC Hematology GA DW9AQ UT WOS:000383947300004 PM 27268088 ER PT J AU Sabatino, M Hu, JH Sommariva, M Gautam, S Fellowes, V Hocker, JD Dougherty, S Qin, HY Klebanoff, CA Fry, TJ Gress, RE Kochenderfer, JN Stroncek, DF Ji, Y Gattinoni, L AF Sabatino, Marianna Hu, Jinhui Sommariva, Michele Gautam, Sanjivan Fellowes, Vicki Hocker, James D. Dougherty, Sean Qin, Haiying Klebanoff, Christopher A. Fry, Terry J. Gress, Ronald E. Kochenderfer, James N. Stroncek, David F. Ji, Yun Gattinoni, Luca TI Generation of clinical-grade CD19-specific CAR-modified CD8(+) memory stem cells for the treatment of human B-cell malignancies SO BLOOD LA English DT Article ID CHIMERIC-ANTIGEN-RECEPTOR; SUPERIOR ANTITUMOR IMMUNITY; CD19-TARGETED T-CELLS; ADOPTIVE IMMUNOTHERAPY; IN-VIVO; DIFFERENTIATION; EFFECTOR; SUBSETS; CHEMOTHERAPY; REMISSIONS AB Long-lived, self-renewing, multipotent T memory stem cells (T-SCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, clinically compliant procedures to generate relevant numbers of this T-cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical-grade tumor-redirected T-SCM starting from naive precursors. CD8(+) CD62L(+)CD45RA(+) naive T cells enriched by streptamer-based serial-positive selection were activated by CD3/CD28 engagement in the presence of interleukin-7 (IL-7), IL-21, and the glycogen synthase-3 beta inhibitor TWS119, and genetically engineered to express a CD19-specific chimeric antigen receptor (CD19-CAR). These conditions enabled the generation of CD19-CAR-modifiedCD8(+) T-SCM that were phenotypically, functionally, and transcriptomically equivalent to their naturally occurring counterpart. Compared with CD8(+) T cells generated with clinical protocols currently under investigation, CD19-CAR-modified CD8(+) T-SCM exhibited enhanced metabolic fitness and mediated robust, long-lasting antitumor responses against systemic acute lymphoblastic leukemia xenografts. This clinical-grade platform provides the basis for a phase 1 trial evaluating the activity of CD19-CAR-modified CD8(+) T-SCM in patients with B-cell malignancies refractory to prior allogeneic hematopoietic stem cell transplantation. C1 [Sabatino, Marianna; Sommariva, Michele; Stroncek, David F.] NIH, Dept Transfus Med, Cell Proc Sect, Ctr Clin, Bethesda, MD 20892 USA. [Hu, Jinhui; Gautam, Sanjivan; Fellowes, Vicki; Hocker, James D.; Dougherty, Sean; Klebanoff, Christopher A.; Gress, Ronald E.; Kochenderfer, James N.; Ji, Yun; Gattinoni, Luca] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Room 3E 3510,10 Ctr Dr, Bethesda, MD 20892 USA. [Sommariva, Michele] Univ Milan, Dipartimento Sci Biomed Salute, Milan, Italy. [Qin, Haiying; Fry, Terry J.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Room 3E 3510,10 Ctr Dr, Bethesda, MD 20892 USA. RP Gattinoni, L (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Room 3E 3510,10 Ctr Dr, Bethesda, MD 20892 USA. EM gattinol@mail.nih.gov RI Gattinoni, Luca/A-2281-2008; Ji, Yun/B-7245-2009; Sommariva, Michele/C-1174-2017 OI Gattinoni, Luca/0000-0003-2239-3282; Ji, Yun/0000-0001-6340-7009; Sommariva, Michele/0000-0002-7622-0996 FU National Institutes of Health (NIH) Bench-to-Bedside Award; Intramural Research Program of the US NIH, National Cancer Institute, Center for Cancer Research [ZIABC011480] FX This work was supported by the 2014 National Institutes of Health (NIH) Bench-to-Bedside Award and the Intramural Research Program of the US NIH, National Cancer Institute, Center for Cancer Research (grant ZIABC011480). NR 67 TC 4 Z9 4 U1 4 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 28 PY 2016 VL 128 IS 4 BP 519 EP 528 DI 10.1182/blood-2015-11-683847 PG 10 WC Hematology SC Hematology GA DW9AQ UT WOS:000383947300010 PM 27226436 ER PT J AU Sharma, A Conteh, S Langhorne, J Duffy, PE AF Sharma, Ankur Conteh, Solomon Langhorne, Jean Duffy, Patrick E. TI Heterologous Infection of Pregnant Mice Induces Low Birth Weight and Modifies Offspring Susceptibility to Malaria SO PLOS ONE LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; NECROSIS-FACTOR-ALPHA; RODENT MALARIA; MOSQUITO TRANSMISSION; CHONDROITIN-SULFATE; ANTIGENIC VARIATION; PLACENTAL MALARIA; CHABAUDI-CHABAUDI; IMMUNE-RESPONSES; IFN-GAMMA AB Pregnancy malaria (PM) is associated with poor pregnancy outcomes, and can arise due to relapse, recrudescence or a re-infection with heterologous parasites. We have used the Plasmodium chabaudi model of pregnancy malaria in C57BL/6 mice to examine recrudescence and heterologous infection using CB and AS parasite strains. After an initial course of patent parasitemia and first recrudescence, CB but not AS parasites were observed to recrudesce again in most animals that became pregnant. Pregnancy exacerbated heterologous CB infection of AS-experienced mice, leading to mortality and impaired post-natal growth of pups. Parasites were detected in placental blood without evidence of sequestration, unlike P. falciparum but similar to other malaria species that infect pregnant women. Inflammatory cytokine levels were elevated in pregnant females during malaria, and associated with intensity of infection and with poor outcomes. Pups born to dams during heterologous infection were more resistant to malaria infections at 6-7 weeks of age, compared to pups born to malaria-experienced but uninfected dams or to malaria-naive dams. In summary, our mouse model reproduces several features of human PM, including recrudescences, heterologous infections, poor pregnancy outcomes associated with inflammatory cytokines, and modulation of offspring susceptibility to malaria. This model should be further studied to explore mechanisms underlying PM pathogenesis. C1 [Sharma, Ankur; Conteh, Solomon; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. [Langhorne, Jean] Francis Crick Inst, Mill Hill Lab, London, England. RP Duffy, PE (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. EM patrick.duffy@nih.gov FU Division of Intramural Research, NIAID/NIH; Francis Crick Institute; UK Medical Research Council [U117584248]; Cancer Research UK; Wellcome Trust [WT104777MA] FX This research was supported by the Division of Intramural Research, NIAID/NIH. JL is supported by the Francis Crick Institute, which receives its core funding from the UK Medical Research Council (U117584248), Cancer Research UK, and the Wellcome Trust (WT104777MA). NR 65 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 28 PY 2016 VL 11 IS 7 AR e0160120 DI 10.1371/journal.pone.0160120 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5IL UT WOS:000381516100117 PM 27467392 ER PT J AU Yong, KJ Milenic, DE Baidoo, KE Brechbiel, MW AF Yong, Kwon Joong Milenic, Diane E. Baidoo, Kwamena E. Brechbiel, Martin W. TI Cell Killing Mechanisms and Impact on Gene Expression by Gemcitabine and Pb-212-Trastuzumab Treatment in a Disseminated i.p. Tumor Model SO PLOS ONE LA English DT Article ID DISSEMINATED PERITONEAL DISEASE; DNA-DAMAGE; CYCLE CHECKPOINT; MISMATCH REPAIR; HOMOLOGOUS RECOMBINATION; EPITHELIAL-CELLS; MAMMALIAN-CELLS; TARGETING HER2; RADIOIMMUNOTHERAPY; RADIATION AB In pre-clinical studies, combination therapy with gemcitabine and targeted radioimmunotherapy (RIT) using Pb-212-trastuzumab showed tremendous therapeutic potential in the LS-174T tumor xenograft model of disseminated intraperitoneal disease. To better understand the underlying molecular basis for the observed cell killing efficacy, gene expression profiling was performed after a 24 h exposure to Pb-212-trastuzumab upon gemcitabine (Gem) pre-treatment in this model. DNA damage response genes in tumors were quantified using a real time quantitative PCR array (qRT-PCR array) covering 84 genes. The combination of Gem with alpha-radiation resulted in the differential expression of apoptotic genes (BRCA1, CIDEA, GADD45 alpha, GADD45 gamma, IP6K3, PCBP4, RAD21, and p73), cell cycle regulatory genes (BRCA1, CHK1, CHK2, FANCG, GADD45 alpha, GTSE1, PCBP4, MAP2K6, NBN, PCBP4, and SESN1), and damaged DNA binding and repair genes (BRCA1, BTG2, DMC1, ERCC1, EXO1, FANCG, FEN1, MSH2, MSH3, NBN, NTHL1, OGG1, PRKDC, RAD18, RAD21, RAD51B, SEMA4G, p73, UNG, XPC, and XRCC2). Of these genes, the expression of CHK1, GTSE1, EXO1, FANCG, RAD18, UNG and XRCC2 were specific to Gem/Pb-212-trastuzumab administration. In addition, the present study demonstrates that increased stressful growth arrest conditions induced by Gem/Pb-212-trastuzumab could suppress cell proliferation possibly by up-regulating genes involved in apoptosis such as p73, by down-regulating genes involved in cell cycle check point such as CHK1, and in damaged DNA repair such as RAD51 paralogs. These events may be mediated by genes such as BRCA1/MSH2, a member of BARC (BRCA-associated genome surveillance complex). The data suggest that up-regulation of genes involved in apoptosis, perturbation of checkpoint genes, and a failure to correctly perform HR-mediated DSB repair and mismatch-mediated SSB repair may correlate with the previously observed inability to maintain the G2/M arrest, leading to cell death. C1 [Yong, Kwon Joong; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; AREVA Med LLC; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and AREVA Med LLC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and AREVA Med LLC. NR 46 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 28 PY 2016 VL 11 IS 7 AR e0159904 DI 10.1371/journal.pone.0159904 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5IL UT WOS:000381516100070 PM 27467592 ER PT J AU Ghosh, AK Osswald, HL Glauninger, K Agniswamy, J Wang, YF Hayashi, H Aoki, M Weber, IT Mitsuya, H AF Ghosh, Arun K. Osswald, Heather L. Glauninger, Kristof Agniswamy, Johnson Wang, Yuan-Fang Hayashi, Hironori Aoki, Manabu Weber, Irene T. Mitsuya, Hiroaki TI Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RESOLUTION CRYSTAL-STRUCTURES; DRUG-RESISTANT MUTANTS; ALPHA-AMINO-ACIDS; IN-VITRO; THERAPY; LIGANDS; REPLICATION; AMANTADINE; COMPLEXES; GRL-0519 AB A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF, and THF-THP were examined. The S1' pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1' ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor 15d is improved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h, and 15i with HIV-1 protease complexes revealed molecular insight into the inhibitor-protein interaction. C1 [Ghosh, Arun K.; Osswald, Heather L.; Glauninger, Kristof] Purdue Univ, Dept Chem, 560 Oval Dr, W Lafayette, IN 47907 USA. [Ghosh, Arun K.; Osswald, Heather L.; Glauninger, Kristof] Purdue Univ, Dept Med Chem, 560 Oval Dr, W Lafayette, IN 47907 USA. [Agniswamy, Johnson; Wang, Yuan-Fang; Weber, Irene T.] Georgia State Univ, Dept Biol, Mol Basis Dis, Atlanta, GA 30303 USA. [Hayashi, Hironori; Aoki, Manabu; Mitsuya, Hiroaki] Kumamoto Univ, Dept Infect Dis, Grad Sch Med Sci, Kumamoto 8608556, Japan. [Hayashi, Hironori; Aoki, Manabu; Mitsuya, Hiroaki] Kumamoto Univ, Dept Hematol, Grad Sch Med Sci, Kumamoto 8608556, Japan. [Aoki, Manabu] Kumamoto Hlth Sci Univ, Dept Med Technol, Kumamoto 8615598, Japan. [Mitsuya, Hiroaki] Natl Ctr Global Hlth & Med, Ctr Clin Sci, Tokyo 1628655, Japan. [Aoki, Manabu; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Ghosh, AK (reprint author), Purdue Univ, Dept Chem, 560 Oval Dr, W Lafayette, IN 47907 USA.; Ghosh, AK (reprint author), Purdue Univ, Dept Med Chem, 560 Oval Dr, W Lafayette, IN 47907 USA. EM akghosh@purdue.edu FU National Institutes of Health [GM53386, GM 62920]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho); Ministry of Health, Welfare, and Labor of Japan FX This research was supported by the National Institutes of Health (grant GM53386 to A.K.G. and grant GM 62920 to I.W.). X-ray data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamline 22BM at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-Eng-38. This work was also supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and in part by a Grant-in-Aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho), a Grant for Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan, and the grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo) of Monbu-Kagakusho. We thank the Purdue University Center for Cancer Research, which supports the shared NMR and mass spectrometry facilities. NR 40 TC 0 Z9 0 U1 3 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JUL 28 PY 2016 VL 59 IS 14 BP 6826 EP 6837 DI 10.1021/acs.jmedchem.6b00639 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DS4DC UT WOS:000380730600016 PM 27389367 ER PT J AU Toti, KS Osborne, D Ciancetta, A Boison, D Jacobson, KA AF Toti, Kiran S. Osborne, Danielle Ciancetta, Antonella Boison, Detlev Jacobson, Kenneth A. TI South (S)- and North (N)-Methanocarba-7-Deazaadenosine Analogues as Inhibitors of Human Adenosine Kinase SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MOLECULAR-DYNAMICS; ENZYME-INHIBITION; SUGAR RING; NUCLEOSIDE TRANSPORTERS; ANTISEIZURE ACTIVITY; RECEPTOR LIGANDS; FORCE-FIELD; DISCOVERY; CELLS; BRAIN AB Adenosine kinase (AdK) inhibitors raise endogenous adenosine levels, particularly in disease states, and have potential for treatment of seizures, neurodegeneration, and inflammation. On the basis of the South (S) ribose conformation and molecular dynamics (MD) analysis of nucleoside inhibitors bound in AdK X-ray crystallographic structures, (S)- and North (N)-methanocarba (bicyclo[3.1.0]hexane) derivatives of known inhibitors were prepared and compared as human (h) AdK inhibitors. 5'-Hydroxy (34, MRS4202 (S); 55, MRS4380 (N)) and 5'-deoxy 38a (MRS4203 (S)) analogues, containing 7- and N-6-NH phenyl groups in 7-deazaadenine, robustly inhibited AdK activity (IC50 similar to 100 nM), while the 5'-hydroxy derivative 30 lacking the phenyl substituents was weak. Docking in the hAdK X-ray structure and MD simulation suggested a mode of binding similar to 5'-deoxy-5-iodotubercidin and other known inhibitors. Thus, a structure-based design approach for further potency enhancement is possible. The potent AdK inhibitors in this study are ready to be further tested in animal models of epilepsy. C1 [Toti, Kiran S.; Ciancetta, Antonella; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Osborne, Danielle; Boison, Detlev] Legacy Res Inst, Robert Stone Dow Neurobiol Labs, 1225 NE Second Ave, Portland, OR 97232 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Boison, Detlev/0000-0002-7740-5781 FU Intramural Research Program of the NIH; National Institute of Diabetes and Digestive and Kidney Diseases [ZIA DK031117-28]; National Institute of Neurological Disorders and Stroke [R21 NS088024]; National Institute of Mental Health [R01 MH083973]; National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C] FX We thank Dr. John Lloyd and Dr. Noel Whittaker (NIDDK) for mass spectral determinations. This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (ZIA DK031117-28), National Institute of Neurological Disorders and Stroke (R21 NS088024), and National Institute of Mental Health (R01 MH083973). We thank Prof. Artem Melman (Clarkson College) for helpful discussions. We thank Dr. Bryan L. Roth (University of North Carolina at Chapel Hill) and National Institute of Mental Health's Psychoactive Drug Screening Program (contract no. HHSN-271-2008-00025-C) for screening data. NR 83 TC 1 Z9 1 U1 6 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JUL 28 PY 2016 VL 59 IS 14 BP 6860 EP 6877 DI 10.1021/acs.jmedchem.6b00689 PG 18 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DS4DC UT WOS:000380730600019 PM 27410258 ER PT J AU Yu, GQ Gail, MH Consonni, D Carugno, M Humphrys, M Pesatori, AC Caporaso, NE Goedert, JJ Ravel, J Landi, MT AF Yu, Guoqin Gail, Mitchell H. Consonni, Dario Carugno, Michele Humphrys, Michael Pesatori, Angela C. Caporaso, Neil E. Goedert, James J. Ravel, Jacques Landi, Maria Teresa TI Characterizing human lung tissue microbiota and its relationship to epidemiological and clinical features SO GENOME BIOLOGY LA English DT Article DE Air pollution; Tumor stage; 16S rRNA ID OBSTRUCTIVE PULMONARY-DISEASE; LAND-USE REGRESSION; GUT MICROBIOTA; COMMUNITIES; ASSOCIATION; SIGNATURE; DATABASE AB Background: The human lung tissue microbiota remains largely uncharacterized, although a number of studies based on airway samples suggest the existence of a viable human lung microbiota. Here we characterized the taxonomic and derived functional profiles of lung microbiota in 165 non-malignant lung tissue samples from cancer patients. Results: We show that the lung microbiota is distinct from the microbial communities in oral, nasal, stool, skin, and vagina, with Proteobacteria as the dominant phylum (60 %). Microbiota taxonomic alpha diversity increases with environmental exposures, such as air particulates, residence in low to high population density areas, and pack-years of tobacco smoking and decreases in subjects with history of chronic bronchitis. Genus Thermus is more abundant in tissue from advanced stage (IIIB, IV) patients, while Legionella is higher in patients who develop metastases. Moreover, the non-malignant lung tissues have higher microbiota alpha diversity than the paired tumors. Conclusions: Our results provide insights into the human lung microbiota composition and function and their link to human lifestyle and clinical outcomes. Studies among subjects without lung cancer are needed to confirm our findings. C1 [Yu, Guoqin; Caporaso, Neil E.; Landi, Maria Teresa] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Gail, Mitchell H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Consonni, Dario; Pesatori, Angela C.] Osped Maggiore Policlin, Fdn IRCCS Ca Granda, Epidemiol Unit, Milan, Italy. [Carugno, Michele; Pesatori, Angela C.] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Humphrys, Michael; Ravel, Jacques] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. EM landim@mail.nih.gov OI pesatori, angela/0000-0002-0261-3252 FU Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics FX This study was supported by the Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics. NR 44 TC 5 Z9 5 U1 10 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD JUL 28 PY 2016 VL 17 AR 163 DI 10.1186/s13059-016-1021-1 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DS5WY UT WOS:000380854900001 PM 27468850 ER PT J AU Arendt, D King, N Carroll, SB Wittkopp, P Koonin, E Kruglyak, L AF Arendt, Detlev King, Nicole Carroll, Sean B. Wittkopp, Patricia Koonin, Eugene Kruglyak, Leonid TI Big Questions in Evolution SO CELL LA English DT Editorial Material C1 [Arendt, Detlev] European Mol Biol Lab, Grenoble, France. [King, Nicole] Univ Calif Berkeley, HHMI, Berkeley, CA 94720 USA. [Carroll, Sean B.] Univ Wisconsin, HHMI, Madison, WI 53706 USA. [Wittkopp, Patricia] Univ Michigan, Ann Arbor, MI 48109 USA. [Koonin, Eugene] NIH, Bethesda, MD USA. [Kruglyak, Leonid] Univ Calif Los Angeles, HHMI, Los Angeles, CA 90024 USA. RP Arendt, D (reprint author), European Mol Biol Lab, Grenoble, France. NR 0 TC 0 Z9 0 U1 18 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 28 PY 2016 VL 166 IS 3 BP 528 EP 529 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS2ED UT WOS:000380546500003 ER PT J AU Joyce, MG Wheatley, AK Thomas, PV Chuang, GY Soto, C Bailer, RT Druz, A Georgiev, IS Gillespie, RA Kanekiyo, M Kong, WP Leung, K Narpala, SN Prabhakaran, MS Yang, ES Zhang, BS Zhang, Y Asokan, M Boyington, JC Bylund, T Darko, S Lees, CR Ransier, A Shen, CH Wang, LS Whittle, JR Wu, XL Yassine, HM Santos, C Matsuoka, Y Tsybovsky, Y Baxa, U Mullikin, JC Subbarao, K Douek, DC Graham, BS Koup, RA Ledgerwood, JE Roederer, M Shapiro, L Kwong, PD Mascola, JR McDermott, AB AF Joyce, M. Gordon Wheatley, Adam K. Thomas, Paul V. Chuang, Gwo-Yu Soto, Cinque Bailer, Robert T. Druz, Aliaksandr Georgiev, Ivelin S. Gillespie, Rebecca A. Kanekiyo, Masaru Kong, Wing-Pui Leung, Kwanyee Narpala, Sandeep N. Prabhakaran, Madhu S. Yang, Eun Sung Zhang, Baoshan Zhang, Yi Asokan, Mangaiarkarasi Boyington, Jeffrey C. Bylund, Tatsiana Darko, Sam Lees, Christopher R. Ransier, Amy Shen, Chen-Hsiang Wang, Lingshu Whittle, James R. Wu, Xueling Yassine, Hadi M. Santos, Celia Matsuoka, Yumiko Tsybovsky, Yaroslav Baxa, Ulrich Mullikin, James C. Subbarao, Kanta Douek, Daniel C. Graham, Barney S. Koup, Richard A. Ledgerwood, Julie E. Roederer, Mario Shapiro, Lawrence Kwong, Peter D. Mascola, John R. McDermott, Adrian B. CA NISC Comparative Sequencing TI Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses SO CELL LA English DT Article ID MEMORY B-CELLS; HEMAGGLUTININ-STEM; BINDING SITE; EPITOPE; IDENTIFICATION; RECOGNITION; REPERTOIRE; MATURATION; IMMUNOGEN; INTERVAL AB Antibodies capable of neutralizing divergent influenza A viruses could form the basis of a universal vaccine. Here, from subjects enrolled in an H5N1 DNA/MIV-prime-boost influenza vaccine trial, we sorted hemagglutinin cross-reactive memory B cells and identified three antibody classes, each capable of neutralizing diverse subtypes of group 1 and group 2 influenza A viruses. Co-crystal structures with hemagglutinin revealed that each class utilized characteristic germline genes and convergent sequence motifs to recognize overlapping epitopes in the hemagglutinin stem. All six analyzed subjects had sequences from at least one multidonor class, and-in half the subjects-multidonor-class sequences were recovered from>40% of cross-reactive B cells. By contrast, these multidonor-class sequences were rare in published antibody datasets. Vaccination with a divergent hemagglutinin can thus increase the frequency of B cells encoding broad influenza A-neutralizing antibodies. We propose the sequence signature-quantified prevalence of these B cells as a metric to guide universal influenza A immunization strategies. C1 [Joyce, M. Gordon; Wheatley, Adam K.; Thomas, Paul V.; Chuang, Gwo-Yu; Soto, Cinque; Bailer, Robert T.; Druz, Aliaksandr; Georgiev, Ivelin S.; Gillespie, Rebecca A.; Kanekiyo, Masaru; Kong, Wing-Pui; Leung, Kwanyee; Narpala, Sandeep N.; Prabhakaran, Madhu S.; Yang, Eun Sung; Zhang, Baoshan; Zhang, Yi; Asokan, Mangaiarkarasi; Boyington, Jeffrey C.; Bylund, Tatsiana; Darko, Sam; Lees, Christopher R.; Ransier, Amy; Shen, Chen-Hsiang; Wang, Lingshu; Whittle, James R.; Wu, Xueling; Yassine, Hadi M.; Santos, Celia; Douek, Daniel C.; Graham, Barney S.; Koup, Richard A.; Ledgerwood, Julie E.; Roederer, Mario; Shapiro, Lawrence; Kwong, Peter D.; Mascola, John R.; McDermott, Adrian B.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Georgiev, Ivelin S.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. [Georgiev, Ivelin S.] Vanderbilt Univ, Med Ctr, Vanderbilt Vaccine Ctr, Nashville, TN 37232 USA. [Georgiev, Ivelin S.] Vanderbilt Univ, Dept Elect Engn & Comp Sci, Nashville, TN 37232 USA. [Yassine, Hadi M.; Santos, Celia; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Tsybovsky, Yaroslav; Baxa, Ulrich] Frederick Natl Lab Canc Res, Electron Microscopy Lab, Canc Res Technol Program, Leidos Biomed Res, Frederick, MD 21702 USA. [Mullikin, James C.; NISC Comparative Sequencing] NHGRI, NISC, NIH, Bethesda, MD 20892 USA. [Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10027 USA. [Shapiro, Lawrence] Columbia Univ, Dept Syst Biol, New York, NY 10027 USA. RP Kwong, PD; Mascola, JR; McDermott, AB (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov; jmascola@nih.gov; adrian.mcdermott@nih.gov OI Wheatley, Adam/0000-0002-5593-9387 FU Intramural Research Program of the Vaccine Research Center; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank D. Ambrosak and R. Nguyen for assistance with flow cytometry; J. Chrzas, J. Gonczy, U. Chinte, and staff at Southeast Regional Collaborative Access Team (SER-CAT) for help with X-ray diffraction data collection; G. Georgiou and S.R. Quake for human antibody sequences; J. Stuckey for assistance with figures; and members of the Structural Biology Section, Structural Bioinformatics Core Section and Virology Laboratory of the Vaccine Research Center for helpful comments. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. This work was supported in part with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E. Use of insertion device 22 (SER-CAT) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38. NR 35 TC 5 Z9 5 U1 4 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 28 PY 2016 VL 166 IS 3 BP 609 EP 623 DI 10.1016/j.cell.2016.06.043 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS2ED UT WOS:000380546500013 PM 27453470 ER PT J AU Zhang, H Liu, T Zhang, Z Payne, SH Zhang, B McDermott, JE Zhou, JY Petyuk, VA Chen, L Ray, D Sun, SS Yang, F Chen, LJ Wang, J Shah, P Cha, SW Aiyetan, P Woo, S Tian, Y Gritsenko, MA Clauss, TR Choi, C Monroe, ME Thomas, S Nie, S Wu, CC Moore, RJ Yu, KH Tabb, DL Fenyo, D Bafna, V Wang, Y Rodriguez, H Boja, ES Hiltke, T Rivers, RC Sokoll, L Zhu, H Shih, IM Cope, L Pandey, A Zhang, B Snyder, MP Levine, DA Smith, RD Chan, DW Rodland, KD AF Zhang, Hui Liu, Tao Zhang, Zhen Payne, Samuel H. Zhang, Bai McDermott, Jason E. Zhou, Jian-Ying Petyuk, Vladislav A. Chen, Li Ray, Debjit Sun, Shisheng Yang, Feng Chen, Lijun Wang, Jing Shah, Punit Cha, Seong Won Aiyetan, Paul Woo, Sunghee Tian, Yuan Gritsenko, Marina A. Clauss, Therese R. Choi, Caitlin Monroe, Matthew E. Thomas, Stefani Nie, Song Wu, Chaochao Moore, Ronald J. Yu, Kun-Hsing Tabb, David L. Fenyo, David Bafna, Vineet Wang, Yue Rodriguez, Henry Boja, Emily S. Hiltke, Tara Rivers, Robert C. Sokoll, Lori Zhu, Heng Shih, Ie-Ming Cope, Leslie Pandey, Akhilesh Zhang, Bing Snyder, Michael P. Levine, Douglas A. Smith, Richard D. Chan, Daniel W. Rodland, Karin D. CA CPTAC Investigators TI Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer SO CELL LA English DT Article ID EPITHELIAL OVARIAN; PHASE-II; HOMOLOGOUS RECOMBINATION; HISTONE DEACETYLASE; PROTEIN EXPRESSION; NETWORK ANALYSIS; NEXT-GENERATION; CARCINOMA; TUMORS; REPAIR AB To provide a detailed analysis of the molecular components and underlying mechanisms associated with ovarian cancer, we performed a comprehensive mass-spectrometry-based proteomic characterization of 174 ovarian tumors previously analyzed by The Cancer Genome Atlas (TCGA), of which 169 were high-grade serous carcinomas (HGSCs). Integrating our proteomic measurements with the genomic data yielded a number of insights into disease, such as how different copy-number alternations influence the proteome, the proteins associated with chromosomal instability, the sets of signaling pathways that diverse genome rearrangements converge on, and the ones most associated with short overall survival. Specific protein acetylations associated with homologous recombination deficiency suggest a potential means for stratifying patients for therapy. In addition to providing a valuable resource, these findings provide a view of how the somatic genome drives the cancer proteome and associations between protein and post-translational modification levels and clinical outcomes in HGSC. C1 [Zhang, Hui; Zhang, Zhen; Zhang, Bai; Zhou, Jian-Ying; Chen, Li; Sun, Shisheng; Chen, Lijun; Shah, Punit; Aiyetan, Paul; Tian, Yuan; Choi, Caitlin; Thomas, Stefani; Sokoll, Lori; Zhu, Heng; Chan, Daniel W.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21231 USA. [Liu, Tao; Payne, Samuel H.; McDermott, Jason E.; Petyuk, Vladislav A.; Ray, Debjit; Yang, Feng; Gritsenko, Marina A.; Clauss, Therese R.; Monroe, Matthew E.; Nie, Song; Wu, Chaochao; Moore, Ronald J.; Smith, Richard D.; Rodland, Karin D.] Pacific Northwest Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Wang, Jing; Tabb, David L.; Zhang, Bing] Vanderbilt Univ, Dept Biomed Informat, Sch Med, Nashville, TN 37203 USA. [Cha, Seong Won; Woo, Sunghee] Univ Calif San Diego, Dept Elect & Comp Engn, San Diego, CA 92093 USA. [Yu, Kun-Hsing] Stanford Univ, Biomed Informat Training Program, Sch Med, Stanford, CA 94305 USA. [Yu, Kun-Hsing; Snyder, Michael P.] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [Fenyo, David] NYU, Sch Med, Ctr Hlth Informat & Bioinformat, New York, NY 10016 USA. [Fenyo, David] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA. [Bafna, Vineet] Univ Calif San Diego, Dept Comp Sci & Engn, San Diego, CA 92093 USA. [Wang, Yue] Virginia Polytech Inst & State Univ, Bradley Dept Elect & Comp Engn, Arlington, VA 22203 USA. [Rodriguez, Henry; Boja, Emily S.; Hiltke, Tara; Rivers, Robert C.] NCI, Off Canc Clin Prote Res, Bethesda, MD 20892 USA. [Shih, Ie-Ming] Johns Hopkins Med Inst, Dept Gynecol & Obstet, Baltimore, MD 21231 USA. [Cope, Leslie] Johns Hopkins Med Inst, Dept Oncol, Baltimore, MD 21231 USA. [Pandey, Akhilesh] Johns Hopkins Med Inst, McKusick Nathans Inst Genet Med, Baltimore, MD 21287 USA. [Levine, Douglas A.] NYU, Laura & Isaac Perlmutter Canc Ctr, Dept Gynecol Oncol, Langone Med Ctr, New York, NY 10016 USA. RP Chan, DW (reprint author), Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21231 USA.; Rodland, KD (reprint author), Pacific Northwest Natl Lab, Div Biol Sci, Richland, WA 99352 USA. EM dchan@jhmi.edu; karin.rodland@pnnl.gov RI Smith, Richard/J-3664-2012; OI Smith, Richard/0000-0002-2381-2349; Fenyo, David/0000-0001-5049-3825 FU National Cancer Institute (NCI) [U24CA160019, U24CA160036]; NIH [P41GM103493]; DOE [DE-AC05-76RL01830] FX This work was supported by National Cancer Institute (NCI) CPTAC awards U24CA160019 and U24CA160036 and by NIH grant P41GM103493. The PNNL proteomics work described herein was performed in the Environmental Molecular Sciences Laboratory, a U.S. Department of Energy (DOE) National Scientific User Facility located at PNNL in Richland, WA. PNNL is a multi-program national laboratory operated by the Battelle Memorial Institute for the DOE under contract DE-AC05-76RL01830. Genomics data for this study were generated by the TCGA Pilot Project, established by the NCI and the National Human Genome Research Institute. NR 44 TC 21 Z9 21 U1 15 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 28 PY 2016 VL 166 IS 3 BP 755 EP 765 DI 10.1016/j.cell.2016.05.069 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS2ED UT WOS:000380546500024 PM 27372738 ER PT J AU Dao, P Hoinka, J Takahashi, M Zhou, JH Ho, M Wang, YJ Costa, F Rossi, JJ Backofen, R Burnett, J Przytycka, TM AF Phuong Dao Hoinka, Jan Takahashi, Mayumi Zhou, Jiehua Ho, Michelle Wang, Yijie Costa, Fabrizio Rossi, John J. Backofen, Rolf Burnett, John Przytycka, Teresa M. TI AptaTRACE Elucidates RNA Sequence-Structure Motifs from Selection Trends in HT-SELEX Experiments SO CELL SYSTEMS LA English DT Article ID FACTOR-BINDING SPECIFICITIES; IN-VITRO SELECTION; NEXT-GENERATION; APTAMERS; DISCOVERY; LIGANDS; SITES AB Aptamers, short RNA or DNA molecules that bind distinct targets with high affinity and specificity, can be identified using high-throughput systematic evolution of ligands by exponential enrichment (HT-SELEX), but scalable analytic tools for understanding sequence-function relationships from diverse HT-SELEX data are not available. Here we present AptaTRACE, a computational approach that leverages the experimental design of the HT-SELEX protocol, RNA secondary structure, and the potential presence of many secondary motifs to identify sequence-structure motifs that show a signature of selection. We apply AptaTRACE to identify nine motifs in C-C chemokine receptor type 7 targeted by aptamers in an in vitro cell-SELEX experiment. We experimentally validate two aptamers whose binding required both sequence and structural features. AptaTRACE can identify low-abundance motifs, and we show through simulations that, because of this, it could lower HT-SELEX cost and time by reducing the number of selection cycles required. C1 [Phuong Dao; Hoinka, Jan; Wang, Yijie; Przytycka, Teresa M.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Takahashi, Mayumi; Zhou, Jiehua; Ho, Michelle; Rossi, John J.; Burnett, John] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol & Cellular Biol, Duarte, CA 91010 USA. [Costa, Fabrizio; Backofen, Rolf] Univ Freiburg, Dept Comp Sci, Bioinformat Grp, D-79110 Freiburg, Germany. RP Przytycka, TM (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM przytyck@ncbi.nlm.nih.gov RI Wang, Yijie/Q-5739-2016; OI Costa, Fabrizio/0000-0002-4900-995X FU Intramural Research Program of the NIH, National Library of Medicine; NIH FX This work was supported by the Intramural Research Program of the NIH, National Library of Medicine (J.H., P.D., and T.M.P.). Funding for the open access charge was provided by the NIH. This work utilized the computational resources of the NIH HPC Biowulf cluster. J.J.R., J.Z., and M.T. have patent disclosures entitled "CCR7 and CD2 RNA Aptamer-Functionalized Conjugates to Target and Activate HIV Latently Infected Lymphocytes,'' City of Hope, filed in January 2016. An early version of this paper was submitted to and peer-reviewed at the 2016 Annual International Conference on Research in Computational Molecular Biology (RECOMB). The manuscript was revised and then independently further reviewed at Cell Systems. NR 31 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2405-4712 EI 2405-4720 J9 CELL SYST JI Cell Syst. PD JUL 27 PY 2016 VL 3 IS 1 BP 62 EP 70 DI 10.1016/j.cels.2016.07.003 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN1LW UT WOS:000395772700011 PM 27467247 ER PT J AU Neumann, S Padia, U Cullen, MJ Eliseeva, E Nir, EA Place, RF Morgan, SJ Gershengorn, MC AF Neumann, Susanne Padia, Umesh Cullen, Mary Jane Eliseeva, Elena Nir, Eshel A. Place, Robert F. Morgan, Sarah J. Gershengorn, Marvin C. TI An Enantiomer of an Oral Small-Molecule TSH Receptor Pharmacologic Properties SO FRONTIERS IN ENDOCRINOLOGY LA English DT Article DE TSH receptor; agonist; allosteric; enantiomer; racemic ID THYROID-STIMULATING HORMONE; PROTEIN-COUPLED RECEPTORS; RECOMBINANT HUMAN TSH; THYROTROPIN RECEPTOR; NODULAR GOITER; SYMPORTER; EXPRESSION; QUALITY; CLONING; CANCER AB We are developing an orally available small-molecule, allosteric TSH receptor (TSHR) agonist for follow-up diagnostics of patients with thyroid cancer. The agonist C2 (NCGC00161870) that we have studied so far is a racemic mixture containing equal amounts of two enantiomers, E1 and E2. As enantiomers of many drugs exhibit different pharmacologic properties, we assessed the properties of E1 and E2. We separated the two enantiomers by chiral chromatography and determined E2 as the (S)-(+) isomer via crystal structure analysis. E1 and E2 were shown to bind differently to a homology model of the transmembrane domain of TSHR in which E2 was calculated to exhibit lower binding energy than E1 and was, therefore, predicted to be more potent than E1. In HEK293 cells expressing human TSHRs, C2, E1, and E2 were equally efficacious in stimulating cAMP production, but their potencies were different. E2 was more potent (EC50 = 18 nM) than C2 (EC50 = 46 nM), which was more potent than E1 (EC50 = 217 nM). In primary cultures of human thyrocytes, C2, E1, and E2 stimulated increases in thyroperoxidase mRNA of 92-, 55-, and 137-fold and in sodium-iodide symporter mRNA of 20-, 4-, and 121-fold above basal levels, respectively. In mice, C2 stimulated an increase in radioactive iodine uptake of 1.5-fold and E2 of 2.8-fold above basal level, whereas E1 did not have an effect. C2 stimulated an increase in serum T4 of 2.4-fold, E1 of 1.9-fold, and E2 of 5.6-fold above basal levels, and a 5-day oral dosing regimen of E2 increased serum T4 levels comparable to recombinant human TSH (rhTSH, Thyrogen (R)). Thus, E2 is more effective than either C2 or E1 in stimulating thyroid function and as efficacious as rhTSH in vivo. E2 represents the next step toward developing an oral drug for patients with thyroid cancer. C1 [Neumann, Susanne; Padia, Umesh; Cullen, Mary Jane; Eliseeva, Elena; Nir, Eshel A.; Place, Robert F.; Morgan, Sarah J.; Gershengorn, Marvin C.] Natl Inst Diabet & Digest & Kidney Dis, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. RP Neumann, S (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. EM susannen@intra.niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program [Z01 DK047045] FX This work was funded by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program Z01 DK047045. NR 34 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PD JUL 27 PY 2016 VL 7 AR 105 DI 10.3389/fendo.2016.00105 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DY7GT UT WOS:000385298300002 PM 27512388 ER PT J AU Ahmad, M Xue, YT Lee, SK Martindale, JL Shen, WP Li, W Zou, SG Ciaramella, M Debat, H Nadal, M Leng, FF Zhang, HL Wang, Q Siaw, GEL Niu, HY Pommier, Y Gorospe, M Hsieh, TS Tse-Dinh, YC Xu, DY Wang, WD AF Ahmad, Muzammil Xue, Yutong Lee, Seung Kyu Martindale, Jennifer L. Shen, Weiping Li, Wen Zou, Sige Ciaramella, Maria Debat, Helene Nadal, Marc Leng, Fenfei Zhang, Hongliang Wang, Quan Siaw, Grace Ee-Lu Niu, Hengyao Pommier, Yves Gorospe, Myriam Hsieh, Tao-Shih Tse-Dinh, Yuk-Ching Xu, Dongyi Wang, Weidong TI RNA topoisomerase is prevalent in all domains of life and associates with polyribosomes in animals SO NUCLEIC ACIDS RESEARCH LA English DT Article ID X-SYNDROME PROTEIN; DNA TOPOISOMERASE; ESCHERICHIA-COLI; REVERSE GYRASE; CRYSTAL-STRUCTURE; CELL-LINES; COMPLEX; BINDING; GENOME; RELAXATION AB DNA Topoisomerases are essential to resolve topological problems during DNA metabolism in all species. However, the prevalence and function of RNA topoisomerases remain uncertain. Here, we show that RNA topoisomerase activity is prevalent in Type IA topoisomerases from bacteria, archaea, and eukarya. Moreover, this activity always requires the conserved Type IA core domains and the same catalytic residue used in DNA topoisomerase reaction; however, it does not absolutely require the non-conserved carboxyl- terminal domain (CTD),which is necessary for relaxation reactions of supercoiled DNA. The RNA topoisomerase activity of human Top3 beta differs from that of Escherichia coli topoisomerase I in that the former but not the latter requires the CTD, indicating that topoisomerases have developed distinct mechanisms during evolution to catalyze RNA topoisomerase reactions. Notably, Top3 beta proteins from several animals associate with polyribosomes, which are units of mRNA translation, whereas the Top3 homologs from E. coli and yeast lack the association. The Top3 beta-polyribosome association requires TDRD3, which directly interacts with Top3 beta and is present in animals but not bacteria or yeast. We propose that RNA topoisomerases arose in the early RNA world, and that they are retained through all domains of DNA-based life, where they mediate mRNA translation as part of polyribosomes in animals. C1 [Ahmad, Muzammil; Xue, Yutong; Lee, Seung Kyu; Shen, Weiping; Wang, Weidong] NIA, Genome Instabil & Chromatin Remodeling Sect, Genet Lab, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Martindale, Jennifer L.; Gorospe, Myriam] NIA, RNA Regulat Sect, Genet Lab, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Li, Wen; Xu, Dongyi] Peking Univ, State Key Lab Prot & Plant Gene Res, Sch Life Sci, Beijing 1000871, Peoples R China. [Zou, Sige] NIA, Translat Gerontol Branch, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Ciaramella, Maria] Natl Res Council Italy, Inst Biosci & Bioresources, I-80131 Naples, Italy. [Debat, Helene; Nadal, Marc] Univ Paris Diderot, CNRS, Inst Jacques Monod, UMR7592, 15 Rue Helene Brion, F-75205 Paris, France. [Leng, Fenfei; Tse-Dinh, Yuk-Ching] Florida Int Univ, Dept Chem & Biochem, Biomol Sci Inst, Miami, FL 33199 USA. [Zhang, Hongliang; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zhang, Hongliang; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wang, Quan; Niu, Hengyao] Indiana Univ, Dept Mol & Cellular Biochem, 212 South Hawthorne Dr, Bloomington, IN 47405 USA. [Siaw, Grace Ee-Lu; Hsieh, Tao-Shih] Acad Sinica, Inst Cellular Organist Biol, Taipei 11529, Taiwan. [Hsieh, Tao-Shih] Duke Univ, Med Ctr, Dept Biochem, Durham, NC USA. RP Wang, WD (reprint author), NIA, Genome Instabil & Chromatin Remodeling Sect, Genet Lab, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA.; Xu, DY (reprint author), Peking Univ, State Key Lab Prot & Plant Gene Res, Sch Life Sci, Beijing 1000871, Peoples R China. EM xudongyi@pku.edu.cn; wangw@grc.nia.nih.gov OI Xu, Dongyi/0000-0001-5711-2618 FU Intramural Research Program of the National Institute on Aging [Z01 AG000657-08]; National Cancer Institute [Z01 BC006161]; National Institutes of Health; National Basic Research Program of China [2013CB911002]; National Natural Science Foundation of China [31271435]; National Institute on Aging, NIH, Intramural funding FX Intramural Research Program of the National Institute on Aging [Z01 AG000657-08]; National Cancer Institute [Z01 BC006161]; National Institutes of Health; the National Basic Research Program of China [2013CB911002)]; National Natural Science Foundation of China [31271435]. Funding for open access charge: National Institute on Aging, NIH, Intramural funding. NR 59 TC 5 Z9 5 U1 4 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 27 PY 2016 VL 44 IS 13 BP 6335 EP 6349 DI 10.1093/nar/gkw508 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5VR UT WOS:000382999300031 PM 27257063 ER PT J AU Pirtskhalava, M Gabrielian, A Cruz, P Griggs, HL Squires, RB Hurt, DE Grigolava, M Chubinidze, M Gogoladze, G Vishnepolsky, B Alekseyev, V Rosenthal, A Tartakovsky, M AF Pirtskhalava, Malak Gabrielian, Andrei Cruz, Phillip Griggs, Hannah L. Squires, R. Burke Hurt, Darrell E. Grigolava, Maia Chubinidze, Mindia Gogoladze, George Vishnepolsky, Boris Alekseyev, Vsevolod Rosenthal, Alex Tartakovsky, Michael TI DBAASP v.2: an enhanced database of structure and antimicrobial/cytotoxic activity of natural and synthetic peptides (vol 44, pg D1104, 2016) SO NUCLEIC ACIDS RESEARCH LA English DT Correction C1 [Pirtskhalava, Malak; Grigolava, Maia; Chubinidze, Mindia; Gogoladze, George; Vishnepolsky, Boris] Ivane Beritashvili Ctr Expt Biomed, GE-0160 Tbilisi, Rep of Georgia. [Gabrielian, Andrei; Cruz, Phillip; Griggs, Hannah L.; Squires, R. Burke; Hurt, Darrell E.; Alekseyev, Vsevolod; Rosenthal, Alex; Tartakovsky, Michael] NIAID, Off Cyber Infrastruct & Computat Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Pirtskhalava, M (reprint author), Ivane Beritashvili Ctr Expt Biomed, GE-0160 Tbilisi, Rep of Georgia. EM m.pirtskhalava@lifescience.org.ge NR 1 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 27 PY 2016 VL 44 IS 13 BP 6503 EP 6503 DI 10.1093/nar/gkw243 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5VR UT WOS:000382999300045 PM 27060142 ER PT J AU Ranganathan, M Heise, L Pettifor, A Silverwood, RJ Selin, A MacPhail, C Delany-Moretlwe, S Kahn, K Gomez-Olive, FX Hughes, JP Piwowar-Manning, E Laeyendecker, O Watts, C AF Ranganathan, Meghna Heise, Lori Pettifor, Audrey Silverwood, Richard J. Selin, Amanda MacPhail, Catherine Delany-Moretlwe, Sinead Kahn, Kathleen Gomez-Olive, F. Xavier Hughes, James P. Piwowar-Manning, Estelle Laeyendecker, Oliver Watts, Charlotte TI Transactional sex among young women in rural South Africa: prevalence, mediators and association with HIV infection SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Article DE transactional sex; structural drivers; HIV; adolescent women; young women; sub-Saharan Africa; risky sexual behaviours ID SUB-SAHARAN AFRICA; GENDER-BASED VIOLENCE; ADOLESCENT GIRLS; DRINKING VENUES; SURVIVAL SEX; ALCOHOL-USE; CONDOM USE; BEHAVIOR; RISK; YOUTH AB Introduction: Young adolescent women in sub-Saharan Africa are three to four times more likely to be HIV-positive than boys or men. One of the relationship dynamics that is likely to be associated with young women's increased vulnerability to HIV is transactional sex. There are a range of HIV-related risk behaviours that may drive this vulnerability. However, to date, limited epidemiological data exist on the role of transactional sex in increasing HIV acquisition, especially among young women in subSaharan Africa. Our paper presents data on the prevalence of self-reported engagement in transactional sex and explores whether transactional sex is associated with increased risk of HIV infection among a cohort of young, rural, sexually active South African women. We also explore whether this relationship is mediated through certain HIV-related risk behaviours. Methods: We analyzed baseline data from a phase III trial of conditional cash transfers for HIV prevention of 693 sexually active, school-going young women aged 13-20 years in rural South Africa. We examined the association between young women's engagement in transactional sex and HIV infection. Transactional sex is defined as a non-commercial, non-marital sexual relationship whereby sex is exchanged for money and/or gifts. We explored whether this relationship is mediated by certain HIVrelated risk behaviours. We used logistic and multinomial regression and report unadjusted and adjusted odds ratios with 95% CI. Results: Overall, 14% (n = 97) of sexually active young women reported engaging in transactional sex. Engagement in transactional sex was associated with an increased risk of being HIV-positive (aOR: 2.5, CI: 95% 1.19-5.25, p = 0.01). The effect size of this association remained nearly unchanged when adjusted for certain other dimensions of HIV risk that might help explain the underlying pathways for this relationship. Conclusions: This study provides quantitative support demonstrating that transactional sex is associated with HIV infection in young women. Even though the specific variables tested do not mediate the relationship, a potential explanation for this association may be that the men with whom young women are having sex belong to networks of sexually connected individuals who are at a "high risk" for HIV infection. The results highlight the importance of structural intervention approaches that can alter the context of young women's HIV risk. C1 [Ranganathan, Meghna; Heise, Lori; Watts, Charlotte] London Sch Hyg & Trop Med, Fac Publ Hlth & Policy, Dept Global Hlth & Dev, 15-17 Tavistock Pl, London WC1H 9SH, England. [Ranganathan, Meghna; Pettifor, Audrey; MacPhail, Catherine; Delany-Moretlwe, Sinead] Univ Witwatersrand, Wits Reprod Hlth & HIV Inst, Johannesburg, South Africa. [Pettifor, Audrey; Selin, Amanda] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Pettifor, Audrey] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Pettifor, Audrey; MacPhail, Catherine; Kahn, Kathleen; Gomez-Olive, F. Xavier] Univ Witwatersrand, MRC Wits Rural Publ Hlth & Hlth Transit Unit Agin, Fac Hlth Sci, Sch Publ Hlth, Johannesburg, South Africa. [Silverwood, Richard J.] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, Dept Med Stat, London, England. [MacPhail, Catherine] Univ New England, Sch Hlth, Armidale, NSW, Australia. [Kahn, Kathleen] Umea Univ, Div Epidemiol & Global Hlth, Dept Publ Hlth & Clin Med, Umea Ctr Global Hlth Res, Umea, Sweden. [Kahn, Kathleen] Int Network Demog Evaluat Populat & Their Hlth IN, Accra, Ghana. [Hughes, James P.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Piwowar-Manning, Estelle] Johns Hopkins Univ, Sch Med, Dept Pathol, HPTN Lab Ctr, Baltimore, MD 21205 USA. [Laeyendecker, Oliver] NIAID, Lab Immunoregulat, NIH, Baltimore, MD USA. [Laeyendecker, Oliver] Johns Hopkins Univ, Dept Med & Epidemiol, Baltimore, MD USA. RP Ranganathan, M (reprint author), London Sch Hyg & Trop Med, Fac Publ Hlth & Policy, Dept Global Hlth & Dev, 15-17 Tavistock Pl, London WC1H 9SH, England. EM Meghna.Ranganathan@lshtm.ac.uk FU STRIVE research programme consortium - UKaid from the Department for International Development; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Mental Health (NIMH); National Institute on Drug Abuse (NIDA) of the National Institutes of Health (NIH) [UM1AI068619, UM1AI068617, UM1AI068613]; Division of Intramural Research, NIAID; [5R01MH087118-02]; [R24 HD050924] FX This research was supported by the STRIVE research programme consortium funded by UKaid from the Department for International Development. However, the views expressed do not necessarily reflect the department's official policies. Overall support for the HIV Prevention Trials Network (HPTN) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA) of the National Institutes of Health (NIH) under Award Numbers UM1AI068619 (HPTN Leadership and Operations Center), UM1AI068617 (HPTN Statistical and Data Management Center) and UM1AI068613 (HPTN Laboratory Center). Additional funding was provided in part by the Division of Intramural Research, NIAID. The study was also funded under Award Number 5R01MH087118-02 and R24 HD050924 to the Carolina Population Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. NR 61 TC 1 Z9 1 U1 10 U2 13 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD JUL 27 PY 2016 VL 19 AR 20749 DI 10.7448/IAS.19.1.20749 PG 13 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DU0QT UT WOS:000381910300001 PM 27469061 ER PT J AU Boyington, JC Joyce, MG Sastry, M Stewart-Jones, GBE Chen, M Kong, WP Ngwuta, JO Thomas, PV Tsybovsky, Y Yang, YP Zhang, BS Chen, L Druz, A Georgiev, IS Ko, K Zhou, TQ Mascola, JR Graham, BS Kwong, PD AF Boyington, Jeffrey C. Joyce, M. Gordon Sastry, Mallika Stewart-Jones, Guillaume B. E. Chen, Man Kong, Wing-Pui Ngwuta, Joan O. Thomas, Paul V. Tsybovsky, Yaroslav Yang, Yongping Zhang, Baoshan Chen, Lei Druz, Aliaksandr Georgiev, Ivelin S. Ko, Kiyoon Zhou, Tongqing Mascola, John R. Graham, Barney S. Kwong, Peter D. TI Structure-Based Design of Head-Only Fusion Glycoprotein Immunogens for Respiratory Syncytial Virus SO PLOS ONE LA English DT Article ID NEUTRALIZING ANTIBODY; F-PROTEIN; MONOCLONAL-ANTIBODY; HEMAGGLUTININ-STEM; CRYSTAL-STRUCTURE; VACCINE; INFECTION; RSV; PROTECTION; EPITOPE AB Respiratory syncytial virus (RSV) is a significant cause of severe respiratory illness worldwide, particularly in infants, young children, and the elderly. Although no licensed vaccine is currently available, an engineered version of the metastable RSV fusion (F) surface glycoprotein-stabilized in the pre-fusion (pre-F) conformation by "DS-Cav1" mutations-elicits high titer RSV-neutralizing responses. Moreover, pre-F-specific antibodies, often against the neutralization-sensitive antigenic site empty set in the membrane-distal head region of trimeric F glycoprotein, comprise a substantial portion of the human response to natural RSV infection. To focus the vaccine-elicited response to antigenic site empty set, we designed a series of RSV F immunogens that comprised the membrane-distal head of the F glycoprotein in its pre-F conformation. These "head-only" immunogens formed monomers, dimers, and trimers. Antigenic analysis revealed that a majority of the 70 engineered head-only immunogens displayed reactivity to site empty set-targeting antibodies, which was similar to that of the parent RSV F DS-Cav1 trimers, often with increased thermostability. We evaluated four of these head-only immunogens in detail, probing their recognition by antibodies, their physical stability, structure, and immunogenicity. When tested in naive mice, a head-only trimer, half the size of the parent RSV F trimer, induced RSV titers, which were statistically comparable to those induced by DS-Cav1. When used to boost DS-Cav1-primed mice, two head-only RSV F immunogens, a dimer and a trimer, boosted RSV-neutralizing titers to levels that were comparable to those boosted by DS-Cav1, although with higher site empty set-directed responses. Our results provide proof-of-concept for the ability of the smaller head-only RSV F immunogens to focus the vaccine-elicited response to antigenic site empty set. Decent primary immunogenicity, enhanced physical stability, potential ease of manufacture, and potent immunogenicity upon boosting suggest these head-only RSV F immunogens, engineered to retain the pre-fusion conformation, may have advantages as candidate RSV vaccines. C1 [Boyington, Jeffrey C.; Joyce, M. Gordon; Sastry, Mallika; Stewart-Jones, Guillaume B. E.; Chen, Man; Kong, Wing-Pui; Ngwuta, Joan O.; Thomas, Paul V.; Yang, Yongping; Zhang, Baoshan; Chen, Lei; Druz, Aliaksandr; Georgiev, Ivelin S.; Ko, Kiyoon; Zhou, Tongqing; Mascola, John R.; Graham, Barney S.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Tsybovsky, Yaroslav] Leidos Biomed Res Inc, Electron Microscopy Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov FU Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases [ZIA AI005024-15]; Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Leidos Biomedical Research, Inc. FX Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, ZIA AI005024-15. This project has been funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. Leidos Biomedical Research, Inc., provided support in the form of a salary for author YT. The funders had no role in the studydesign, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 0 Z9 0 U1 12 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 27 PY 2016 VL 11 IS 7 AR e0159709 DI 10.1371/journal.pone.0159709 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5IJ UT WOS:000381515900048 PM 27463224 ER PT J AU Vigorito, E Kuchenbaecker, KB Beesley, J Adlard, J Agnarsson, BA Andrulis, IL Arun, BK Barjhoux, L Belotti, M Benitez, J Berger, A Bojesen, A Bonanni, B Brewer, C Caldes, T Caligo, MA Campbell, I Chan, SB Claes, KBM Cohn, DE Cook, J Daly, MB Damiola, F Davidson, R de Pauw, A Delnatte, C Diez, O Domchek, SM Dumont, M Durda, K Dworniczak, B Easton, DF Eccles, D Ardnor, CE Eeles, R Ejlertsen, B Ellis, S Evans, DG Feliubadalo, L Fostira, F Foulkes, WD Friedman, E Frost, D Gaddam, P Ganz, PA Garber, J Garcia-Barberan, V Gauthier-Villars, M Gehrig, A Gerdes, AM Giraud, S Godwin, AK Goldgar, DE Hake, CR Hansen, TVO Healey, S Hodgson, S Hogervorst, FBL Houdayer, C Hulick, PJ Imyanitov, EN Isaacs, C Izatt, L Izquierdo, A Jacobs, L Jakubowska, A Janavicius, R Jaworska-Bieniek, K Jensen, UB John, EM Vijai, J Karlan, BY Kast, K Khan, S Kwong, A Laitman, Y Lester, J Lesueur, F Liljegren, A Lubinski, J Mai, PL Manoukian, S Mazoyer, S Meindl, A Mensenkamp, AR Montagna, M Nathanson, KL Neuhausen, SL Nevanlinna, H Niederacher, D Olah, E Olopade, OI Ong, KR Osorio, A Park, SK Paulsson-Karlsson, Y Pedersen, IS Peissel, B Peterlongo, P Pfeiler, G Phelan, CM Piedmonte, M Poppe, B Pujana, MA Radice, P Rennert, G Rodriguez, GC Rookus, MA Ross, EA Schmutzler, RK Simard, J Singer, CF Slavin, TP Soucy, P Southey, M Steinemann, D Stoppa-Lyonnet, D Sukiennicki, G Sutter, C Szabo, CI Tea, MK Teixeira, MR Teo, SH Terry, MB Thomassen, M Tibiletti, MG Tihomirova, L Tognazzo, S van Rensburg, EJ Varesco, L Varon-Mateeva, R Vratimos, A Weitzel, JN McGuffog, L Kirk, J Toland, AE Hamann, U Lindor, N Ramus, SJ Greene, MH Couch, FJ Offit, K Pharoah, PDP Chenevix-Trench, G Antoniou, AC AF Vigorito, Elena Kuchenbaecker, Karoline B. Beesley, Jonathan Adlard, Julian Agnarsson, Bjarni A. Andrulis, Irene L. Arun, Banu K. Barjhoux, Laure Belotti, Muriel Benitez, Javier Berger, Andreas Bojesen, Anders Bonanni, Bernardo Brewer, Carole Caldes, Trinidad Caligo, Maria A. Campbell, Ian Chan, Salina B. Claes, Kathleen B. M. Cohn, David E. Cook, Jackie Daly, Mary B. Damiola, Francesca Davidson, Rosemarie de Pauw, Antoine Delnatte, Capucine Diez, Orland Domchek, Susan M. Dumont, Martine Durda, Katarzyna Dworniczak, Bernd Easton, Douglas F. Eccles, Diana Ardnor, Christina Edwinsdotter Eeles, Ros Ejlertsen, Bent Ellis, Steve Evans, D. Gareth Feliubadalo, Lidia Fostira, Florentia Foulkes, William D. Friedman, Eitan Frost, Debra Gaddam, Pragna Ganz, Patricia A. Garber, Judy Garcia-Barberan, Vanesa Gauthier-Villars, Marion Gehrig, Andrea Gerdes, Anne-Marie Giraud, Sophie Godwin, Andrew K. Goldgar, David E. Hake, Christopher R. Hansen, Thomas V. O. Healey, Sue Hodgson, Shirley Hogervorst, Frans B. L. Houdayer, Claude Hulick, Peter J. Imyanitov, Evgeny N. Isaacs, Claudine Izatt, Louise Izquierdo, Angel Jacobs, Lauren Jakubowska, Anna Janavicius, Ramunas Jaworska-Bieniek, Katarzyna Jensen, Uffe Birk John, Esther M. Vijai, Joseph Karlan, Beth Y. Kast, Karin Khan, Sofia Kwong, Ava Laitman, Yael Lester, Jenny Lesueur, Fabienne Liljegren, Annelie Lubinski, Jan Mai, Phuong L. Manoukian, Siranoush Mazoyer, Sylvie Meindl, Alfons Mensenkamp, Arjen R. Montagna, Marco Nathanson, Katherine L. Neuhausen, Susan L. Nevanlinna, Heli Niederacher, Dieter Olah, Edith Olopade, Olufunmilayo I. Ong, Kai-ren Osorio, Ana Park, Sue Kyung Paulsson-Karlsson, Ylva Pedersen, Inge Sokilde Peissel, Bernard Peterlongo, Paolo Pfeiler, Georg Phelan, Catherine M. Piedmonte, Marion Poppe, Bruce Angel Pujana, Miquel Radice, Paolo Rennert, Gad Rodriguez, Gustavo C. Rookus, Matti A. Ross, Eric A. Schmutzler, Rita Katharina Simard, Jacques Singer, Christian F. Slavin, Thomas P. Soucy, Penny Southey, Melissa Steinemann, Doris Stoppa-Lyonnet, Dominique Sukiennicki, Grzegorz Sutter, Christian Szabo, Csilla I. Tea, Muy-Kheng Teixeira, Manuel R. Teo, Soo-Hwang Terry, Mary Beth Thomassen, Mads Tibiletti, Maria Grazia Tihomirova, Laima Tognazzo, Silvia van Rensburg, Elizabeth J. Varesco, Liliana Varon-Mateeva, Raymonda Vratimos, Athanassios Weitzel, Jeffrey N. McGuffog, Lesley Kirk, Judy Toland, Amanda Ewart Hamann, Ute Lindor, Noralane Ramus, Susan J. Greene, Mark H. Couch, Fergus J. Offit, Kenneth Pharoah, Paul D. P. Chenevix-Trench, Georgia Antoniou, Antonis C. CA Kconfab Investigators TI Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; BREAST; INVESTIGATORS; CONSORTIUM; PATHOLOGY; CENTLEIN AB Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95% CI: 0.68 to 0.79, p-value 2x 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95% CI: 0.59 to 0.80, p-value 1.0 x 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. 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[Barjhoux, Laure; Damiola, Francesca; Mazoyer, Sylvie] Ctr Leon Berard, Batiment Cheney D,28 Rue Laennec, Lyon, France. [Belotti, Muriel; de Pauw, Antoine; Gauthier-Villars, Marion; Houdayer, Claude; Stoppa-Lyonnet, Dominique] Inst Curie, Serv Geneit Oncol, 26 Rue Ulm, Paris 05, France. [Benitez, Javier] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain. [Berger, Andreas] Med Univ Vienna, Dept OB GYN, Vienna, Austria. [Bojesen, Anders] Vejle Hosp, Dept Clin Genet, Kabbeltoft 25, Vejle, Denmark. [Bonanni, Bernardo] IEO, Div Canc Prevent & Genet, Via Ripamonti 435, I-20141 Milan, Italy. [Brewer, Carole] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter, Devon, England. [Caldes, Trinidad; Garcia-Barberan, Vanesa] Hosp Clin San Carlos, IdISSC Inst Invest Sanitaria, Mol Oncol Lab, Martin Lagos S-N, Madrid, Spain. [Caligo, Maria A.] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy. [Caligo, Maria A.] Univ Hosp Pisa, Pisa, Italy. [Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Locked Bag 1,ABeckett St, Melbourne, Vic 8006, Australia. [Chan, Salina B.] 1600 Div St,C415, San Francisco, CA 94143 USA. [Claes, Kathleen B. M.; Poppe, Bruce] Univ Ghent, Ctr Med Genet, De Pintelaan 185, B-9000 Ghent, Belgium. [Cohn, David E.] Ohio State Univ, Columbus Canc Council GYN Oncol, 3651 Ridge Mill Dr, Columbus, OH 43026 USA. [Cook, Jackie] Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England. [Daly, Mary B.] Fox Chase Canc Ctr, Dept Clin Oncol, 333 Cottman Ave, Philadelphia, PA USA. [Davidson, Rosemarie] South Glasgow Univ Hosp, Dept Clin Genet, Glasgow, Lanark, Scotland. [Delnatte, Capucine] ICO Ctr Rene Gauducheau, Unite Oncogenet, Blvd Jacques Monod, F-44805 St Herblain, France. [Diez, Orland] Vall Hebron Univ Hosp, VHIO, Oncogenet Grp, Passeig Vall Hebron 119-129, Barcelona, Spain. [Diez, Orland] Univ Autonoma Barcelona, Passeig Vall Hebron 119-129, Barcelona, Spain. [Domchek, Susan M.; Nathanson, Katherine L.] Univ Penn, Dept Med, Abramson Canc Ctr, Perelman Sch Med, 3400 Civic Ctr Blvd, Philadelphia, PA 19104 USA. [Dumont, Martine; Simard, Jacques; Soucy, Penny] CHU, Quebec Res Ctr, Genom Ctr, 2705 Laurier Blvd, Quebec City, PQ, Canada. [Dumont, Martine; Simard, Jacques; Soucy, Penny] Univ Laval, 2705 Laurier Blvd, Quebec City, PQ, Canada. [Durda, Katarzyna; Jakubowska, Anna; Jaworska-Bieniek, Katarzyna; Lubinski, Jan; Sukiennicki, Grzegorz] Pomeranian Med Univ, Dept Genet & Pathol, Polabska 4, Szczecin, Poland. [Dworniczak, Bernd] Univ Munster, Inst Human Genet, Munster, Germany. [Eccles, Diana] Southampton Univ Hosp NHS Trust, Fac Med, Southampton, Hants, England. [Ardnor, Christina Edwinsdotter] Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden. [Eeles, Ros] Inst Canc Res, Oncogenet Team, Sutton, Surrey, England. [Eeles, Ros] Royal Marsden NHS Fdn Trust, Sutton, Surrey, England. [Ejlertsen, Bent] Univ Copenhagen Hosp, Dept Oncol, Rigshosp, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. [Ellis, Steve; Frost, Debra] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Strangeways Res Lab, Cambridge, England. [Evans, D. Gareth] Univ Manchester, Cent Manchester Univ Hosp NHS Fdn Trust, Inst Human Dev, Genom Med,Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Feliubadalo, Lidia] Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, IDIBELL Bellvitge Biomed Res Inst, Gran Via lHospitalet,199-203, Barcelona 08908, Spain. [Fostira, Florentia; Vratimos, Athanassios] Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Patriarchou Gregoriou & Neapoleos Str, Athens, Greece. [Foulkes, William D.] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada. [Foulkes, William D.] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Friedman, Eitan] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Ramat Gan, Israel. [Friedman, Eitan] Tel Aviv Univ, Sackler Fac Med, IL-69978 Ramat Aviv, Israel. [Gaddam, Pragna] Mem Sloane Kettering Canc Ctr, Clin Canc Genet Lab, New York, NY USA. [Ganz, Patricia A.] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Med, 650 Charles Young Dr South,Room A2-125 HS, Los Angeles, CA 90095 USA. [Ganz, Patricia A.] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Publ Hlth, 650 Charles Young Dr South,Room A2-125 HS, Los Angeles, CA 90095 USA. [Garber, Judy] Dana Farber Canc Inst, Canc Risk & Prevent Clin, 450 Brookline Ave, Boston, MA 02115 USA. [Gehrig, Andrea] Univ Wurzburg, Inst Human Genet, Dept Med Genet, Ctr Familial Breast & Ovarian Canc, Wurzburg, Germany. [Gerdes, Anne-Marie] Rigshosp 4062, Dept Clin Genet, Blegdamsvej 9, Copenhagen O, Denmark. [Giraud, Sophie] Hospices Civils Lyon, Serv Genet Mol & Clin, Lyon 04, France. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, 3901 Rainbow Blvd,4019 Wahl Hall East,MS 3040, Kansas City, KS USA. [Goldgar, David E.] Univ Utah, Sch Med, Dept Dermatol, 30 North 1900 East,SOM 4B454, Salt Lake City, UT 84132 USA. [Hake, Christopher R.] City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Hansen, Thomas V. O.] Univ Copenhagen Hosp, Ctr Genom Med, Rigshosp, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. [Hodgson, Shirley] St Georges Univ London, Med Genet Unit, London, England. [Hogervorst, Frans B. L.] Netherlands Canc Inst, Family Canc Clin, POB 90203, NL-1000 BE Amsterdam, Netherlands. [Hulick, Peter J.] Univ Chicago, Pritzker Sch Med, Ctr Med Genet, NorthShore Univ Hlth Syst, 1000 Cent St,Suite 620, Evanston, IL 60201 USA. [Imyanitov, Evgeny N.] NN Petrov Inst Oncol, St Petersburg 197758, Russia. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, 3800 Reservoir Rd NW, Washington, DC USA. [Izatt, Louise] Guys & St Thomas NHS Fdn Trust, Clin Genet, London, England. [Izquierdo, Angel] Catalan Inst Oncol, Genet Counseling Unit, Hereditary Canc Program, IDIBGI Inst Invest Biomed Girona, Av Franca S-N, Girona 1707, Spain. [Jacobs, Lauren; Vijai, Joseph] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Res Lab, 1275 York Ave, New York, NY 10044 USA. [Janavicius, Ramunas] Vilnius Univ Hosp Santariskiu Clin, Hematol Oncol & Transfus Med Ctr, Dept Mol & Regenerat Med, State Res Inst Ctr Innovat Med, Santariskiu St,Zygymantu St 9, Vilnius, Lithuania. [Jensen, Uffe Birk] Aarhus Univ Hosp, Dept Clin Genet, Brendstrupgaardsvej 21C, Aarhus N, Denmark. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, 2201 Walnut Ave,Suite 300, Fremont, CA 94538 USA. [Karlan, Beth Y.; Lester, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, 8700 Beverly Blvd,Suite 290W, Los Angeles, CA 90048 USA. [Kast, Karin] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Obstet & Gynaecol, Dresden, Germany. [Kconfab Investigators] Peter MacCallum Canc Inst, Kathleen Cuningham Consortium Res Familial Breast, Melbourne, Australia. [Khan, Sofia; Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, POB 700,Haartmaninkatu 8, Helsinki 00029, Finland. [Khan, Sofia; Nevanlinna, Heli] Helsinki Univ Hosp, Biomed Helsinki, POB 700,Haartmaninkatu 8, Helsinki 00029, Finland. [Kwong, Ava] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China. [Laitman, Yael] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. Inst Curie, Inserm U900, Genet Epidemiol Canc team, Mines ParisTech,26 Rue Ulm, F-75248 Paris 05, France. [Liljegren, Annelie] Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden. [Mai, Phuong L.; Greene, Mark H.] NCI, DCEG, Clin Genet Branch, NIH, 9609 Med Ctr Dr,Room 6E-454, Bethesda, MD 20892 USA. [Manoukian, Siranoush; Peissel, Bernard] Ist Nazl Tumori, Fdn IRCCS Ist Ricovero Cura & Caratter Sci, Dept Prevent & Predict Med, Unit Med Genet, Via Giacomo Venezian 1, I-20133 Milan, Italy. [Meindl, Alfons] Tech Univ Munich, Klinikum Rechts Isar, Div Tumor Genet, Dept Obstet & Gynaecol, Munich, Germany. [Mensenkamp, Arjen R.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, POB 9101, NL-6500 HB Nijmegen, Netherlands. [Montagna, Marco; Tognazzo, Silvia] Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Via Gattamelata 64, Padua, Italy. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA USA. [Niederacher, Dieter] Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Obstet & Gynaecol, Dusseldorf, Germany. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Olopade, Olufunmilayo I.] Univ Chicago Med, 5841 South Maryland Ave,MC 2115, Chicago, IL 60637 USA. [Ong, Kai-ren] Birmingham Womens Hosp Healthcare NHS Trust, West Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Osorio, Ana] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Park, Sue Kyung] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Dept Prevent Med,Coll Med, 103 Daehak Ro, Seoul 110799, South Korea. [Park, Sue Kyung] Seoul Natl Univ, Canc Res Inst, 103 Daehak Ro, Seoul 110799, South Korea. [Paulsson-Karlsson, Ylva] Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden. [Pedersen, Inge Sokilde] Aalborg Univ Hosp, Sect Mol Diagnost, Dept Biochem, Reberbansgade 15, Aalborg, Denmark. [Peterlongo, Paolo] Inst Mol Oncol, IFOM, FIRC Italian Fdn Canc Res, IFOM-IEO Campus,Via Adamello 16, I-20139 Milan, Italy. [Pfeiler, Georg] Med Univ Vienna, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. [Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Piedmonte, Marion] Roswell Pk Canc Inst, NRG Oncol, Stat & Data Management Ctr, Elm St & Carlton St, Buffalo, NY 14263 USA. [Angel Pujana, Miquel] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Translat Res Lab, Barcelona, Spain. [Radice, Paolo] Ist Nazl Tumori, Unit Mol Bases Genet Risk & Genet Testing, Dept Prevent & Predicted Med, Fdn IRCCS Ist Ricovero Cura Caratter Sci, Amaedeolab,Via GA Amadeo 42, I-20133 Milan, Italy. [Rennert, Gad] Clalit Natl Israeli Canc Control Ctr, 7 Michal St, IL-34362 Haifa, Israel. [Rennert, Gad] Carmel Hosp, Dept Community Med & Epidemiol, 7 Michal St, IL-34362 Haifa, Israel. [Rennert, Gad] B Rappaport Fac Med, 7 Michal St, IL-34362 Haifa, Israel. [Rodriguez, Gustavo C.] Univ Chicago, NorthShore Univ HealthSyst, Div Gynecol Oncol, 2650 Ridge Ave Suite 1507 Walgreens, Evanston, IL 60201 USA. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, POB 90203, NL-1000 BE Amsterdam, Netherlands. [Ross, Eric A.] Fox Chase Canc Ctr, Biostat & Bioinformat Facil, 333 Coltman Ave, Philadelphia, PA 19111 USA. [Schmutzler, Rita Katharina] Univ Hosp Cologne, Fac Med, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany. [Singer, Christian F.; Tea, Muy-Kheng] Med Univ Vienna, Dept OB GYN, A-1090 Vienna, Austria. [Singer, Christian F.; Tea, Muy-Kheng] Waehringer Guertel 18-20, A-1090 Vienna, Austria. [Slavin, Thomas P.; Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic, Australia. [Steinemann, Doris] Hannover Med Sch, Inst Cell & Mol Pathol, Hannover, Germany. [Sutter, Christian] Univ Heidelberg Hosp, Dept Human Genet, Inst Human Genet, Heidelberg, Germany. [Szabo, Csilla I.] NHGRI, NIH, Bldg 50,Room 5312,50 South Dr,MSC 004, Bethesda, MD 20892 USA. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Rua Dr Antonio Bernardino de Almeida, P-4200072 Oporto, Portugal. [Teo, Soo-Hwang] Sime Darby Med Ctr, Canc Res Initiat Fdn, 1 Jalan SS12-1A, Subang Jaya 47500, Malaysia. [Terry, Mary Beth] Columbia Univ, Dept Epidemiol, New York, NY USA. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, Sonder Blvd 29, Odense C, Denmark. [Tibiletti, Maria Grazia] Osped Circolo Univ Insubria, UO Anat Patol, Via O Rossi 9, I-21100 Varese, Italy. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Ratsupites Str 1, Riga, Latvia. [van Rensburg, Elizabeth J.] Univ Pretoria, Dept Genet, Canc Genet Lab, Private Bag X323, ZA-0007 Arcadia, South Africa. [Varesco, Liliana] AOU San Martino IST Ist Nazl Ric Cancro, IRCCS, Dept Epidemiol Prevent & Special Funct, Unit Hereditary Canc, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. [Varon-Mateeva, Raymonda] Charite, Inst Human Genet, Campus Virchov Klinikum, Berlin, Germany. [Kirk, Judy] Westmead Hosp, Familial Canc Serv, Hawkesbury Rd,POB 533, Wentworthville, NSW 2145, Australia. [Toland, Amanda Ewart] Ohio State Univ, Dept Internal Med, Div Human Canc Genet, 998 Biomed Res Tower, Columbus, OH 43210 USA. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Hamann, Ute] German Canc Res Ctr, Mol Genet Breast Canc, Neuenheimer Feld 580, D-69120 Heidelberg, Germany. [Lindor, Noralane] Mayo Clin, Dept Hlth Sci Res, 13400 E Scottsdale Blvd, Scottsdale, AZ USA. [Ramus, Susan J.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN USA. [Couch, Fergus J.] Mayo Clin, Hlth Sci Res, 200 First St SW, Rochester, MN USA. [Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Res Lab, Dept Med Canc Biol & Genet, 1275 York Ave, New York, NY 10044 USA. [Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge, England. RP Antoniou, AC (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. EM antonis@srl.cam.ac.uk RI Osorio, Ana/I-4324-2014; Teo, Soo-hwang/H-2353-2014; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Peissel, Bernard/E-8187-2017; montagna, marco/E-2225-2012; OI Osorio, Ana/0000-0001-8124-3984; Peissel, Bernard/0000-0001-9233-3571; montagna, marco/0000-0002-4929-2150; Khan, Sofia/0000-0003-4185-8882; Evans, Gareth/0000-0002-8482-5784 FU Cancer Research - UK [C12292/A11174, C1287/A10118]; MRC Advanced Studentship award; NHMRC; National Breast Cancer Foundation; Cancer Australia; National Institute of Health (USA) FX The CIMBA data management and data analysis were supported by Cancer Research - UK grants C12292/A11174 and C1287/A10118. EV was supported by an MRC Advanced Studentship award. Details of the funding of individual studies participating in CIMBA are included in S1 Text of the manuscript.; BCFR-AU acknowledges Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis. BCFR-NY wishes to thank members and participants in the New York site of the Breast Cancer Family Registry for their contributions to the study. BCFR-ON wishes to thank members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. BFBOCC-LT acknowledges Vilius Rudaitis, Laimonas Grigkeviequs. BMBSA We wish to thank the families who contribute to the BMBSA study. BRICOH wishes to thank Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management. CBCS thanks Bent Ejlertsen for the recruitment and genetic counseling of participants. CNIO thanks Alicia Barroso, Rosario Alonso and Guillermo Pita for their assistance. CONSIT TEAM acknowledges Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale deti Tumori, Milano, Italy: Monica Barile and Irene Feroce of the Istituto Europeo di Oncologia, Milano, Italy; Alessandra Viel and Riccardo Dolcetti of the CRO Aviano National Cancer Institute, Aviano (PN), Italy; Laura Papi and Gabriele Capone of the University of Florence, Florence, Italy; Laura Ottini and Giuseppe Giannini of the "Sapienza" University, Rome, Italy; Antonella Savarese and Alyne Martayan of the Istituto Nazionale Tumori Regina Elena, Rome, Italy; Stefania Tommasi of the Istituto Nazionale Tumori "Giovanni Paolo II" Bari, Italy. GCHBOC thanks Ms. JoEllen Weaver and Dr. Betsy Bove for their technical support. GEMO wishes to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30th June 2014, and to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon Centre Leon Berard, & Equipe Genetique du cancer du sein, Centre de Recherche en Cancerologie de Lyon: Olga Sinilnikovat, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Melanie Leone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de Genetique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agnes Collet, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues, Emmanuelle Fourme, Anne -Marie Birot. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, Clermont-Ferrand: Yves -Jean Bignon, Nancy Uhrhammer. Centre Leon Berard, Lyon: Christine Lasset, Valerie Bonadona, Sandrine Handallou. Centre Francois Baclesse, Caen: Agnes Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, Francois Eisinger. CHU Arnaud -de -Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean -Philippe Peyrat, Joelle Fournier, Francoise Revillion, Philippe Vennint, Claude Adenis. Centre Paul Strauss, Strasbourg: Daniele Muller, Jean-Pierre Fricker. Institut Bergonie, Bordeaux: Emmanuelle Barouk-Simonet, Francoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU Grenoble: Dominique Leroux, Helene Dreyfus, Christine Rebischung, Magalie Peysselon.; CHU Dijon: Fanny Coron, Laurence Faivre. CHU St -Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz. Hotel Dieu Centre Hospitalier, Chambery: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frenay. CHU Limoges: Laurence Venat-Bouvet. CHU Nantes: Capucine Delnatte. CHU Bretonneau, Tours: Isabelle Mortemousque. Groupe Hospitalier Pitie-Salpetriere, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy: Johanna Sokolowska, Myriam Bronner. CHU Besancon: Marie -Agnes Collonge-Rame, Alexandre Damette. Creighton University, Omaha, USA: Henry T. Lynch, Carrie L. Snyder. HCSC acknowledges Alicia Tosar and Paula Diaque for their technical assistance. HEBCS would like to thank Dr. Kristiina Aittomaki, Taru A. Muranen, Drs. Carl Blomqvist and Kirsimari Aaltonen and RNs Irja Erkkila and Virpi Palola for their help with the HEBCS data and samples. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, J.L. de Lange, R. Wijnands; Erasmus Medical Center, Rotterdam, NL: J.M. Collee, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C. J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, NL: E.B. Gomez -Garcia, M.J. Blok; University Medical Center Groningen, NL: J.C. Oosterwijk, A. H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. HEBON thanks the registration teams of IKNL and PALGA for part of the data collection. HRBCP wishes to thank Hong Kong Sanatorium and Hospital for their continued support. HUNBOCS wishes to thank the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Tibor Vaszko, Aniko Bozsik, Timea Pocza, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study. ICO wishes to thank the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella. INHERIT would like to thank Dr Martine Dumont, Martine Tranchant for sample management and skilful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping coordinating group of iCOGS (BCAC and CIMBA). IPOBCS wishes to thank Drs. Ana Peixoto, Catarina Santos, Patricia Rocha and Pedro Pinto for their skilful contribution to the study.; KCONFAB wishes to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. MCGILL Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MODSQUAD acknowledges ModSQuaD members Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA); Lenka Foretova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic); and Michal Zikan, Petr Pohlreich and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic). NICCC wishes to thank the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the lab team led by Dr. Flavio Lejbkowicz, and the research field operations team led by Dr. Mila Pinchev. OCGN We wish to thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study. OSU CCG Leigha Senter, Kevin Sweet, Caroline Craven, and Michelle O'Conor were instrumental in accrual of study participants, ascertainment of medical records and database management. Samples were processed by the OSU Human Genetics Sample Bank. SEABASS would like to thank Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan and all the research nurses, research assistants and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection and sample preparation. In addition, we thank Philip Iau, Sng Jen-Hwei and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study respectively. SMC team wishes to acknowledge the assistance of the Meirav Comprehensive breast cancer center team at the Sheba Medical Center for assistance in this study. SWE-BRCA Swedish scientists participating as SWE-BRCA collaborators are: from Lund University and University Hospital: Ake Borg, Hakan Olsson, Helena Jernstrom, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Ofverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Ume5. University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellstrom Pigg, Richard Rosenquist; from Linkoping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren. UCHICAGO wishes to thank Cecilia Zvocec, Qun Niu, physicians, genetic counselors, research nurses and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our program. UCLA thanks Joyce Seldon MSGC and Lorna Kwan, MPH for assembling the data for this study. UCSF would like to thank Dr Robert Nussbaum and the following genetic counsellors for participant recruitment: Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad. And thanks to Ms. Salina Chan for her data management.; UKFOCR thanks Simon Gayther, Carole Pye, Patricia Harrington and Eva Wozniak for their contributions towards the UKFOCR. UPENN Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. VFCTG acknowledges Geoffrey Lindeman, Marion Harris, Martin Delatycki of the Victorian Familial Cancer Trials Group. We thank Sarah Sawyer and Rebecca Driessen for assembling this data and Ella Thompson for performing all DNA amplification NR 21 TC 0 Z9 0 U1 11 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 27 PY 2016 VL 11 IS 7 AR e0158801 DI 10.1371/journal.pone.0158801 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5IJ UT WOS:000381515900021 PM 27463617 ER PT J AU Zheng, Y Levens, D AF Zheng, Ying Levens, David TI Tuning the MYC response SO ELIFE LA English DT Editorial Material ID C-MYC; CELLS C1 [Zheng, Ying; Levens, David] NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. RP Levens, D (reprint author), NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. EM levensd@mail.nih.gov RI Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X NR 10 TC 0 Z9 0 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUL 27 PY 2016 VL 5 AR e18871 DI 10.7554/eLife.18871 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DS5QP UT WOS:000380837600001 ER PT J AU Andradas, C Blasco-Benito, S Castillo-Lluva, S Dillenburg-Pilla, P Diez-Alarcia, R Juanes-Garcia, A Garcia-Taboada, E Hernando-Llorente, R Soriano, J Hamann, S Wenners, A Alkatout, I Klapper, W Rocken, C Bauer, M Arnold, N Quintanilla, M Megias, D Vicente-Manzanares, M Uriguen, L Gutkind, JS Guzman, M Perez-Gomez, E Sanchez, C AF Andradas, Clara Blasco-Benito, Sandra Castillo-Lluva, Sonia Dillenburg-Pilla, Patricia Diez-Alarcia, Rebeca Juanes-Garcia, Alba Garcia-Taboada, Elena Hernando-Llorente, Rodrigo Soriano, Joaquim Hamann, Sigrid Wenners, Antonia Alkatout, Ibrahim Klapper, Wolfram Rocken, Christoph Bauer, Maret Arnold, Norbert Quintanilla, Miguel Megias, Diego Vicente-Manzanares, Miguel Uriguen, Leyre Gutkind, J. Silvio Guzman, Manuel Perez-Gomez, Eduardo Sanchez, Cristina TI Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer SO ONCOTARGET LA English DT Article DE GPR55; G protein-coupled receptor; cannabinoids; metastasis; triple-negative breast cancer ID PROTEIN-COUPLED RECEPTORS; L-ALPHA-LYSOPHOSPHATIDYLINOSITOL; CANNABINOID RECEPTOR; CELL PROLIFERATION; CONCISE GUIDE; PHARMACOLOGY; MIGRATION; LYSOPHOSPHOLIPIDS; ANANDAMIDE; REVEALS AB The orphan G protein-coupled receptor GPR55 has been directly or indirectly related to basic alterations that drive malignant growth: uncontrolled cancer cell proliferation, sustained angiogenesis, and cancer cell adhesion and migration. However, little is known about the involvement of this receptor in metastasis. Here, we show that elevated GPR55 expression in human tumors is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and therefore poor patient prognosis. Activation of GPR55 by its proposed endogenous ligand lysophosphatidylinositol confers pro-invasive features on breast cancer cells both in vitro and in vivo. Specifically, this effect is elicited by coupling to G(q/11) heterotrimeric proteins and the subsequent activation, through ERK, of the transcription factor ETV4/PEA3. Together, these data show that GPR55 promotes breast cancer metastasis, and supports the notion that this orphan receptor may constitute a new therapeutic target and potential biomarker in the highly aggressive triple-negative subtype. C1 [Andradas, Clara; Blasco-Benito, Sandra; Castillo-Lluva, Sonia; Garcia-Taboada, Elena; Hernando-Llorente, Rodrigo; Guzman, Manuel; Perez-Gomez, Eduardo; Sanchez, Cristina] Univ Complutense, Sch Biol, Dept Biochem & Mol Biol 1, Madrid, Spain. [Andradas, Clara; Blasco-Benito, Sandra; Perez-Gomez, Eduardo; Sanchez, Cristina] Hosp 12 Octubre, Inst Invest, Madrid, Spain. [Dillenburg-Pilla, Patricia; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Diez-Alarcia, Rebeca] Univ Basque Country UPV EHU, Dept Pharmacol, Bilbao, Spain. [Diez-Alarcia, Rebeca] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain. [Juanes-Garcia, Alba; Vicente-Manzanares, Miguel] Univ Princesa, Sanitaria Hosp, Inst Invest, Madrid, Spain. [Juanes-Garcia, Alba; Vicente-Manzanares, Miguel] Univ Autonoma Madrid, Sch Med, Madrid, Spain. [Soriano, Joaquim; Megias, Diego] Spanish Natl Canc Res Ctr CNIO, Madrid, Spain. [Hamann, Sigrid; Wenners, Antonia; Alkatout, Ibrahim; Bauer, Maret; Arnold, Norbert] Univ Hosp Schleswig Holstein, Dept Gynecol & Obstet, Kiel, Germany. [Klapper, Wolfram; Rocken, Christoph] Univ Hosp Schleswig Holstein, Inst Pathol, Kiel, Germany. [Quintanilla, Miguel] Univ Autonoma Madrid, CSIC, Inst Invest Biomed Alberto Sols, Madrid, Spain. [Gutkind, J. Silvio] Univ Calif San Diego, Dept Pharmacol, Moores Canc Ctr, La Jolla, CA 92093 USA. [Guzman, Manuel] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain. [Guzman, Manuel] IRYCIS, Madrid, Spain. RP Perez-Gomez, E; Sanchez, C (reprint author), Univ Complutense, Sch Biol, Dept Biochem & Mol Biol 1, Madrid, Spain.; Perez-Gomez, E; Sanchez, C (reprint author), Hosp 12 Octubre, Inst Invest, Madrid, Spain. EM eduperez@ucm.es; cristina.sanchez@quim.ucm.es RI Rocken, Christoph/A-9239-2010; Klapper, Wolfram/S-6314-2016; Arnold, Norbert/E-3012-2010; OI Rocken, Christoph/0000-0002-6989-8002; Arnold, Norbert/0000-0003-4523-8808; Vicente-Manzanares, Miguel/0000-0001-5943-3220; DIEZ ALARCIA, REBECA/0000-0002-0806-9825 FU Spanish Ministry of Economy and Competitiveness [PI11/00295, PI14/01101, SAF2013-46183-R, SAF2014-54705-R]; European Regional Development (FEDER); Madrid Regional Government [S2010/BMD-2308, 2010/BMD-2359]; Fundacion Cientifica Asociacion Espanola Contra el Cancer; Federation of the Societies of Biochemistry and Molecular Biology (FEBS) Short-term Fellowship FX This work was supported by grants from Spanish Ministry of Economy and Competitiveness [PI11/00295 to CS, PI14/01101 to CS and EP-G, SAF2013-46183-R to MQ, and SAF2014-54705-R to MV-M, supported with European Regional Development (FEDER) funds] and Madrid Regional Government (S2010/BMD-2308 to MG, and 2010/BMD-2359 to MQ). EPG was a recipient of a Postdoctoral Research Contract from Fundacion Cientifica Asociacion Espanola Contra el Cancer and a Federation of the Societies of Biochemistry and Molecular Biology (FEBS) Short-term Fellowship. SB-B and SC-L are recipients of a Formacion de Profesorado Universitario (FPU) fellowship and a Ramon y Cajal research contract, respectively, from the Spanish Ministry of Economy and Competitiveness. NR 45 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 26 PY 2016 VL 7 IS 30 BP 47565 EP 47575 DI 10.18632/oncotarget.10206 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8WP UT WOS:000385413000057 PM 27340777 ER PT J AU Kirshenbaum, AS Cruse, G Desai, A Bandara, G Leerkes, M Lee, CCR Fischer, ER O'Brien, KJ Gochuico, BR Stone, K Gahl, WA Metcalfe, DD AF Kirshenbaum, Arnold S. Cruse, Glenn Desai, Avanti Bandara, Geethani Leerkes, Maarten Lee, Chyi-Chia R. Fischer, Elizabeth R. O'Brien, Kevin J. Gochuico, Bernadette R. Stone, Kelly Gahl, William A. Metcalfe, Dean D. TI Immunophenotypic and Ultrastructural Analysis of Mast Cells in Hermansky-Pudlak Syndrome Type-1: A Possible Connection to Pulmonary Fibrosis SO PLOS ONE LA English DT Article ID MASTOCYTOSIS; DEGRANULATION; BIOGENESIS; DISORDERS; BASOPHILS; LEUKEMIA; MUTATION; DISEASE; NUMBERS; CD34(+) AB Hermansky-Pudlak Syndrome type-1 (HPS-1) is an autosomal recessive disorder caused by mutations in HPS1 which result in reduced expression of the HPS-1 protein, defective lysosome-related organelle (LRO) transport and absence of platelet delta granules. Patients with HPS-1 exhibit oculocutaneous albinism, colitis, bleeding and pulmonary fibrosis postulated to result from a dysregulated immune response. The effect of the HPS1 mutation on human mast cells (HuMCs) is unknown. Since HuMC granules classify as LROs along with platelet granules and melanosomes, we set out to determine if HPS-1 cutaneous and CD34+ culture-derived HuMCs have distinct granular and cellular characteristics. Cutaneous and cultured CD34+-derived HuMCs from HPS-1 patients were compared with normal cutaneous and control HuMCs, respectively, for any morphological and functional differences. One cytokine-independent HPS-1 culture was expanded, cloned, designated the HP proMastocyte (HPM) cell line and characterized. HPS-1 and idiopathic pulmonary fibrosis (IPF) alveolar interstitium showed numerous HuMCs; HPS-1 dermal mast cells exhibited abnormal granules when compared to healthy controls. HPS-1 HuMCs showed increased CD63, CD203c and reduced mediator release following FceRI aggregation when compared with normal HuMCs. HPM cells also had the duplication defect, expressed FceRI and intracytoplasmic proteases and exhibited less mediator release following FceRI aggregation. HPM cells constitutively released IL-6, which was elevated in patients' serum, in addition to IL-8, fibronectin-1 (FN-1) and galectin-3 (LGALS3). Transduction with HPS1 rescued the abnormal HPM morphology, cytokine and matrix secretion. Microarray analysis of HPS-1 HuMCs and non-transduced HPM cells confirmed upregulation of differentially expressed genes involved in fibrogenesis and degranulation. Cultured HPS-1 HuMCs appear activated as evidenced by surface activation marker expression, a decrease in mediator content and impaired releasibility. The near-normalization of constitutive cytokine and matrix release following rescue by HPS1 transduction of HPM cells suggests that HPS-1 HuMCs may contribute to pulmonary fibrosis and constitute a target for therapeutic intervention. C1 [Kirshenbaum, Arnold S.; Cruse, Glenn; Desai, Avanti; Bandara, Geethani; Stone, Kelly; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Leerkes, Maarten] NIAID, Bioinformat & Computat Biosci Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lee, Chyi-Chia R.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Fischer, Elizabeth R.] NIAID, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [O'Brien, Kevin J.; Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Gochuico, Bernadette R.; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Kirshenbaum, AS (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM akirshenba@niaid.nih.gov FU Intramural Research Programs of the National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Human Genome Research Institute at the National Institutes of Health FX This study was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the National Human Genome Research Institute at the National Institutes of Health. NR 32 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 26 PY 2016 VL 11 IS 7 AR e0159177 DI 10.1371/journal.pone.0159177 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5IH UT WOS:000381515600012 PM 27459687 ER PT J AU D'Hulst, C Mina, RB Gershon, Z Jamet, S Cerullo, A Tomoiaga, D Bai, L Belluscio, L Rogers, ME Sirotin, Y Feinstein, P AF D'Hulst, Charlotte Mina, Raena B. Gershon, Zachary Jamet, Sophie Cerullo, Antonio Tomoiaga, Delia Bai, Li Belluscio, Leonardo Rogers, Matthew E. Sirotin, Yevgeniy Feinstein, Paul TI MouSensor: A Versatile Genetic Platform to Create Super Sniffer Mice for Studying Human Odor Coding SO CELL REPORTS LA English DT Article ID OLFACTORY SENSORY NEURONS; RECEPTOR EXPRESSION; AXON GUIDANCE; IN-VIVO; BULB; SYSTEM; SENSITIVITY; MODEL; SCALE AB Typically, similar to 0.1% of the total number of olfactory sensory neurons (OSNs) in the main olfactory epithelium express the same odorant receptor (OR) in a singular fashion and their axons coalesce into homotypic glomeruli in the olfactory bulb. Here, we have dramatically increased the total number of OSNs expressing specific cloned OR coding sequences by multimerizing a 21-bp sequence encompassing the predicted homeodomain binding site sequence, TAATGA, known to be essential in OR gene choice. Singular gene choice is maintained in these "MouSensors.'' In vivo synaptopHluorin imaging of odor-induced responses by known M71 ligands shows functional glomerular activation in an M71 MouSensor. Moreover, a behavioral avoidance task demonstrates that specific odor detection thresholds are significantly decreased in multiple transgenic lines, expressing mouse or human ORs. We have developed a versatile platform to study gene choice and axon identity, to create biosensors with great translational potential, and to finally decode human olfaction. C1 [D'Hulst, Charlotte; Mina, Raena B.; Gershon, Zachary; Jamet, Sophie; Cerullo, Antonio; Tomoiaga, Delia; Feinstein, Paul] CUNY Hunter Coll, Dept Biol Sci, New York, NY 10065 USA. [D'Hulst, Charlotte; Mina, Raena B.; Gershon, Zachary; Jamet, Sophie; Cerullo, Antonio; Tomoiaga, Delia; Feinstein, Paul] CUNY, Grad Ctr, Biochem Program, New York, NY 10065 USA. [D'Hulst, Charlotte; Mina, Raena B.; Gershon, Zachary; Jamet, Sophie; Cerullo, Antonio; Tomoiaga, Delia; Feinstein, Paul] CUNY, Grad Ctr, Biol Program, New York, NY 10065 USA. [D'Hulst, Charlotte; Mina, Raena B.; Gershon, Zachary; Jamet, Sophie; Cerullo, Antonio; Tomoiaga, Delia; Feinstein, Paul] CUNY, Grad Ctr, Biopsychol & Behav Neurosci Program, New York, NY 10065 USA. [Bai, Li; Belluscio, Leonardo] NINDS, Dev Neural Plast Sect, NIH, Bethesda, MD 20892 USA. [Rogers, Matthew E.] Firmenich Inc, Corp Res & Dev, Plainsboro, NJ 08536 USA. [Sirotin, Yevgeniy] Rockefeller Univ, Shelby White & Leon Levy Ctr Neurobiol & Behav, New York, NY 10065 USA. RP Feinstein, P (reprint author), CUNY Hunter Coll, Dept Biol Sci, New York, NY 10065 USA.; Feinstein, P (reprint author), CUNY, Grad Ctr, Biochem Program, New York, NY 10065 USA.; Feinstein, P (reprint author), CUNY, Grad Ctr, Biol Program, New York, NY 10065 USA.; Feinstein, P (reprint author), CUNY, Grad Ctr, Biopsychol & Behav Neurosci Program, New York, NY 10065 USA. EM feinstein@genectr.hunter.cuny.edu FU National Institute on Minority Health and Health Disparities of the NIH [MD007599, SC1 GM088114]; Hunter College [HHMI UGRAD 52007535] FX We would like to thank the Hunter College Animal Facility Manager Barbara Wolin and Veterinarian Patricia Glennon for help in maintaining the transgenic colony and the Transgenic Core Facility at The Rockefeller University for generating transgenic founders. We would like to thank Dr. Thomas Bozza for helping set up SpH imaging and giving advice on the experiments. The development of the MouSensor technology was made possible by a Research Centers in Minority Institutions Program grant from the National Institute on Minority Health and Health Disparities (MD007599) of the NIH (SC1 GM088114), and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIMHD or the NIH. Firmenich sponsored other parts of the research. Z.G. is supported by the Hunter College HHMI UGRAD 52007535. NR 32 TC 1 Z9 1 U1 5 U2 11 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 JUL 26 PY 2016 VL 16 IS 4 BP 1115 EP 1125 DI 10.1016/j.celrep.2016.06.047 PG 11 WC Cell Biology SC Cell Biology GA DS0DL UT WOS:000380265500019 PM 27396335 ER PT J AU Chen, Y Palczewska, G Masuho, I Gao, SQ Jin, H Dong, ZQ Gieser, L Brooks, MJ Kiser, PD Kern, TS Martemyanov, KA Swaroop, A Palczewski, K AF Chen, Yu Palczewska, Grazyna Masuho, Ikuo Gao, Songqi Jin, Hui Dong, Zhiqian Gieser, Linn Brooks, Matthew J. Kiser, Philip D. Kern, Timothy S. Martemyanov, Kirill A. Swaroop, Anand Palczewski, Krzysztof TI Synergistically acting agonists and antagonists of G protein-coupled receptors prevent photoreceptor cell degeneration SO Science Signaling LA English DT Article ID DIFFERENTIAL EXPRESSION ANALYSIS; HUMAN GENE-THERAPY; RETINAL DEGENERATION; MACULAR DEGENERATION; RETINITIS-PIGMENTOSA; SYSTEMS PHARMACOLOGY; STARGARDT DISEASE; COMPLEX DISEASES; DRUG TARGETS; MOUSE MODEL AB Photoreceptor cell degeneration leads to visual impairment and blindness in several types of retinal disease. However, the discovery of safe and effective therapeutic strategies conferring photoreceptor cell protection remains challenging. Targeting distinct cellular pathways with low doses of different drugs that produce a functionally synergistic effect could provide a strategy for preventing or treating retinal dystrophies. We took a systems pharmacology approach to identify potential combination therapies using a mouse model of light-induced retinal degeneration. We showed that a combination of U.S. Food and Drug Administration-approved drugs that act on different G protein (guanine nucleotide-binding protein)-coupled receptors (GPCRs) exhibited synergistic activity that protected retinas from light-induced degeneration even when each drug was administered at a low dose. In functional assays, the combined effects of these drugs were stimulation of G(i/o) signaling by activating the dopamine receptors D2R and D4R, as well as inhibition of G(s) and G(q) signaling by antagonizing D1R and the alpha(1A)-adrenergic receptor ADRA1A, respectively. Moreover, transcriptome analyses demonstrated that such combined GPCR-targeted treatments preserved patterns of retinal gene expression that were more similar to those of the normal retina than did higher-dose monotherapy. Our study thus supports a systems pharmacology approach to identify treatments for retinopathies, an approach that could extend to other complex disorders. C1 [Chen, Yu] Shanghai Univ Tradit Chinese Med, Yueyang Hosp, Shanghai 200437, Peoples R China. [Chen, Yu] Shanghai Univ Tradit Chinese Med, Clin Res Inst Integrat Med, Shanghai 200437, Peoples R China. [Chen, Yu; Gao, Songqi; Jin, Hui; Kiser, Philip D.; Kern, Timothy S.; Palczewski, Krzysztof] Case Western Reserve Univ, Sch Med, Dept Pharmacol, 10900 Euclid Ave, Cleveland, OH 44106 USA. [Palczewska, Grazyna; Dong, Zhiqian; Palczewski, Krzysztof] Polgenix Inc, Cleveland, OH 44106 USA. [Masuho, Ikuo; Martemyanov, Kirill A.] Scripps Res Inst, Dept Neurosci, 130 Scripps Way, Jupiter, FL 33458 USA. [Gieser, Linn; Brooks, Matthew J.; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Kiser, Philip D.; Kern, Timothy S.] Louis Stokes Cleveland VA Med Ctr, Res Serv, Cleveland, OH 44106 USA. [Kern, Timothy S.] Case Western Reserve Univ, Dept Med, Sch Med, Cleveland, OH 44106 USA. RP Chen, Y (reprint author), Shanghai Univ Tradit Chinese Med, Yueyang Hosp, Shanghai 200437, Peoples R China.; Chen, Y (reprint author), Shanghai Univ Tradit Chinese Med, Clin Res Inst Integrat Med, Shanghai 200437, Peoples R China.; Chen, Y; Palczewski, K (reprint author), Case Western Reserve Univ, Sch Med, Dept Pharmacol, 10900 Euclid Ave, Cleveland, OH 44106 USA.; Palczewski, K (reprint author), Polgenix Inc, Cleveland, OH 44106 USA. EM chenyu6639@hotmail.com; kxp65@case.edu FU NIH [EY018139, R24 EY024864, U01 EY025451]; National Natural Science Foundation of China [81473732]; Department of Veterans Affairs [IK2BX002683]; Intramural Research Program of the National Eye Institute [EY000474, EY000546]; Arnold and Mabel Beckman Foundation; Canadian Institute for Advanced Research FX This work was supported by the NIH (grant EY018139 to K.A.M.; grants R24 EY024864 to T.S.K. and U01 EY025451 to K.P.), the National Natural Science Foundation of China (grant 81473732 to Y.C.), the Department of Veterans Affairs (grant IK2BX002683 to P.D.K.), and the Intramural Research Program of the National Eye Institute (grants EY000474 and EY000546 to A.S.). This work was also supported in part by the Arnold and Mabel Beckman Foundation and the Canadian Institute for Advanced Research. K.P. receives funding as the John H. Hord Professor of Pharmacology. NR 64 TC 2 Z9 2 U1 8 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JUL 26 PY 2016 VL 9 IS 438 AR ra74 DI 10.1126/scisignal.aag0245 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS4VG UT WOS:000380779100001 PM 27460988 ER PT J AU Alqahtani, SA Agha, C Rothstein, T AF Alqahtani, Saeed A. Agha, Caroline Rothstein, Ted TI Isolated Unilateral Tongue Atrophy: A Possible Late Complication of Juxta Cephalic Radiation Therapy SO AMERICAN JOURNAL OF CASE REPORTS LA English DT Article DE Abnormalities; Radiation-Induced; Hypoglossal Nerve; Magnetic Resonance Imaging ID CRANIAL NERVE PALSY; CARCINOMA AB Objective: Rare disease Background: Isolated unilateral hypoglossal nerve injury is extremely rare. It may be caused by radiation therapy targeting neoplasms of the cephalic region. Case Report: A 51-year-old man with synovial sarcoma of the left upper arm status post extensive radiation therapy in 1980 presented in late 2014 with gradual onset of speech difficulty and difficulty moving his tongue for a couple of weeks. Neurological examination revealed isolated left-sided unilateral tongue atrophy. Postradiation residual extensive cicatrix with erythema over the whole left upper extremity extending to the neck on the affected side was noticed. On head magnetic resonance imaging (MRI) before and after administration of gadolinium, he was found to have asymmetrically fatty striations, atrophy, and fibrosis in the left tongue consistent with radiation toxicity. The patient's tongue weakness persisted without improvement. Conclusions: The diagnosis of unilateral hypoglossal nerve injury is usually difficult. Detailed neurological examinations and thorough investigations including head MRI are very helpful. Previous exposure to radiation therapy is a potential cause of hypoglossal nerve injury. To our knowledge, this is the first case report that presents isolated unilateral tongue atrophy as a late complication of juxta cephalic radiation therapy. C1 [Alqahtani, Saeed A.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Agha, Caroline; Rothstein, Ted] George Washington Univ, Sch Med & Hlth Sci, Dept Neurol, Washington, DC 20052 USA. RP Alqahtani, SA (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM saeedqanea@hotmail.com NR 5 TC 0 Z9 0 U1 0 U2 0 PU INT SCIENTIFIC LITERATURE, INC PI SMITHTOWN PA 361 FOREST LANE, SMITHTOWN, NY 11787 USA SN 1941-5923 J9 AM J CASE REP JI Am. J. Case Rep. PD JUL 26 PY 2016 VL 17 BP 535 EP 537 DI 10.12659/AJCR.897989 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DS1VB UT WOS:000380388200001 PM 27458010 ER PT J AU Lin, CTM Leibovitch, EC Almira-Suarez, MI Jacobson, S AF Lin, Cheng-Te Major Leibovitch, Emily C. Almira-Suarez, M. Isabel Jacobson, Steven TI Human herpesvirus multiplex ddPCR detection in brain tissue from low- and high-grade astrocytoma cases and controls SO INFECTIOUS AGENTS AND CANCER LA English DT Article DE CMV; HHV-6A; HHV-6B; EBV; Herpesvirus; Astrocytoma; Glioblastoma; ddPCR ID EPSTEIN-BARR-VIRUS; CENTRAL-NERVOUS-SYSTEM; DROPLET DIGITAL PCR; POLYMERASE-CHAIN-REACTION; GLIOBLASTOMA-MULTIFORME; HUMAN CYTOMEGALOVIRUS; PERIPHERAL-BLOOD; CEREBROSPINAL-FLUID; INFECTION; DNA AB Background: Glioblastoma (GBM) is a fatal CNS malignancy, representing 50 % of all gliomas with approximately 12-18 months survival time after initial diagnosis. Recently, the human herpesvirus cytomegalovirus (CMV) has been suggested to have an oncogenic role, yet this association remains controversial. In addition, human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) have also been associated with low-grade gliomas, but few studies have examined HHV-6 and EBV in glioblastomas. Droplet digital PCR (ddPCR) is a highly precise diagnostic tool that enables the absolute quantification of target DNA. This study examines the association between multiple human herpesviruses and astrocytomas. Methods: This study analyzed 112 brain tissue specimens, including 45 glioblastoma, 12 astrocytoma grade III, 2 astrocytoma grade II, 4 astrocytoma grade I, and 49 controls. All brain tissue samples were de-identified and pathologically confirmed. Each tissue block was sectioned for DNA extraction and CMV, EBV, HHV-6A and HHV-6B, and a cellular housekeeping gene were amplified by ddPCR. Results: Neither CMV nor HHV-6A were detected in any of the astrocytoma samples. However, HHV-6B (p = 0.147) and EBV (p = 0.049) had a higher positivity frequency in the GBM compared to the controls. Conclusion: The undetectable CMV DNA in the astrocytoma cohort does not support the observation of an increased prevalence of CMV DNA in GBM, as reported in other studies. EBV has a significantly higher positivity in the GBM cohort compared to the controls, while HHV-6B has a higher but not statistically significant positivity in the case cohort. Whether these viruses play an oncogenic role in GBM remains to be further investigated. C1 [Lin, Cheng-Te Major; Leibovitch, Emily C.; Jacobson, Steven] NINDS, NIH, BG 10 RM 5C103 10 Ctr Dr, Bethesda, MD 20892 USA. [Lin, Cheng-Te Major; Leibovitch, Emily C.; Almira-Suarez, M. Isabel] George Washington Univ, Sch Med & Hlth Sci, Ross Hall 2300 Eye St NW, Washington, DC 20037 USA. RP Jacobson, S (reprint author), NINDS, NIH, BG 10 RM 5C103 10 Ctr Dr, Bethesda, MD 20892 USA. EM steven.jacobson@nih.gov FU intramural research program of NINDS FX This work was supported by the intramural research program of NINDS, and the funders had no role in study design, data collection, data analysis, decision to publish or manuscript preparation. NR 50 TC 1 Z9 1 U1 5 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-9378 J9 INFECT AGENTS CANCER JI Infect. Agents Cancer PD JUL 26 PY 2016 VL 11 AR 32 DI 10.1186/s13027-016-0081-x PG 10 WC Oncology; Immunology SC Oncology; Immunology GA DS0GN UT WOS:000380273600001 PM 27462365 ER PT J AU Puskas, JD Halkos, ME DeRose, JJ Bagiella, E Miller, MA Overbey, J Bonatti, J Srinivas, VS Vesely, M Sutter, F Lynch, J Kirkwood, K Shapiro, TA Boudoulas, KD Crestanello, J Gehrig, T Smith, P Ragosta, M Hoff, SJ Zhao, D Gelijns, AC Szeto, WY Weisz, G Argenziano, M Vassiliades, T Liberman, H Matthai, W Ascheim, DD AF Puskas, John D. Halkos, Michael E. DeRose, Joseph J. Bagiella, Emilia Miller, Marissa A. Overbey, Jessica Bonatti, Johannes Srinivas, V. S. Vesely, Mark Sutter, Francis Lynch, Janine Kirkwood, Katherine Shapiro, Timothy A. Boudoulas, Konstantinos D. Crestanello, Juan Gehrig, Thomas Smith, Peter Ragosta, Michael Hoff, Steven J. Zhao, David Gelijns, Annetine C. Szeto, Wilson Y. Weisz, Giora Argenziano, Michael Vassiliades, Thomas Liberman, Henry Matthai, William Ascheim, Deborah D. TI Hybrid Coronary Revascularization for the Treatment of Multivessel Coronary Artery Disease A Multicenter Observational Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE coronary artery bypass; coronary vessels; drug-eluting stents; follow-up studies; percutaneous coronary intervention ID BYPASS GRAFT-SURGERY; ELUTING STENTS; FOLLOW-UP; STENOSIS; STRATEGIES; INFARCTION; DECREASE; TRIAL; RISK AB BACKGROUND Hybrid coronary revascularization (HCR) combines minimally invasive surgical coronary artery bypass grafting of the left anterior descending artery with percutaneous coronary intervention (PCI) of non-left anterior descending vessels. HCR is increasingly used to treat multivessel coronary artery disease that includes stenoses in the proximal left anterior descending artery and at least 1 other vessel, but its effectiveness has not been rigorously evaluated. OBJECTIVES This National Institutes of Health-funded, multicenter, observational study was conducted to explore the characteristics and outcomes of patients undergoing clinically indicated HCR and multivessel PCI for hybrid-eligible coronary artery disease, to inform the design of a confirmatory comparative effectiveness trial. METHODS Over 18 months, 200 HCR and 98 multivessel PCI patients were enrolled at 11 sites. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE) (i.e., death, stroke, myocardial infarction, repeat revascularization) within 12 months post-intervention. Cox proportional hazards models were used to model time to first MACCE event. Propensity scores were used to balance the groups. RESULTS Mean age was 64.2 +/- 11.5 years, 25.5% of patients were female, 38.6% were diabetic, and 4.7% had previous stroke. Thirty-eight percent had 3-vessel coronary artery disease, and the mean SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score was 19.7 +/- 9.6. Adjusted for baseline risk, MACCE rates were similar between groups within 12 months post-intervention (hazard ratio [HR]: 1.063; p = 0.80) and during a median 17.6 months of follow-up (HR: 0.868; p = 0.53). CONCLUSIONS These observational data from this first multicenter study of HCR suggest that there is no significant difference in MACCE rates over 12 months between patients treated with multivessel PCI or HCR, an emerging modality. A randomized trial with long-term outcomes is needed to definitively compare the effectiveness of these 2 revascularization strategies. (Hybrid Revascularization Observational Study; NCT01121263) (C) 2016 by the American College of Cardiology Foundation. C1 [Puskas, John D.; Ascheim, Deborah D.] Icahn Sch Med Mt Sinai, Cardiovasc Inst, Dept Cardiovasc Surg, New York, NY 10029 USA. [Puskas, John D.] Mt Sinai Beth Israel, Mt Sinai Heart, New York, NY USA. [Halkos, Michael E.; Vassiliades, Thomas; Liberman, Henry] Emory Univ, Atlanta, GA 30322 USA. [DeRose, Joseph J.; Srinivas, V. S.] Montefiore Einstein Heart Ctr, Dept Surg, Div Cardiothorac Surg, Bronx, NY USA. [Bagiella, Emilia; Overbey, Jessica; Kirkwood, Katherine; Gelijns, Annetine C.; Ascheim, Deborah D.] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, New York, NY 10029 USA. [Miller, Marissa A.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Bonatti, Johannes] Cleveland Clin Abu Dhabi, Dept Cardiothorac Surg, Abu Dhabi, U Arab Emirates. [Vesely, Mark] Univ Maryland, Dept Surg, Div Cardiothorac Surg, Baltimore, MD 21201 USA. [Sutter, Francis; Shapiro, Timothy A.] Lankenau Hosp, Philadelphia, PA USA. [Lynch, Janine; Boudoulas, Konstantinos D.; Crestanello, Juan] Ohio State Univ, Columbus, OH 43210 USA. [Gehrig, Thomas; Smith, Peter] Duke Univ, Durham, NC USA. [Ragosta, Michael] Univ Virginia, Charlottesville, VA USA. [Hoff, Steven J.] Vanderbilt Heart Inst, Nashville, TN USA. [Zhao, David] Wake Forest Univ, Winston Salem, NC 27109 USA. [Szeto, Wilson Y.; Matthai, William] Univ Penn, Philadelphia, PA 19104 USA. [Weisz, Giora; Argenziano, Michael] Columbia Univ, New York, NY USA. [Vassiliades, Thomas] Medtronic Inc, Fridley, MN USA. RP Puskas, JD (reprint author), Mt Sinai Beth Israel, Dept Cardiovasc Surg, 317 East 17th St,11th Floor,Fierman Hall, New York, NY 10003 USA. EM john.puskas@mountsinai.org FU National Institutes of Health; National Heart, Lung, and Blood Institutes [1-RC1-HL100951] FX National Institutes of Health and National Heart, Lung, and Blood Institutes grant 1-RC1-HL100951 to Drs. Puskas and Ascheim funded this study. Dr. Halkos has served as a consultant to Intuitive Surgical and Medtronic. Dr. Sutter serves on the Speakers Bureau of Intuitive Surgical. Dr. Shapiro serves on the Speakers' Bureau of Astra Zeneca; and serves as a consultant to Intuitive Surgical. Dr. Hoff serves as a peer trainer and consultant for Medtronic. Dr. Vassiliades is a full-time employee of Medtronic. All other authors have reported that they no relationships relevant to the contents of this paper to disclose. Friedrich-Wilhelm Mohr, MD, PhD, served as Guest Editor for this paper. NR 16 TC 4 Z9 4 U1 4 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 26 PY 2016 VL 68 IS 4 BP 356 EP 365 DI 10.1016/j.jacc.2016.05.032 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DR7JT UT WOS:000380076600005 PM 27443431 ER PT J AU Ngo, D Sinha, S Shen, DX Kuhn, EW Keyes, MJ Shi, X Benson, MD O'Sullivan, JF Keshishian, H Farrell, LA Fifer, MA Vasan, RS Sabatine, MS Larson, MG Carr, SA Wang, TJ Gerszten, RE AF Ngo, Debby Sinha, Sumita Shen, Dongxiao Kuhn, Eric W. Keyes, Michelle J. Shi, Xu Benson, Mark D. O'Sullivan, John F. Keshishian, Hasmik Farrell, Laurie A. Fifer, Michael A. Vasan, Ramachandran S. Sabatine, Marc S. Larson, Martin G. Carr, Steven A. Wang, Thomas J. Gerszten, Robert E. TI Aptamer-Based Proteomic Profiling Reveals Novel Candidate Biomarkers and Pathways in Cardiovascular Disease SO CIRCULATION LA English DT Editorial Material DE aptamer, nucleotides; cardiovascular diseases; mass spectrometry; myocardial infarction; proteomics ID HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY; ACUTE MYOCARDIAL-INFARCTION; CORONARY-HEART-DISEASE; ACID-BINDING PROTEIN; MASS-SPECTROMETRY; SEPTAL REDUCTION; GROWTH-FACTOR; HUMAN PLASMA; FACTOR-I; RISK AB BACKGROUND: Single-stranded DNA aptamers are oligonucleotides of approximate to 50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. Emerging DNA aptamer-based technologies may address limitations of existing proteomic techniques, including low sample throughput, which have hindered proteomic analyses of large cohorts. METHODS: To identify early biomarkers of myocardial injury, we applied an aptamer-based proteomic platform that measures 1129 proteins to a clinically relevant perturbational model of planned myocardial infarction (PMI), patients undergoing septal ablation for hypertrophic cardiomyopathy. Blood samples were obtained before and at 10 and 60 minutes after PMI, and protein changes were assessed by repeated-measures analysis of variance. The generalizability of our PMI findings was evaluated in a spontaneous myocardial infarction cohort (Wilcoxon rank-sum). We then tested the platform's ability to detect associations between proteins and Framingham Risk Score components in the Framingham Heart Study, performing regression analyses for each protein versus each clinical trait. RESULTS: We found 217 proteins that significantly changed in the peripheral vein blood after PMI in a derivation cohort (n=15; P<5.70E-5). Seventy-nine of these proteins were validated in an independent PMI cohort (n=15; P<2.30E-4); >85% were directionally consistent and reached nominal significance. We detected many protein changes that are novel in the context of myocardial injury, including Dickkopf-related protein 4, a WNT pathway inhibitor (peak increase 124%, P=1.29E-15) and cripto, a growth factor important in cardiac development (peak increase 64%, P=1.74E-4). Among the 40 validated proteins that increased within 1 hour after PMI, 23 were also elevated in patients with spontaneous myocardial infarction (n=46; P<0.05). Framingham Heart Study analyses revealed 156 significant protein associations with the Framingham Risk Score (n=899), including aminoacylase 1 (beta=0.3386, P=2.54E-22) and trigger factor 2 (beta=0.2846, P=5.71E-17). Furthermore, we developed a novel workflow integrating DNA-based immunoaffinity with mass spectrometry to analytically validate aptamer specificity. CONCLUSIONS: Our results highlight an emerging proteomics tool capable of profiling >1000 low-abundance analytes with high sensitivity and high precision, applicable both to well-phenotyped perturbational studies and large human cohorts, as well. C1 [Gerszten, Robert E.] Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, 330 Brookline Ave, Boston, MA 02115 USA. [Kuhn, Eric W.; Keshishian, Hasmik; Carr, Steven A.; Gerszten, Robert E.] Broad Inst Harvard & MIT, 415 Main St, Cambridge, MA 02142 USA. [Ngo, Debby] Harvard Med Sch, Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Dept Med, Boston, MA USA. [Ngo, Debby; Sinha, Sumita; Shen, Dongxiao; Keyes, Michelle J.; Shi, Xu; Benson, Mark D.; O'Sullivan, John F.; Farrell, Laurie A.; Gerszten, Robert E.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA USA. [Benson, Mark D.; Sabatine, Marc S.] Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. [Fifer, Michael A.; Sabatine, Marc S.; Gerszten, Robert E.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Vasan, Ramachandran S.] Boston Univ, Dept Med, Prevent Med Sect, Sch Med, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Larson, Martin G.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiovasc Med, 221 Kirkland Hall, Nashville, TN 37235 USA. RP Gerszten, RE (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, 330 Brookline Ave, Boston, MA 02115 USA.; Carr, SA (reprint author), Broad Inst Harvard & MIT, 415 Main St, Cambridge, MA 02142 USA. EM scarr@broadinstitute.org; rgerszte@bidmc.harvard.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU [R01HL132320]; NCI NIH HHS [U24 CA160034]; NHLBI NIH HHS [HHSN268201000033C, N01HC25195, R01 HL132320, T32 HL007208]; NIGMS NIH HHS [K01 GM103817] NR 40 TC 6 Z9 6 U1 4 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUL 26 PY 2016 VL 134 IS 4 BP 270 EP + DI 10.1161/CIRCULATIONAHA.116.021803 PG 145 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DR8GP UT WOS:000380136700008 PM 27444932 ER PT J AU Spong, CY AF Spong, Catherine Y. TI Improving Birth Outcomes Key to Improving Global Health SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID LATE-PRETERM; TERM; DELIVERY C1 [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 31 Ctr Dr,2A03, Bethesda, MD 20892 USA. RP Spong, CY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 31 Ctr Dr,2A03, Bethesda, MD 20892 USA. EM spongc@dir49.nichd.nih.gov NR 10 TC 0 Z9 0 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 26 PY 2016 VL 316 IS 4 BP 395 EP 396 DI 10.1001/jama.2016.9851 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DR9MV UT WOS:000380221700015 PM 27458942 ER PT J AU Cookson, MR AF Cookson, Mark R. TI Structure, function, and leucine-rich repeat kinase 2: On the importance of reproducibility in understanding Parkinson's disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID LRRK2 MUTATION; DOMAIN; INTERACTOME; TOXICITY; GTPASE; GENE C1 [Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM Cookson@mail.nih.gov NR 25 TC 0 Z9 0 U1 4 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2016 VL 113 IS 30 BP 8346 EP 8348 DI 10.1073/pnas.1609311113 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS1HJ UT WOS:000380346200027 PM 27422551 ER PT J AU Dittmore, A Silver, J Sarkar, SK Marmer, B Goldberg, GI Neuman, KC AF Dittmore, Andrew Silver, Jonathan Sarkar, Susanta K. Marmer, Barry Goldberg, Gregory I. Neuman, Keir C. TI Internal strain drives spontaneous periodic buckling in collagen and regulates remodeling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE collagenase; matrix metalloproteinase; single molecule; pattern formation; mechanosensing ID I COLLAGEN; EXTRACELLULAR-MATRIX; MECHANICAL STRAIN; ACTIVE-SITE; DEGRADATION; FIBRILS; METALLOPROTEINASES; STABILITY; TRACKING; MODEL AB Fibrillar collagen, an essential structural component of the extracellular matrix, is remarkably resistant to proteolysis, requiring specialized matrix metalloproteinases (MMPs) to initiate its remodeling. In the context of native fibrils, remodeling is poorly understood; MMPs have limited access to cleavage sites and are inhibited by tension on the fibril. Here, single-molecule recordings of fluorescently labeled MMPs reveal cleavage-vulnerable binding regions arrayed periodically at similar to 1-mu m intervals along collagen fibrils. Binding regions remain periodic even as they migrate on the fibril, indicating a collective process of thermally activated and self-healing defect formation. An internal strain relief model involving reversible structural rearrangements quantitatively reproduces the observed spatial patterning and fluctuations of defects and provides a mechanism for tension-dependent stabilization of fibrillar collagen. This work identifies internal-strain-driven defects that may have general and widespread regulatory functions in self-assembled biological filaments. C1 [Dittmore, Andrew; Silver, Jonathan; Sarkar, Susanta K.; Neuman, Keir C.] NHLBI, Lab Single Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. [Marmer, Barry; Goldberg, Gregory I.] Washington Univ, Sch Med, Dept Med, Div Dermatol, St Louis, MO 63130 USA. RP Neuman, KC (reprint author), NHLBI, Lab Single Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA.; Goldberg, GI (reprint author), Washington Univ, Sch Med, Dept Med, Div Dermatol, St Louis, MO 63130 USA. EM goldberg@medicine.wustl.edu; neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU National Cancer Institute Grant [R01CA123363]; Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR040618] FX We thank Hemai Parthasarathy and three anonymous referees for comments on the manuscript. This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant R01AR040618, and National Cancer Institute Grant R01CA123363 (to G.G.). NR 57 TC 1 Z9 1 U1 4 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2016 VL 113 IS 30 BP 8436 EP 8441 DI 10.1073/pnas.1523228113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS1HJ UT WOS:000380346200044 PM 27402741 ER PT J AU Tippana, R Hwang, H Opresko, PL Bohr, VA Myong, S AF Tippana, Ramreddy Hwang, Helen Opresko, Patricia L. Bohr, Vilhelm A. Myong, Sua TI Single-molecule imaging reveals a common mechanism shared by G-quadruplex-resolving helicases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE G-quadruplex; resolving activity; RHAU; BLM; WRN ID WERNER SYNDROME PROTEIN; DEAH-BOX HELICASE; BLM HELICASE; LOOP-LENGTH; MYC PROMOTER; DNA; RNA; STABILITY; REPLICATION; INSTABILITY AB G-quadruplex (GQ) is a four stranded DNA secondary structure that arises from a guanine rich sequence. Stable formation of GQ in genomic DNA can be counteracted by the resolving activity of specialized helicases including RNA helicase AU (associated with AU rich elements) (RHAU) (G4 resolvase 1), Bloom helicase (BLM), and Werner helicase (WRN). However, their substrate specificity and the mechanism involved in GQ unfolding remain uncertain. Here, we report that RHAU, BLM, and WRN exhibit distinct GQ conformation specificity, but use a common mechanism of repetitive unfolding that leads to disrupting GQ structure multiple times in succession. Such unfolding activity of RHAU leads to efficient annealing exclusively within the same DNA molecule. The same resolving activity is sufficient to dislodge a stably bound GQ ligand, including BRACO-19, NMM, and Phen-DC3. Our study demonstrates a plausible biological scheme where different helicases are delegated to resolve specific GQ structures by using a common repetitive unfolding mechanism that provides a robust resolving power. C1 [Tippana, Ramreddy; Myong, Sua] Johns Hopkins Univ, Biophys Dept, Baltimore, MD 21218 USA. [Hwang, Helen; Myong, Sua] Univ Illinois, Bioengn Dept, Urbana, IL 61801 USA. [Hwang, Helen] Univ Illinois, Med Scholars Program, Urbana, IL 61801 USA. [Opresko, Patricia L.] Univ Pittsburgh, Dept Environm & Occupat Hlth, Pittsburgh, PA 15213 USA. [Bohr, Vilhelm A.] Biomed Res Ctr, Lab Mol Gerontol, Baltimore, MD 21224 USA. [Myong, Sua] Univ Illinois, Phys Frontier Ctr, Ctr Phys Living Cells, Urbana, IL 61801 USA. RP Myong, S (reprint author), Johns Hopkins Univ, Biophys Dept, Baltimore, MD 21218 USA.; Myong, S (reprint author), Univ Illinois, Bioengn Dept, Urbana, IL 61801 USA.; Myong, S (reprint author), Univ Illinois, Phys Frontier Ctr, Ctr Phys Living Cells, Urbana, IL 61801 USA. EM smyong@jhu.edu FU American Cancer Society Grant [RSG-12-066-01-DMC]; NIH [1DP2GM105453]; National Science Foundation Physics Frontiers Center Program through the Center for the Physics of Living Cells [0822613]; Intramural Program of the National Institute on Aging, National Institutes of Health FX This work was supported by American Cancer Society Grant RSG-12-066-01-DMC; NIH Grant 1DP2GM105453; National Science Foundation Physics Frontiers Center Program 0822613 through the Center for the Physics of Living Cells (to R.T, H.H., and S.M.); and funds from the Intramural Program of the National Institute on Aging, National Institutes of Health (V.A.B.). NR 47 TC 5 Z9 5 U1 19 U2 35 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2016 VL 113 IS 30 BP 8448 EP 8453 DI 10.1073/pnas.1603724113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS1HJ UT WOS:000380346200046 PM 27407146 ER PT J AU Akman, G Desai, R Bailey, LJ Yasukawa, T Rosa, ID Durigon, R Holmes, JB Moss, CF Mennuni, M Houlden, H Crouch, RJ Hanna, MG Pitceathly, RDS Spinazzola, A Holt, IJ AF Akman, Gokhan Desai, Radha Bailey, Laura J. Yasukawa, Takehiro Rosa, Ilaria Dalla Durigon, Romina Holmes, J. Bradley Moss, Chloe F. Mennuni, Mara Houlden, Henry Crouch, Robert J. Hanna, Michael G. Pitceathly, Robert D. S. Spinazzola, Antonella Holt, Ian J. TI Pathological ribonuclease H1 causes R-loop depletion and aberrant DNA segregation in mitochondria SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE RNase H1; R-loop; mitochondrial DNA; DNA segregation; mitochondrial disease ID IMPAIR MTDNA REPLICATION; LIGHT-STRAND PROMOTER; ACCESSORY SUBUNIT; DISPLACEMENT LOOP; ORIGIN; MUTATIONS; REGION; MAINTENANCE; DELETIONS; NUCLEOIDS AB The genetic information in mammalian mitochondrial DNA is densely packed; there are no introns and only one sizeable noncoding, or control, region containing key cis-elements for its replication and expression. Many molecules of mitochondrial DNA bear a third strand of DNA, known as "7S DNA," which forms a displacement (D-) loop in the control region. Here we show that many other molecules contain RNA as a third strand. The RNA of these R-loops maps to the control region of the mitochondrial DNA and is complementary to 7S DNA. Ribonuclease H1 is essential for mitochondrial DNA replication; it degrades RNA hybridized to DNA, so the R-loop is a potential substrate. In cells with a pathological variant of ribonuclease H1 associated with mitochondrial disease, R-loops are of low abundance, and there is mitochondrial DNA aggregation. These findings implicate ribonuclease H1 and RNA in the physical segregation of mitochondrial DNA, perturbation of which represents a previously unidentified disease mechanism. C1 [Akman, Gokhan; Desai, Radha; Rosa, Ilaria Dalla; Durigon, Romina; Moss, Chloe F.; Mennuni, Mara; Spinazzola, Antonella; Holt, Ian J.] MRC, Mill Hill Lab, London NW7 1AA, England. [Bailey, Laura J.; Yasukawa, Takehiro; Holmes, J. Bradley] MRC, Mitochondrial Biol Unit, Cambridge CB1 9SY, England. [Holmes, J. Bradley; Crouch, Robert J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD 20892 USA. [Houlden, Henry; Hanna, Michael G.; Pitceathly, Robert D. S.] UCL, Inst Neurol, MRC, Ctr Neuromuscular Dis, London WC1N 3BG, England. [Houlden, Henry; Hanna, Michael G.; Pitceathly, Robert D. S.] Natl Hosp Neurol & Neurosurg, London WC1N 3BG, England. [Pitceathly, Robert D. S.] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Basic & Clin Neurosci, London SE5 8AF, England. [Yasukawa, Takehiro] Kyushu Univ, Grad Sch Med Sci, Dept Clin Chem, Fukuoka 8128582, Japan. [Yasukawa, Takehiro] Kyushu Univ, Grad Sch Med Sci, Lab Med, Fukuoka 8128582, Japan. RP Spinazzola, A; Holt, IJ (reprint author), MRC, Mill Hill Lab, London NW7 1AA, England. EM Antonella.Spinazzola@crick.ac.uk; ian.holt@headoffice.mrc.ac.uk RI Houlden, Henry/C-1532-2008 OI Houlden, Henry/0000-0002-2866-7777 FU European Commission, MEET Project Grant [317433]; Medical Research Council (MRC) Intramural Award; MRC Senior Non-Clinical Fellowship [MC_ PC_ 13029]; MRC Centre for Neuromuscular Diseases Grant [G0601943]; UK National Health Service Specialised Service for Rare Mitochondrial Diseases of Adults and Children; National Institute for Health Research University College London Hospitals/University College London Biomedical Research Centre; NIH Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH FX J.B.H. was an NIH-CamGrad Scholar (2006-2010). M.M. is supported by the European Commission, MEET Project Grant 317433. The study was funded by a Medical Research Council (MRC) Intramural Award (to I.J.H.) and MRC Senior Non-Clinical Fellowship MC_ PC_ 13029 (to A.S.). R.D.S.P., H.H., and M.G.H. are supported by MRC Centre for Neuromuscular Diseases Grant G0601943, the UK National Health Service Specialised Service for Rare Mitochondrial Diseases of Adults and Children, and the National Institute for Health Research University College London Hospitals/University College London Biomedical Research Centre. R.J.C. is supported by the NIH Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 46 TC 0 Z9 0 U1 7 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2016 VL 113 IS 30 BP E4276 EP E4285 DI 10.1073/pnas.1600537113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS1HJ UT WOS:000380346200006 PM 27402764 ER PT J AU Shiloach, J AF Shiloach, Joseph TI Improved expression of recombinant proteins from mammalian cells by utilizing non-coding RNAs: microRNA and siRNA SO NEW BIOTECHNOLOGY LA English DT Meeting Abstract C1 [Shiloach, Joseph] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1871-6784 EI 1876-4347 J9 NEW BIOTECHNOL JI New Biotech. PD JUL 25 PY 2016 VL 33 SU S MA O10-2 BP S32 EP S32 DI 10.1016/j.nbt.2016.06.838 PG 1 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA EJ7KM UT WOS:000393400600101 ER PT J AU Fu, Y Romero, MJ Salassa, L Cheng, X Habtemariam, A Clarkson, GJ Prokes, I Rodger, A Costantini, G Sadler, PJ AF Fu, Ying Romero, Maria J. Salassa, Luca Cheng, Xi Habtemariam, Abraha Clarkson, Guy J. Prokes, Ivan Rodger, Alison Costantini, Giovanni Sadler, Peter J. TI Os-2-Os-4 Switch Controls DNA Knotting and Anticancer Activity SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE cancer; DNA; organometallic; osmium; supramolecular ID MOLECULAR RECOGNITION; BRIDGED COMPLEXES; METAL-COMPLEXES; RUTHENIUM(II); BINDING; CYLINDERS; CHEMISTRY; CISPLATIN; ADDUCTS; DRUGS AB Dinuclear trihydroxido-bridged osmium-arene complexes are inert and biologically inactive, but we show here that linking dihydroxido-bridged Os-II-arene fragments by a bridging di-imine to form a metallacycle framework results in strong antiproliferative activity towards cancer cells and distinctive knotting of DNA. The shortened spacer length reduces biological activity and stability in solution towards decomposition to biologically inactive dimers. Significant differences in behavior toward plasmid DNA condensation are correlated with biological activity. C1 [Fu, Ying; Romero, Maria J.; Salassa, Luca; Cheng, Xi; Habtemariam, Abraha; Clarkson, Guy J.; Prokes, Ivan; Rodger, Alison; Costantini, Giovanni; Sadler, Peter J.] Univ Warwick, Dept Chem, Coventry CV4 7AL, W Midlands, England. [Fu, Ying] NCI, Mol Biol Lab, Ctr Canc Res, Bldg 37,Room 5011, Bethesda, MD 20892 USA. [Romero, Maria J.] Univ Santiago Compostela, Fac Quim, Dept Quim Inorgan, Santiago De Compostela 15782, Spain. [Salassa, Luca] CIC BiomaGUNE, Paseo Miramon 182, Donostia San Sebastian 20009, Spain. RP Sadler, PJ (reprint author), Univ Warwick, Dept Chem, Coventry CV4 7AL, W Midlands, England. EM P.J.Sadler@warwick.ac.uk RI Romero Castro, Maria J./H-9990-2015; Rodger, Alison/A-1063-2009 OI Romero Castro, Maria J./0000-0002-6299-4325; Rodger, Alison/0000-0002-7111-3024 FU ERC [247450 BIOINCMED]; EPSRC [EP/F034210/1]; BBSRC [BB/F011199/1]; Science City/EU ERDF/AWM; ERC Grant "VISUAL-MS"; MC CIG fellowship UCnanomat4iPACT [321791]; MINECO grants [CTQ2012-39315, RYC-2011-07787] FX We thank the ERC (grant no. 247450 BIOINCMED), EPSRC (grant no. EP/F034210/1), BBSRC (grant no. BB/F011199/1), and Science City/EU ERDF/AWM for funding. G. C. acknowledges financial support through the ERC Grant "VISUAL-MS". M.J.R. thanks Fundacion Barrie fellowship. L.S. thanks the MC CIG fellowship UCnanomat4iPACT (grant no. 321791) and the MINECO grants (CTQ2012-39315 and RYC-2011-07787). We thank colleagues in the EC COST Action CM1105 for stimulating discussions, and Ben Moreton for his help with AFM. NR 42 TC 1 Z9 1 U1 17 U2 20 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD JUL 25 PY 2016 VL 55 IS 31 BP 8909 EP 8912 DI 10.1002/anie.201602995 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DV9II UT WOS:000383253700018 PM 27240103 ER PT J AU Wilhelm, C Harrison, OJ Schmitt, V Pelletier, M Spencer, SP Urban, JF Ploch, M Ramalingam, TR Siegel, RM Belkaid, Y AF Wilhelm, Christoph Harrison, Oliver J. Schmitt, Vanessa Pelletier, Martin Spencer, Sean P. Urban, Joseph F., Jr. Ploch, Michelle Ramalingam, Thirumalai R. Siegel, Richard M. Belkaid, Yasmine TI Critical role of fatty acid metabolism in ILC2-mediated barrier protection during malnutrition and helminth infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID INNATE LYMPHOID-CELLS; RETINOIC ACID; T-CELLS; IMMUNITY; ALPHA; INFLAMMATION; ADAPTATION; ACTIVATION; LIPOLYSIS; TISSUE AB Innate lymphoid cells (ILC) play an important role in many immune processes, including control of infections, inflammation, and tissue repair. To date, little is known about the metabolism of ILC and whether these cells can metabolically adapt in response to environmental signals. Here we show that type 2 innate lymphoid cells (ILC2), important mediators of barrier immunity, predominantly depend on fatty acid (FA) metabolism during helminth infection. Further, in situations where an essential nutrient, such as vitamin A, is limited, ILC2 sustain their function and selectively maintain interleukin 13 (IL-13) production via increased acquisition and utilization of FA. Together, these results reveal that ILC2 preferentially use FAs to maintain their function in the context of helminth infection or malnutrition and propose that enhanced FA usage and FA-dependent IL-13 production by ILC2 could represent a host adaptation to maintain barrier immunity under dietary restriction. C1 [Wilhelm, Christoph; Harrison, Oliver J.; Spencer, Sean P.; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ramalingam, Thirumalai R.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Pelletier, Martin; Ploch, Michelle; Siegel, Richard M.] NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Wilhelm, Christoph; Schmitt, Vanessa] Univ Bonn, Univ Hosp Bonn, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Germany. [Spencer, Sean P.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Inst Immunol, Philadelphia, PA 19104 USA. [Urban, Joseph F., Jr.] ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. [Pelletier, Martin] Univ Laval, CHU Quebec, Ctr Rech, Dept Microbiol & Immunol, Quebec City, PQ G1V 4G2, Canada. [Spencer, Sean P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Wilhelm, C; Belkaid, Y (reprint author), NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Wilhelm, C (reprint author), Univ Bonn, Univ Hosp Bonn, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Germany. EM christoph.wilhelm@uni-bonn.de; ybelkaid@niaid.nih.gov OI Spencer, Sean/0000-0002-7328-5399; Wilhelm, Christoph/0000-0002-9839-0291; Pelletier, Martin/0000-0001-5033-4947; Ploch, Michelle/0000-0003-2565-1750 FU Division of Intramural Research of the NIAID; Ministry for Science and Education of North-Rhine-Westfalia; Deutsche Forschungsgemeinschaft Excellence Cluster ImmunoSensation; Human Frontier Science Program; U.S. Department of Agriculture/Agricultural Research Service Project Plan [8040-51000-058-00D] FX This work was supported by the Division of Intramural Research of the NIAID, the Ministry for Science and Education of North-Rhine-Westfalia (C. Wilhelm), the Deutsche Forschungsgemeinschaft Excellence Cluster ImmunoSensation (C. Wilhelm), and the Human Frontier Science Program and by funds from the U.S. Department of Agriculture/Agricultural Research Service Project Plan #8040-51000-058-00D (J.F. Urban Jr.). The NIAID Division of Intramural Research Animal Care and Use Program, as part of the National Institutes of Health Intramural Research Program, approved all of the experimental procedures (protocol LP3D-7E). NR 32 TC 2 Z9 2 U1 3 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUL 25 PY 2016 VL 213 IS 8 BP 1409 EP 1418 DI 10.1084/jem.20151448 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DS5VN UT WOS:000380851200004 PM 27432938 ER PT J AU Ma, CS Wong, N Rao, G Nguyen, A Avery, DT Payne, K Torpy, J O'Young, P Deenick, E Bustamante, J Puel, A Okada, S Kobayashi, M Martinez-Barricarte, R Elliott, M Kilic, SS El Baghdadi, J Minegishi, Y Bousfiha, A Robertson, N Hambleton, S Arkwright, PD French, M Blincoe, AK Hsu, P Campbell, DE Stormon, MO Wong, M Adelstein, S Fulcher, DA Cook, MC Stepensky, P Boztug, K Beier, R Ikinciogullari, A Ziegler, JB Gray, P Picard, C Boisson-Dupuis, S Phan, TG Grimbacher, B Warnatz, K Holland, SM Uzel, G Casanova, JL Tangye, SG AF Ma, Cindy S. Wong, Natalie Rao, Geetha Nguyen, Akira Avery, Danielle T. Payne, Kathryn Torpy, James O'Young, Patrick Deenick, Elissa Bustamante, Jacinta Puel, Anne Okada, Satoshi Kobayashi, Masao Martinez-Barricarte, Ruben Elliott, Michael Kilic, Sara Sebnem El Baghdadi, Jamila Minegishi, Yoshiyuki Bousfiha, Aziz Robertson, Nic Hambleton, Sophie Arkwright, Peter D. French, Martyn Blincoe, Annaliesse K. Hsu, Peter Campbell, Dianne E. Stormon, Michael O. Wong, Melanie Adelstein, Stephen Fulcher, David A. Cook, Matthew C. Stepensky, Polina Boztug, Kaan Beier, Rita Ikinciogullari, Aydan Ziegler, John B. Gray, Paul Picard, Capucine Boisson-Dupuis, Stephanie Tri Giang Phan Grimbacher, Bodo Warnatz, Klaus Holland, Steven M. Uzel, Gulbu Casanova, Jean-Laurent Tangye, Stuart G. TI Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4(+) T cells into distinct effector subsets SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HYPER-IGE SYNDROME; CHRONIC MUCOCUTANEOUS CANDIDIASIS; FOLLICULAR-HELPER-CELLS; COMMON VARIABLE IMMUNODEFICIENCY; ESSENTIAL MODULATOR MUTATION; ANTIBODY-RESPONSES; ECTODERMAL DYSPLASIA; IL-10 PRODUCTION; ICOS DEFICIENCY; BCL6 EXPRESSION AB Naive CD4(+) T cells differentiate into specific effector subsets-Th1, Th2, Th17, and T follicular helper (Tfh)-that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12R beta 1/TYK2 and IFN-gamma R/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10-secreting cells. IL12R beta 1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation. C1 [Ma, Cindy S.; Wong, Natalie; Rao, Geetha; Nguyen, Akira; Avery, Danielle T.; Payne, Kathryn; Torpy, James; O'Young, Patrick; Deenick, Elissa; Tri Giang Phan; Tangye, Stuart G.] Garvan Inst Med Res, Div Immunol, Darlinghurst, NSW 2010, Australia. [Ma, Cindy S.; Nguyen, Akira; O'Young, Patrick; Deenick, Elissa; Tri Giang Phan; Tangye, Stuart G.] St Vincents Clin Sch, Darlinghurst, NSW 2010, Australia. [Bustamante, Jacinta; Puel, Anne; Picard, Capucine; Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent] INSERM U1163, Necker Branch, Lab Human Genet Infect Dis, F-75270 Paris, France. [Bustamante, Jacinta; Puel, Anne; Picard, Capucine] Necker Hosp Sick Children, AP HP, Study Ctr Primary Immunodeficiencies, F-75015 Paris, France. [Casanova, Jean-Laurent] Necker Hosp Sick Children, AP HP, Pediat Hematol & Immunol Unit, F-75015 Paris, France. [Bustamante, Jacinta; Martinez-Barricarte, Ruben; Picard, Capucine; Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA. [Okada, Satoshi; Kobayashi, Masao] Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Dept Pediat, Hiroshima 7358911, Japan. [Elliott, Michael; Adelstein, Stephen] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Fulcher, David A.] Univ Sydney, Westmead Hosp, Dept Immunol, Westmead, NSW 2145, Australia. [Elliott, Michael] Royal Prince Alfred Hosp, Chris OBrien Lifehouse Canc Ctr, Camperdown, NSW 2050, Australia. [Adelstein, Stephen] Royal Prince Alfred Hosp, Clin Immunol, Camperdown, NSW 2050, Australia. [Kilic, Sara Sebnem] Uludag Univ, Fac Med, Dept Pediat Immunol, TR-16059 Gorukle, Bursa, Turkey. [El Baghdadi, Jamila] Mil Hosp Mohamed V, Genet Unit, Rabat 10100, Morocco. [Minegishi, Yoshiyuki] Univ Tokushima, Inst Genome Res, Div Mol Med, Tokushima 7708503, Japan. [Bousfiha, Aziz] CHU Ibn Rochd, Dept Pediat, Clin Immunol Unit, Casablanca 20100, Morocco. [Robertson, Nic; Hambleton, Sophie] Newcastle Univ, Inst Cellular Med, Primary Immunodeficiency Grp, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Arkwright, Peter D.] Univ Manchester, Royal Manchester Childrens Hosp, Manchester M13 9WL, Lancs, England. [French, Martyn] Royal Perth Hosp, Dept Clin Immunol, Perth, WA 6009, Australia. [French, Martyn] Univ Western Australia, Sch Pathol & Lab Med, Perth, WA 6009, Australia. [Blincoe, Annaliesse K.] Starship Childrens Hosp, Auckland 1023, New Zealand. [Hsu, Peter; Campbell, Dianne E.; Stormon, Michael O.; Wong, Melanie] Childrens Hosp Westmead, Westmead, NSW 2145, Australia. [Cook, Matthew C.] Australian Natl Univ, Sch Med, Canberra, ACT 0200, Australia. [Cook, Matthew C.] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 0200, Australia. [Cook, Matthew C.] Canberra Hosp, Dept Immunol, Garran 2605, Australia. [Cook, Matthew C.; Stepensky, Polina] Hebrew Univ Jerusalem, Med Ctr, Pediat Hematol Oncol & Bone Marrow Transplantat H, IL-91120 Jerusalem, Israel. [Boztug, Kaan] Med Univ Vienna, Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria. [Boztug, Kaan] Med Univ Vienna, Dept Paediat & Adolescent Med, A-1090 Vienna, Austria. [Beier, Rita] Univ Hosp Essen, Pediat Haematol & Oncol, D-45147 Essen, Germany. [Ikinciogullari, Aydan] Ankara Univ, Sch Med, Dept Pediat Immunol & Allergy, TR-06620 Ankara, Turkey. [Ziegler, John B.; Gray, Paul] Univ New S Wales, Sch Womens & Childrens Hlth, Randwick, NSW 2031, Australia. [Grimbacher, Bodo; Warnatz, Klaus] Univ Freiburg, Fac Med, Med Ctr, Ctr Chron Immunodeficiency, D-79085 Freiburg, Germany. [Holland, Steven M.; Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Casanova, Jean-Laurent] Howard Hughes Med Inst, New York, NY 10065 USA. [Bustamante, Jacinta; Puel, Anne; Picard, Capucine; Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent] Paris Descartes Univ, Necker Med Sch, Imagine Inst, F-75270 Paris, France. RP Ma, CS; Tangye, SG (reprint author), Garvan Inst Med Res, Div Immunol, Darlinghurst, NSW 2010, Australia.; Ma, CS; Tangye, SG (reprint author), St Vincents Clin Sch, Darlinghurst, NSW 2010, Australia. EM c.ma@garvan.org.au; s.tangye@garvan.org.au RI Okada, Satoshi/B-8901-2011 OI Okada, Satoshi/0000-0002-4622-5657 FU National Health and Medical Research Council (NHM RC) of Australia [596813, 1016953, 1066694, 1027400, 1004632]; German Federal Ministry of Education and Research (BMBF) [01EO1303]; Rockefeller University Center for 541 Clinical and Translational science [5UL1RR024143]; NHMRC of Australia [1042925]; Fulbright Commission; [1008820] FX This work was supported National Health and Medical Research Council (NHM RC) of Australia grants 596813, 1016953, 1066694, 1027400, and 1004632 (to CSM, EKD, DAF, MCC, TGP, SGT), the German Federal Ministry of Education and Research (BMBF 01EO1303, to BG and KW), and Rockefeller University Center for 541 Clinical and Translational science (5UL1RR024143, to JLC). CSM is a recipient of a Career Development Fellowship (1008820); SGT is a recipient of a Principal Research Fellowship (1042925) from the NHMRC of Australia and a Senior Scholarship from the Fulbright Commission. NR 85 TC 5 Z9 5 U1 10 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUL 25 PY 2016 VL 213 IS 8 BP 1589 EP 1608 DI 10.1084/jem.20151467 PG 20 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DS5VN UT WOS:000380851200015 PM 27401342 ER PT J AU Rueda, EM Johnson, JE Giddabasappa, A Swaroop, A Brooks, MJ Sigel, I Chaney, SY Fox, DA AF Rueda, Elda M. Johnson, Jerry E., Jr. Giddabasappa, Anand Swaroop, Anand Brooks, Matthew J. Sigel, Irena Chaney, Shawnta Y. Fox, Donald A. TI The cellular and compartmental profile of mouse retinal glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and similar to P transferring kinases SO MOLECULAR VISION LA English DT Article ID ROD OUTER SEGMENTS; NUCLEOSIDE DIPHOSPHATE KINASE; BRAIN ENERGY-METABOLISM; MACAQUE STRIATE CORTEX; NEURON LACTATE SHUTTLE; PYRUVATE-KINASE; CREATINE-KINASE; RAT RETINA; MAMMALIAN RETINA; CYTOCHROME-OXIDASE AB Purpose: The homeostatic regulation of cellular ATP is achieved by the coordinated activity of ATP utilization, synthesis, and buffering. Glucose is the major substrate for ATP synthesis through glycolysis and oxidative phosphorylation (OXPHOS), whereas intermediary metabolism through the tricarboxylic acid (TCA) cycle utilizes non-glucose-derived monocarboxylates, amino acids, and alpha ketoacids to support mitochondrial ATP and GTP synthesis. Cellular ATP is buffered by specialized equilibrium-driven high-energy phosphate (similar to P) transferring kinases. Our goals were twofold: 1) to characterize the gene expression, protein expression, and activity of key synthesizing and regulating enzymes of energy metabolism in the whole mouse retina, retinal compartments, and/or cells and 2) to provide an integrative analysis of the results related to function. Methods: mRNA expression data of energy-related genes were extracted from our whole retinal Affymetrix microarray data. Fixed-frozen retinas from adult C57BL/6N mice were used for immunohistochemistry, laser scanning confocal microscopy, and enzymatic histochemistry. The immunoreactivity levels of well-characterized antibodies, for all major retinal cells and their compartments, were obtained using our established semiquantitative confocal and imaging techniques. Quantitative cytochrome oxidase (COX) and lactate dehydrogenase (LDH) activity was determined histochemically. Results: The Affymetrix data revealed varied gene expression patterns of the ATP synthesizing and regulating enzymes found in the muscle, liver, and brain. Confocal studies showed differential cellular and compartmental distribution of isozymes involved in glucose, glutamate, glutamine, lactate, and creatine metabolism. The pattern and intensity of the antibodies and of the COX and LDH activity showed the high capacity of photoreceptors for aerobic glycolysis and OXPHOS. Competition assays with pyruvate revealed that LDH-5 was localized in the photoreceptor inner segments. The combined results indicate that glycolysis is regulated by the compartmental expression of hexokinase 2, pyruvate kinase M1, and pyruvate kinase M2 in photoreceptors, whereas the inner retinal neurons exhibit a lower capacity for glycolysis and aerobic glycolysis. Expression of nucleoside diphosphate kinase, mitochondria-associated adenylate kinase, and several mitochondria-associated creatine kinase isozymes was highest in the outer retina, whereas expression of cytosolic adenylate kinase and brain creatine kinase was higher in the cones, horizontal cells, and amacrine cells indicating the diversity of ATP-buffering strategies among retinal neurons. Based on the antibody intensities and the COX and LDH activity,Muller glial cells(MGCs) had the lowest capacity for glycolysis, aerobic glycolysis, and OXPHOS. However, they showed high expression of glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate thiokinase, GABA transaminase, and similar to P transferring kinases. This suggests that MGCs utilize TCA cycle anaplerosis and cataplerosis to generate GTP and similar to P transferring kinases to produce ATP that supports MGC energy requirements. Conclusions: Our comprehensive and integrated results reveal that the adult mouse retina expresses numerous iso-forms of ATP synthesizing, regulating, and buffering genes; expresses differential cellular and compartmental levels of glycolytic, OXPHOS, TCA cycle, and similar to P transferring kinase proteins; and exhibits differential layer-by-layer LDH and COX activity. New insights into cell-specific and compartmental ATP and GTP production, as well as utilization and buffering strategies and their relationship with known retinal and cellular functions, are discussed. Developing therapeutic strategies for neuroprotection and treating retinal deficits and degeneration in a cell-specific manner will require such knowledge. This work provides a platform for future research directed at identifying the molecular targets and proteins that regulate these processes. C1 [Rueda, Elda M.; Sigel, Irena; Fox, Donald A.] Univ Houston, Coll Optometry, 4901 Calhoun Rd, Houston, TX 77204 USA. [Johnson, Jerry E., Jr.] Univ Houston Downtown, Dept Nat Sci, Houston, TX USA. [Johnson, Jerry E., Jr.; Giddabasappa, Anand; Chaney, Shawnta Y.; Fox, Donald A.] Univ Houston, Dept Biol & Biochem, Houston, TX USA. [Swaroop, Anand; Brooks, Matthew J.] NEI, Bethesda, MD 20892 USA. [Fox, Donald A.] Univ Houston, Dept Pharmacol & Pharmaceut Sci, Houston, TX USA. RP Fox, DA (reprint author), Univ Houston, Coll Optometry, 4901 Calhoun Rd, Houston, TX 77204 USA. EM dafox@uh.edu FU NIH [RO1ES012482, P30EY07551, T35EY07024, T32EY07024]; UHCO Student Vision Research Support Grants; UHD ORC [206400004B0303] FX We thank Dr. Weimin Xiao for technical assistance, Dr. Cheryl Craft for the M-Car antibody, Dr. Jang-Yen Wu for the GABA-T antibody, and Dr. David R. Beers for the mouse muscle tissue. In addition, we thank Dr. Laura J. Frishman and Dr. Ross A. Poche for valuable discussions. This work was partially supported by NIH Grants RO1ES012482 to DAF, P30EY07551, T32EY07024 for SYC, T35EY07024 for IS, UHCO Student Vision Research Support Grants to EMR, and a UHD ORC Grant 206400004B0303 to JEJ. Part of this data was presented by EMR on a poster at the FASEB Retinal Neurobiology & Visual Processing 2014 annual meeting. NR 189 TC 1 Z9 1 U1 2 U2 2 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUL 23 PY 2016 VL 22 BP 847 EP 885 PG 39 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA DX7LI UT WOS:000384568400001 PM 27499608 ER PT J AU Katan, MB de Ruyter, JC Kuijper, LDJ Chow, CC Hall, KD Olthof, MR AF Katan, Martijn B. de Ruyter, Janne C. Kuijper, Lothar D. J. Chow, Carson C. Hall, Kevin D. Olthof, Margreet R. TI Impact of Masked Replacement of Sugar-Sweetened with Sugar-Free Beverages on Body Weight Increases with Initial BMI: Secondary Analysis of Data from an 18 Month Double-Blind Trial in Children SO PLOS ONE LA English DT Article ID ENERGY-INTAKE; INTERNATIONAL SURVEY; RANDOMIZED-TRIAL; OBESITY; CONSUMPTION; ADOLESCENTS; OVERWEIGHT; VALIDATION; PREVENTION AB Background Substituting sugar-free for sugar-sweetened beverages reduces weight gain. This effect may be more pronounced in children with a high body mass index (BMI) because their sensing of kilocalories might be compromised. We investigated the impact of sugar-free versus sugary drinks separately in children with a higher and a lower initial BMI z score, and predicted caloric intakes and degree of compensation in the two groups. Methods and Findings This is a secondary, explorative analysis of our double-blind randomized controlled trial (RCT) which showed that replacement of one 250-mL sugary drink per day by a sugar-free drink for 18 months significantly reduced weight gain. In the 477 children who completed the trial, mean initial weights were close to the Dutch average. Only 16% were overweight and 3% obese. Weight changes were expressed as BMI z-score, i.e. as standard deviations of the BMI distribution per age and sex group. We designated the 239 children with an initial BMI z-score below the median as 'lower BMI' and the 238 children above the median as 'higher BMI'. The difference in caloric intake from experimental beverages between treatments was 86 kcal/day both in the lower and in the higher BMI group. We used a multiple linear regression and the coefficient of the interaction term (initial BMI group times treatment), indicated whether children with a lower BMI responded differently from children with a higher BMI. Statistical significance was defined as p <= 0.05. Relative to the sugar sweetened beverage, consumption of the sugar-free beverage for 18 months reduced the BMI z-score by 0.05 SD units within the lower BMI group and by 0.21 SD within the higher BMI group. Body weight gain was reduced by 0.62 kg in the lower BMI group and by 1.53 kg in the higher BMI group. Thus the treatment reduced the BMI z-score by 0.16 SD units more in the higher BMI group than in the lower BMI group (p = 0.04; 95% CI -0.31 to -0.01). The impact of the intervention on body weight gain differed by 0.90 kg between BMI groups (p = 0.09; 95% CI -1.95 to 0.14). In addition, we used a physiologically-based model of growth and energy balance to estimate the degree to which children had compensated for the covertly removed sugar kilocalories by increasing their intake of other foods. The model predicts that children with a lower BMI had compensated 65% (95% CI 28 to 102) of the covertly removed sugar kilocalories, whereas children with a higher BMI compensated only 13% (95% CI -37 to 63). Conclusions The children with a BMI above the median might have a reduced tendency to compensate for changes in caloric intake. Differences in these subconscious compensatory mechanisms may be an important cause of differences in the tendency to gain weight. If further research bears this out, cutting down on the intake of sugar-sweetened drinks may benefit a large proportion of children, especially those who show a tendency to become overweight. C1 [Katan, Martijn B.; de Ruyter, Janne C.; Kuijper, Lothar D. J.; Olthof, Margreet R.] Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Dept Hlth Sci, Boelelaan 1085, NL-1081 HV Amsterdam, Netherlands. [Chow, Carson C.; Hall, Kevin D.] NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. RP Olthof, MR (reprint author), Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Dept Hlth Sci, Boelelaan 1085, NL-1081 HV Amsterdam, Netherlands. EM Margreet.Olthof@vu.nl FU Netherlands Heart Foundation [2008B096]; Netherlands Organization for Health Research and Development [120520010]; National Institutes of Health, National Institute of Diabetes & Digestive & Kidney Diseases; Academy Professorship of the Royal Netherlands Academy of Arts and Sciences FX This work was funded by the Netherlands Heart Foundation (https://www.hartstichting.nl/), grant number 2008B096, funding recipient: MBK; and the Netherlands Organization for Health Research and Development (http://www.zonmw.nl/en/), grant number 120520010, funding recipient: MBK. CCC and KDH were supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes & Digestive & Kidney Diseases. MBK was supported by an Academy Professorship of the Royal Netherlands Academy of Arts and Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 1 Z9 1 U1 13 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 22 PY 2016 VL 11 IS 7 AR e0159771 DI 10.1371/journal.pone.0159771 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS5CT UT WOS:000380799000041 PM 27447721 ER PT J AU Nah, K Otsuki, S Chowell, G Nishiura, H AF Nah, Kyeongah Otsuki, Shiori Chowell, Gerardo Nishiura, Hiroshi TI Predicting the international spread of Middle East respiratory syndrome (MERS) SO BMC INFECTIOUS DISEASES LA English DT Article DE Middle East respiratory syndrome; Airline transportation network; Infectious disease; Risk assessment; Importation ID ZIKA VIRUS-INFECTION; REPUBLIC-OF-KOREA; EBOLA-VIRUS; CORONAVIRUS; TRANSMISSION; OUTBREAK; RISK; ANTIBODIES; LIKELIHOOD; NETWORK AB Background: The Middle East respiratory syndrome (MERS) associated coronavirus has been imported via travelers into multiple countries around the world. In order to support risk assessment practice, the present study aimed to devise a novel statistical model to quantify the country-level risk of experiencing an importation of MERS case. Methods: We analyzed the arrival time of each reported MERS importation around the world, i.e., the date on which imported cases entered a specific country, which was modeled as a dependent variable in our analysis. We also used openly accessible data including the airline transportation network to parameterize a hazard-based risk prediction model. The hazard was assumed to follow an inverse function of the effective distance (i.e., the minimum effective length of a path from origin to destination), which was calculated from the airline transportation data, from Saudi Arabia to each country. Both country-specific religion and the incidence data of MERS in Saudi Arabia were used to improve our model prediction. Results: Our estimates of the risk of MERS importation appeared to be right skewed, which facilitated the visual identification of countries at highest risk of MERS importations in the right tail of the distribution. The simplest model that relied solely on the effective distance yielded the best predictive performance (Area under the curve (AUC) = 0. 943) with 100 % sensitivity and 79.6 % specificity. Out of the 30 countries estimated to be at highest risk of MERS case importation, 17 countries (56.7 %) have already reported at least one importation of MERS. Although model fit measured by Akaike Information Criterion (AIC) was improved by including country-specific religion (i.e. Muslim majority country), the predictive performance as measured by AUC was not improved after accounting for this covariate. Conclusions: Our relatively simple statistical model based on the effective distance derived from the airline transportation network data was found to help predicting the risk of importing MERS at the country level. The successful application of the effective distance model to predict MERS importations, particularly when computationally intensive large-scale transmission models may not be immediately applicable could have been benefited from the particularly low transmissibility of the MERS coronavirus. C1 [Nah, Kyeongah] Univ Szeged, Bolyai Inst, Aradi Vertanuk Tere 1, H-6720 Szeged, Hungary. [Nah, Kyeongah; Otsuki, Shiori; Nishiura, Hiroshi] Univ Tokyo, Grad Sch Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. [Otsuki, Shiori; Nishiura, Hiroshi] Japan Sci & Technol Agcy, CREST, Honcho 4-1-8, Kawaguchi, Saitama 3320012, Japan. [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Nah, Kyeongah; Nishiura, Hiroshi] Hokkaido Univ, Grad Sch Med, Kita Ku, Kita 15 Jo Nishi 7 Chome, Sapporo, Hokkaido 0608638, Japan. RP Nishiura, H (reprint author), Univ Tokyo, Grad Sch Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.; Nishiura, H (reprint author), Japan Sci & Technol Agcy, CREST, Honcho 4-1-8, Kawaguchi, Saitama 3320012, Japan.; Nishiura, H (reprint author), Hokkaido Univ, Grad Sch Med, Kita Ku, Kita 15 Jo Nishi 7 Chome, Sapporo, Hokkaido 0608638, Japan. EM nishiurah@m.u-tokyo.ac.jp OI Nah, Kyeongah/0000-0002-7708-1019 FU Japan Society for the Promotion of Science (JSPS) KAKENHI Grant [26670308, 26700028]; Japan Agency for Medical Research and Development; Japan Science and Technology Agency (JST) CREST program; RISTEX program for Science of Science, Technology and Innovation Policy; Division of International Epidemiology and Population Studies, The Fogarty International Center, United States National Institutes of Health - Office of Pandemics and Emerging Threats at the United States Department of Health and Human Services; NSF, joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases program [1414374]; United Kingdom Biotechnology and Biological Sciences Research Council [BB/M008894/1]; NSF-IIS [1518939] FX HN received funding support from the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers 26670308 and 26700028, Japan Agency for Medical Research and Development, the Japan Science and Technology Agency (JST) CREST program and RISTEX program for Science of Science, Technology and Innovation Policy. GC acknowledge financial support from the Division of International Epidemiology and Population Studies, The Fogarty International Center, United States National Institutes of Health, funded in part by the Office of Pandemics and Emerging Threats at the United States Department of Health and Human Services, as well as support from grants NSF grant 1414374 as part of the joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases program, United Kingdom Biotechnology and Biological Sciences Research Council grant BB/M008894/1 and NSF-IIS Grant#1518939. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 4 Z9 4 U1 5 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JUL 22 PY 2016 VL 16 AR 356 DI 10.1186/s12879-016-1675-z PG 9 WC Infectious Diseases SC Infectious Diseases GA DS6IA UT WOS:000380884300001 PM 27449387 ER PT J AU Segre, JA Salafsky, N AF Segre, Julia A. Salafsky, Nick TI Hominid superorganisms SO SCIENCE LA English DT Editorial Material ID MICROBIAL COMMUNITIES; STRAINS C1 [Segre, Julia A.] NHGRI, Microbial Genom Sect, Translat & Funct Genom Branch, Bethesda, MD 20892 USA. [Salafsky, Nick] Fdn Success, Bethesda, MD 20816 USA. RP Segre, JA (reprint author), NHGRI, Microbial Genom Sect, Translat & Funct Genom Branch, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov NR 10 TC 0 Z9 0 U1 13 U2 15 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUL 22 PY 2016 VL 353 IS 6297 BP 350 EP 351 DI 10.1162/science.aag2788 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS2HB UT WOS:000380583400022 PM 27463659 ER PT J AU Wang, F Ranjan, A Wei, DB Wu, C AF Wang, Feng Ranjan, Anand Wei, Debbie Wu, Carl TI Comment on "A histone acetylation switch regulates H2A.Z deposition by the SWR-C remodeling enzyme" SO SCIENCE LA English DT Editorial Material ID NUCLEOSOME; REPLACEMENT; EXCHANGE; COMPLEX; CORE AB Watanabe et al. (Reports, 12 April 2013, p. 195) study the yeast SWR1/SWR-C complex responsible for depositing the histone variant H2A.Z by replacing nucleosomal H2A with H2A.Z. They report that reversal of H2A.Z replacement is mediated by SWR1 and related INO80 on an H2A.Z nucleosome carrying H3K56Q. Using multiple assays and reaction conditions, we find no evidence of such reversal of H2A.Z exchange. C1 [Wang, Feng; Wei, Debbie; Wu, Carl] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, Bldg 37,Room 6114, Bethesda, MD 20892 USA. [Ranjan, Anand; Wu, Carl] Janelia Res Campus, Howard Hughes Med Inst, 19700 Helix Dr, Ashburn, VA 20147 USA. RP Wu, C (reprint author), NCI, Lab Biochem & Mol Biol, Ctr Canc Res, Bldg 37,Room 6114, Bethesda, MD 20892 USA.; Wu, C (reprint author), Janelia Res Campus, Howard Hughes Med Inst, 19700 Helix Dr, Ashburn, VA 20147 USA. EM wuc@janelia.hhmi.org NR 13 TC 0 Z9 0 U1 11 U2 11 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUL 22 PY 2016 VL 353 IS 6297 DI 10.1126/science.aad5921 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS2HB UT WOS:000380583400031 ER PT J AU Yang, HK Han, K Kwon, HS Park, YM Cho, JH Yoon, KH Kang, MI Cha, BY Lee, SH AF Yang, Hae Kyung Han, Kyungdo Kwon, Hyuk-Sang Park, Yong-Moon Cho, Jae-Hyoung Yoon, Kun-Ho Kang, Moo-Il Cha, Bong-Yun Lee, Seung-Hwan TI Obesity, metabolic health, and mortality in adults: a nationwide population-based study in Korea SO SCIENTIFIC REPORTS LA English DT Article ID BODY-MASS INDEX; ALL-CAUSE MORTALITY; TYPE-2 DIABETES-MELLITUS; CORONARY-ARTERY-DISEASE; NORMAL-WEIGHT OBESITY; CARDIOVASCULAR-DISEASE; RISK; ASSOCIATION; PARADOX; INDIVIDUALS AB BMI, metabolic health status, and their interactions should be considered for estimating mortality risk; however, the data are controversial and unknown in Asians. We aimed to investigate this issue in Korean population. Total 323175 adults were followed-up for 96 (60-120) (median [5-95%]) months in a nationwide population-based cohort study. Participants were classified as "obese" (O) or "non-obese" (NO) using a BMI cut-off of 25 kg/m(2). People who developed >= 1 metabolic disease component (hypertension, diabetes, dyslipidaemia) in the index year were considered "metabolically unhealthy" (MU), while those with none were considered "metabolically healthy" (MH). The MUNO group had a significantly higher risk of all-cause (hazard ratio, 1.28 [95% CI, 1.21-1.35]) and cardiovascular (1.88 [1.63-2.16]) mortality, whereas the MHO group had a lower mortality risk (all-cause: 0.81 [0.74-0.88]), cardiovascular: 0.73 [0.57-0.95]), compared to the MHNO group. A similar pattern was noted for cancer and other-cause mortality. Metabolically unhealthy status was associated with higher risk of all-cause and cardiovascular mortality regardless of BMI levels, and there was a dose-response relationship between the number of incident metabolic diseases and mortality risk. In conclusion, poor metabolic health status contributed more to mortality than high BMI did, in Korean adults. C1 [Yang, Hae Kyung; Cho, Jae-Hyoung; Yoon, Kun-Ho; Kang, Moo-Il; Cha, Bong-Yun; Lee, Seung-Hwan] Catholic Univ Korea, Coll Med, Seoul St Marys Hosp, Div Endocrinol & Metab,Dept Internal Med, Seoul 06591, South Korea. [Han, Kyungdo] Catholic Univ Korea, Coll Med, Dept Med Stat, Seoul 06591, South Korea. [Kwon, Hyuk-Sang] Catholic Univ Korea, Coll Med, Yeouido St Marys Hosp, Div Endocrinol & Metab,Dept Internal Med, Seoul 07345, South Korea. [Park, Yong-Moon] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Lee, SH (reprint author), Catholic Univ Korea, Coll Med, Seoul St Marys Hosp, Div Endocrinol & Metab,Dept Internal Med, Seoul 06591, South Korea. EM hwanx2@catholic.ac.kr OI Lee, Seung-Hwan/0000-0002-3964-3877; PARK, YONG-MOON/0000-0002-5879-6879 FU Catholic Medical Center Research Foundation [5-2013-B0001-00254] FX This study was supported by The Catholic Medical Center Research Foundation (5-2013-B0001-00254). NR 47 TC 1 Z9 1 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 22 PY 2016 VL 6 AR 30329 DI 10.1038/srep30329 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR9PE UT WOS:000380227800001 PM 27445194 ER PT J AU Murphy, J Mollica, M AF Murphy, Jeanne Mollica, Michelle TI All Hands on Deck: nurses and Cancer Care Delivery in Women's Health SO FRONTIERS IN ONCOLOGY LA English DT Article DE nursing; advanced practice nursing; oncology; roles ID HPV VACCINE UPTAKE; BREAST-CANCER; PATIENT NAVIGATION; FOLLOW-UP; SURVIVORSHIP CARE; UNITED-STATES; ONCOLOGY; PERSPECTIVES; MANAGEMENT; ADHERENCE C1 [Murphy, Jeanne; Mollica, Michelle] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Rockville, MD 20850 USA. RP Murphy, J (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Rockville, MD 20850 USA. EM jeanne.murphy@nih.gov NR 56 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD JUL 22 PY 2016 VL 6 AR 174 DI 10.3389/fonc.2016.00174 PG 5 WC Oncology SC Oncology GA DR6EY UT WOS:000379996200001 PM 27500124 ER PT J AU Hickey, BW Lumsden, JM Reyes, S Sedegah, M Hollingdale, MR Freilich, DA Luke, TC Charoenvit, Y Goh, LM Berzins, MP Bebris, L Sacci, JB De La Vega, P Wang, RB Ganeshan, H Abot, EN Carucci, DJ Doolan, DL Brice, GT Kumar, A Aguiar, J Nutman, TB Leitman, SF Hoffman, SL Epstein, JE Richie, TL AF Hickey, Bradley W. Lumsden, Joanne M. Reyes, Sharina Sedegah, Martha Hollingdale, Michael R. Freilich, Daniel A. Luke, Thomas C. Charoenvit, Yupin Goh, Lucy M. Berzins, Mara P. Bebris, Lolita Sacci, John B., Jr. De La Vega, Patricia Wang, Ruobing Ganeshan, Harini Abot, Esteban N. Carucci, Daniel J. Doolan, Denise L. Brice, Gary T. Kumar, Anita Aguiar, Joao Nutman, Thomas B. Leitman, Susan F. Hoffman, Stephen L. Epstein, Judith E. Richie, Thomas L. TI Mosquito bite immunization with radiation-attenuated Plasmodium falciparum sporozoites: safety, tolerability, protective efficacy and humoral immunogenicity SO MALARIA JOURNAL LA English DT Article ID HUMAN MALARIA INFECTION; HEPATOCYTE ERYTHROCYTE PROTEIN; DIRECT VENOUS INOCULATION; T-LYMPHOCYTE RESPONSES; IMMUNE-RESPONSES; SURFACE PROTEIN-2; CIRCUMSPOROZOITE PROTEIN; IRRADIATED SPOROZOITES; REPETITIVE EPITOPE; STAGE MALARIA AB Background: In this phase 1 clinical trial, healthy adult, malaria-naive subjects were immunized with radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) by mosquito bite and then underwent controlled human malaria infection (CHMI). The PfRAS model for immunization against malaria had previously induced >90 % sterile protection against homologous CHMI. This study was to further explore the safety, tolerability and protective efficacy of the PfRAS model and to provide biological specimens to characterize protective immune responses and identify protective antigens in support of malaria vaccine development. Methods: Fifty-seven subjects were screened, 41 enrolled and 30 received at least one immunization. The true-immunized subjects received PfRAS via mosquito bite and the mock-immunized subjects received mosquito bites from irradiated uninfected mosquitoes. Sera and peripheral blood mononuclear cells (PBMCs) were collected before and after PfRAS immunizations. Results: Immunization with PfRAS was generally safe and well tolerated, and repeated immunization via mosquito bite did not appear to increase the risk or severity of AEs. Local adverse events (AEs) of true-immunized and mock-immunized groups consisted of erythaema, papules, swelling, and induration and were consistent with reactions from mosquito bites seen in nature. Two subjects, one true-and one mock-immunized, developed large local reactions that completely resolved, were likely a result of mosquito salivary antigens, and were withdrawn from further participation as a safety precaution. Systemic AEs were generally rare and mild, consisting of headache, myalgia, nausea, and low-grade fevers. Two true-immunized subjects experienced fever, malaise, myalgia, nausea, and rigours approximately 16 h after immunization. These symptoms likely resulted from pre-formed antibodies interacting with mosquito salivary antigens. Ten subjects immunized with PfRAS underwent CHMI and five subjects (50 %) were sterilely protected and there was a significant delay to parasitaemia in the other five subjects. All ten subjects developed humoral immune responses to whole sporozoites and to the circumsporozoite protein prior to CHMI, although the differences between protected and non-protected subjects were not statistically significant for this small sample size. Conclusions: The protective efficacy of this clinical trial (50 %) was notably less than previously reported (>90 %). This may be related to differences in host genetics or the inherent variability in mosquito biting behavior and numbers of sporozoites injected. Differences in trial procedures, such as the use of leukapheresis prior to CHMI and of a longer interval between the final immunization and CHMI in these subjects compared to earlier trials, may also have reduced protective efficacy. This trial has been retrospectively registered at ISRCTN ID 17372582, May 31, 2016. C1 [Hickey, Bradley W.; Lumsden, Joanne M.; Reyes, Sharina; Sedegah, Martha; Hollingdale, Michael R.; Freilich, Daniel A.; Luke, Thomas C.; Charoenvit, Yupin; Goh, Lucy M.; Berzins, Mara P.; Bebris, Lolita; De La Vega, Patricia; Wang, Ruobing; Ganeshan, Harini; Abot, Esteban N.; Carucci, Daniel J.; Doolan, Denise L.; Brice, Gary T.; Kumar, Anita; Aguiar, Joao; Hoffman, Stephen L.; Epstein, Judith E.; Richie, Thomas L.] US Mil Malaria Vaccine Program, Naval Med Res Ctr, Silver Spring, MD USA. [Lumsden, Joanne M.; Reyes, Sharina; Hollingdale, Michael R.; Berzins, Mara P.; Bebris, Lolita; Sacci, John B., Jr.; De La Vega, Patricia; Wang, Ruobing; Ganeshan, Harini; Abot, Esteban N.] Henry M Jackson Fdn Adv Mil Med, Rockville, MD USA. [Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Leitman, Susan F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Hoffman, Stephen L.; Richie, Thomas L.] Sanaria Inc, Rockville, MD USA. RP Hollingdale, MR (reprint author), US Mil Malaria Vaccine Program, Naval Med Res Ctr, Silver Spring, MD USA. EM mikedc110@gmail.com FU Military Infectious Diseases Research Program [62787A 870F 1432] FX Military Infectious Diseases Research Program, Award number 62787A 870F 1432, recipient Dr. Stephen L. Hoffman. NR 65 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUL 22 PY 2016 VL 15 AR 377 DI 10.1186/s12936-016-1435-y PG 18 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DR7TE UT WOS:000380101800002 PM 27448805 ER PT J AU Beedie, SL Mahony, C Walker, HM Chau, CH Figg, WD Vargesson, N AF Beedie, Shaunna L. Mahony, Chris Walker, Heather M. Chau, Cindy H. Figg, William D. Vargesson, Neil TI Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model SO SCIENTIFIC REPORTS LA English DT Article ID RENAL-CELL CARCINOMA; TETRAFLUORINATED THALIDOMIDE ANALOGS; CLINICAL DEVELOPMENT; ENDOTHELIAL-CELLS; SIGNALING PATHWAY; LIMB DEFECTS; CANCER; GROWTH; INHIBITOR; PREGNANCY AB Angiogenesis, the formation of new blood vessels, is essential for tumor growth, stabilization and progression. Angiogenesis inhibitors are now widely used in the clinic; however, there are relatively few published studies on the mechanism of their presumed teratogenic effects. To address this issue, we screened a variety of angiogenesis inhibitors in developing zebrafish and chicken embryo models to assess for developmental defects and potential teratogenic effects. We confirmed previous reports that sunitinib, sorafenib and TNP-470 are teratogenic and demonstrate that axitinib, pazopanib, vandetanib, and everolimus are also teratogens in these models. A dose response study identified the drugs inhibit HUVEC cell proliferation in vitro, and also target the developing blood vessels of embryos in vivo. This provides further evidence for the potential risk of fetal toxicity when using these drugs in a clinical setting, and emphasizes the importance of the development and maintenance of the vasculature in the embryo. We conclude that angiogenesis inhibitors, regardless of the molecular target, are teratogenic when exposed to chicken embryos. C1 [Beedie, Shaunna L.; Mahony, Chris; Walker, Heather M.; Vargesson, Neil] Univ Aberdeen, Sch Med Med Sci & Nutr, Inst Med Sci, Foresterhill, Aberdeen, Scotland. [Beedie, Shaunna L.; Chau, Cindy H.; Figg, William D.] NCI, Mol Pharmacol Sect, Genitourinary Malignancies Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Mahony, Chris] Univ Geneva, Fac Med, Dept Pathol & Immunol, CMU, CH-1211 Geneva 4, Switzerland. RP Vargesson, N (reprint author), Univ Aberdeen, Sch Med Med Sci & Nutr, Inst Med Sci, Foresterhill, Aberdeen, Scotland.; Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Genitourinary Malignancies Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov; n.vargesson@abdn.ac.uk RI Figg Sr, William/M-2411-2016; OI Vargesson, Neil/0000-0001-8027-114X FU Wellcome Trust - NIH PhD Studentship [098252/Z/12/Z]; Intramural Research Program of the National Institutes of Health, National Cancer Institute FX The authors would like to thank Maria Kisakyamaria and Scott McMenemy for preliminary experimental data. This work was supported by a Wellcome Trust - NIH PhD Studentship awarded to SB, WDF and NV (Grant number 098252/Z/12/Z). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U. S. Government. NR 67 TC 1 Z9 1 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 22 PY 2016 VL 6 AR 30038 DI 10.1038/srep30038 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR6TF UT WOS:000380033500001 PM 27443489 ER PT J AU Wang, Y Li, Y Pu, WL Wen, K Shugart, YY Xiong, MM Jin, L AF Wang, Yi Li, Yi Pu, Weilin Wen, Kathryn Shugart, Yin Yao Xiong, Momiao Jin, Li TI Random Bits Forest: a Strong Classifier/Regressor for Big Data SO SCIENTIFIC REPORTS LA English DT Article ID ARTIFICIAL NEURAL-NETWORKS; CLASSIFICATION; REGRESSION; MACHINES; TUTORIAL; SEQUENCE; FAILURE; MODELS AB Efficiency, memory consumption, and robustness are common problems with many popular methods for data analysis. As a solution, we present Random Bits Forest (RBF), a classification and regression algorithm that integrates neural networks (for depth), boosting (for width), and random forests (for prediction accuracy). Through a gradient boosting scheme, it first generates and selects similar to 10,000 small, 3-layer random neural networks. These networks are then fed into a modified random forest algorithm to obtain predictions. Testing with datasets from the UCI (University of California, Irvine) Machine Learning Repository shows that RBF outperforms other popular methods in both accuracy and robustness, especially with large datasets (N > 1000). The algorithm also performed highly in testing with an independent data set, a real psoriasis genome-wide association study (GWAS). C1 [Wang, Yi; Li, Yi; Pu, Weilin; Jin, Li] Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, Minist Educ,Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Wen, Kathryn; Shugart, Yin Yao] NIMH, Unit Stat Genom, Div Intramural, Div Programs,NIH, Bethesda, MD 20892 USA. [Xiong, Momiao] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Sch Publ Hlth, Houston, TX 77030 USA. RP Jin, L (reprint author), Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, Minist Educ,Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China.; Shugart, YY (reprint author), NIMH, Unit Stat Genom, Div Intramural, Div Programs,NIH, Bethesda, MD 20892 USA.; Xiong, MM (reprint author), Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Sch Publ Hlth, Houston, TX 77030 USA. EM yin.yao@nih.gov; momiao.xiong@gmail.com; lijin@fudan.edu.cn RI Jin, Li/C-1468-2009 OI Jin, Li/0000-0002-4546-2415 FU Fudan University High-End Computing Center FX The computations involved in this study were supported by the Fudan University High-End Computing Center. The views expressed in this presentation do not necessarily represent the views of the NIMH, NIH, HHS or the United States Government. NR 50 TC 0 Z9 0 U1 11 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 22 PY 2016 VL 6 AR 30086 DI 10.1038/srep30086 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR6QP UT WOS:000380026700001 PM 27444562 ER PT J AU Cinar, R Iyer, MR Liu, ZY Cao, ZX Jourdan, T Erdelyi, K Godlewski, G Szanda, G Liu, J Park, JK Mukhopadhyay, B Rosenberg, AZ Liow, JS Lorenz, RG Pacher, P Innis, RB Kunos, G AF Cinar, Resat Iyer, Malliga R. Liu, Ziyi Cao, Zongxian Jourdan, Tony Erdelyi, Katalin Godlewski, Grzegorz Szanda, Gergo Liu, Jie Park, Joshua K. Mukhopadhyay, Bani Rosenberg, Avi Z. Liow, Jeih-San Lorenz, Robin G. Pacher, Pal Innis, Robert B. Kunos, George TI Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis SO JCI INSIGHT LA English DT Article ID NLRP3 INFLAMMASOME ACTIVATION; HEPATIC CB1 RECEPTORS; NONALCOHOLIC STEATOHEPATITIS; INTEGRIN ALPHA-V-BETA-6; ENDOCANNABINOID SYSTEM; INSULIN-RESISTANCE; BILIARY FIBROSIS; MOUSE MODELS; PROGRESSION; OBESITY AB Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment. Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects. Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases. Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group. In mouse models of fibrosis induced by CCl4 or bile duct ligation, the hybrid CB1R/iNOS antagonist surpassed the antifibrotic efficacy of the CB1R antagonist rimonabant or the iNOS inhibitor 1400W, without inducing anxiety-like behaviors or CB1R occupancy in the CNS. The hybrid inhibitor also targeted CB1R-independent, iNOS-mediated profibrotic pathways, including increased PDGF, Nlrp3/Asc3, and integrin alpha v beta 6 signaling, as judged by its ability to inhibit these pathways in cnr1(-/-) but not in nos2(-/-) mice. Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis. C1 [Cinar, Resat; Iyer, Malliga R.; Liu, Ziyi; Jourdan, Tony; Godlewski, Grzegorz; Szanda, Gergo; Liu, Jie; Park, Joshua K.; Mukhopadhyay, Bani; Kunos, George] NIAAA, Lab Physiol Studies, Washington, DC USA. [Cao, Zongxian; Erdelyi, Katalin; Pacher, Pal] NIAAA, Lab Oxidat Stress & Tissue Injury, Washington, DC USA. [Rosenberg, Avi Z.] NIDDK, Kidney Dis Sect, Washington, DC USA. [Rosenberg, Avi Z.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Liow, Jeih-San; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Lorenz, Robin G.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. RP Cinar, R (reprint author), NIAAA, LPS, NIH, 5625 Fishers Lane,Room 2S-18, Rockville, MD 20852 USA.; Kunos, G (reprint author), NIAAA, NIH, 5625 Fishers Lane,MSC 9413, Bethesda, MD 20892 USA. EM resat.cinar@nih.gov; george.kunos@nih.gov NR 70 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JUL 21 PY 2016 VL 1 IS 11 AR e87336 DI 10.1172/jci.insight.87336 PG 19 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1MH UT WOS:000387115900007 ER PT J AU Chaudhuri, AR Callen, E Ding, X Gogola, E Duarte, AA Lee, JE Wong, N Lafarga, V Calvo, JA Panzarino, NJ John, S Day, A Crespo, AV Shen, BH Starnes, LM de Ruiter, JR Daniel, JA Konstantinopoulos, PA Cortez, D Cantor, SB Fernandez-Capetillo, O Ge, K Jonkers, J Rottenberg, S Sharan, SK Nussenzweig, A AF Chaudhuri, Arnab Ray Callen, Elsa Ding, Xia Gogola, Ewa Duarte, Alexandra A. Lee, Ji-Eun Wong, Nancy Lafarga, Vanessa Calvo, Jennifer A. Panzarino, Nicholas J. John, Sam Day, Amanda Crespo, Anna Vidal Shen, Binghui Starnes, Linda M. de Ruiter, Julian R. Daniel, Jeremy A. Konstantinopoulos, Panagiotis A. Cortez, David Cantor, Sharon B. Fernandez-Capetillo, Oscar Ge, Kai Jonkers, Jos Rottenberg, Sven Sharan, Shyam K. Nussenzweig, Andre TI Replication fork stability confers chemoresistance in BRCA-deficient cells SO NATURE LA English DT Article ID HOMOLOGY-DIRECTED REPAIR; LYSINE-4 METHYLTRANSFERASE COMPLEX; CONDITIONAL MOUSE MODEL; DNA-REPAIR; BREAST-CANCER; END RESECTION; MUTANT-CELLS; RECOMBINATION; 53BP1; RESISTANCE AB Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARP inhibitors and cisplatin resistance is associated with replication fork protection in Brca2-deficient tumour cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of replication fork protection, highlighting the complexities by which tumour cells evade chemotherapeutic interventions and acquire drug resistance. C1 [Chaudhuri, Arnab Ray; Callen, Elsa; Wong, Nancy; John, Sam; Day, Amanda; Crespo, Anna Vidal; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Ding, Xia; Sharan, Shyam K.] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. [Gogola, Ewa; Duarte, Alexandra A.; de Ruiter, Julian R.; Jonkers, Jos; Rottenberg, Sven] Netherlands Canc Inst, Div Mol Pathol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. [Ding, Xia; Gogola, Ewa; de Ruiter, Julian R.; Jonkers, Jos; Rottenberg, Sven] Netherlands Canc Inst, Canc Genom Ctr, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. [Lee, Ji-Eun; Ge, Kai] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Lafarga, Vanessa; Fernandez-Capetillo, Oscar] Spanish Natl Canc Res Ctr CNIO, Genom Instabil Grp, Madrid 28029, Spain. [Calvo, Jennifer A.; Panzarino, Nicholas J.; Cantor, Sharon B.] Univ Massachusetts, Sch Med, UMASS Mem Canc Ctr, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA. [Shen, Binghui] City Hope Natl Med Ctr, Beckman Res Inst, Dept Radiat Biol, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Starnes, Linda M.; Daniel, Jeremy A.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Prot Res, DK-2200 Copenhagen, Denmark. [Konstantinopoulos, Panagiotis A.] Harvard Med Sch, Dana Farber Canc Inst, Dept Gynecol Med Oncol, Boston, MA 02215 USA. [Cortez, David] Vanderbilt Univ, Dept Biochem, Sch Med, 2215 Garland Ave, Nashville, TN 37232 USA. [Rottenberg, Sven] Univ Bern, Vetsuisse Fac, Inst Anim Pathol, Langgassstr 122, CH-3012 Bern, Switzerland. RP Nussenzweig, A (reprint author), NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov RI Daniel, Jeremy/S-4729-2016; OI Daniel, Jeremy/0000-0002-1981-5571; Ge, Kai/0000-0002-7442-5138 FU Intramural Research Program of the National Institutes of Health (NIH), the National Cancer Institute; Center for Cancer Research; Department of Defense [11557134]; Netherlands Organization for Scientific Research; Dutch Cancer Society; Swiss National Science Foundation; Swiss National Science Foundation [PBZHP3 147302]; Human Frontier Science Program Long-Term Fellowship [LT000393/2013]; NIH [R01 CA176166-01A1, R01CA085344]; Novo Nordisk Foundation [NNF14CC0001] FX We thank A. Bhandoola for discussions; K. Wolcott for flow cytometry; R. Faryabi for help with statistical analysis; T. de Lange for Rif1f/f mice, J. Tainer for PFM39, R. Brosh for WRNi and J. Petrini for Mre11 antibodies. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), the National Cancer Institute and the Center for Cancer Research, and by a Department of Defense grant to A.N. (BCRP DOD Idea Expansion Award, grant 11557134), and the Netherlands Organization for Scientific Research, the Dutch Cancer Society and the Swiss National Science Foundation to S.V. A.R.C. was supported by a Prospective Researcher Award from Swiss National Science Foundation (PBZHP3 147302) and Human Frontier Science Program Long-Term Fellowship (LT000393/2013). S.C. was supported by NIH grant R01 CA176166-01A1; B.S. was supported by NIH grant R01CA085344; and J.A.D. was supported by a grant to the Center for Protein Research from the Novo Nordisk Foundation (NNF14CC0001). NR 44 TC 19 Z9 19 U1 10 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 21 PY 2016 VL 535 IS 7612 BP 382 EP + DI 10.1038/nature18325 PG 24 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS1GQ UT WOS:000380344200032 ER PT J AU Ibiza, S Garcia-Cassani, B Ribeiro, H Carvalho, T Almeida, L Marques, R Misic, AM Bartow-McKenney, C Larson, DM Pavan, WJ Eberl, G Grice, EA Veiga-Fernandes, H AF Ibiza, Sales Garcia-Cassani, Bethania Ribeiro, Helder Carvalho, Tania Almeida, Luis Marques, Rute Misic, Ana M. Bartow-McKenney, Casey Larson, Denise M. Pavan, William J. Eberl, Gerard Grice, Elizabeth A. Veiga-Fernandes, Henrique TI Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence SO NATURE LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; TOLL-LIKE RECEPTORS; CITROBACTER-RODENTIUM; TRANSGENIC MICE; SEQUENCING DATA; LAMINA PROPRIA; ENTERIC GLIA; RET; MICROBIOTA; IMMUNITY AB Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation and infection at mucosal barriers(1). ILC3 development is thought to be programmed(1), but how ILC3 perceive, integrate and respond to local environmental signals remains unclear. Here we show that ILC3 in mice sense their environment and control gut defence as part of a glial-ILC3-epithelial cell unit orchestrated by neurotrophic factors. We found that enteric ILC3 express the neuroregulatory receptor RET. ILC3-autonomous Ret ablation led to decreased innate interleukin-22 (IL-22), impaired epithelial reactivity, dysbiosis and increased susceptibility to bowel inflammation and infection. Neurotrophic factors directly controlled innate Il22 downstream of the p38 MAPK/ERK-AKT cascade and STAT3 activation. Notably, ILC3 were adjacent to neurotrophic-factor-expressing glial cells that exhibited stellate-shaped projections into ILC3 aggregates. Glial cells sensed microenvironmental cues in a MYD88-dependent manner to control neurotrophic factors and innate IL-22. Accordingly, glial-intrinsic Myd88 deletion led to impaired production of ILC3-derived IL-22 and a pronounced propensity towards gut inflammation and infection. Our work sheds light on a novel multi-tissue defence unit, revealing that glial cells are central hubs of neuron and innate immune regulation by neurotrophic factor signals. C1 [Ibiza, Sales; Garcia-Cassani, Bethania; Ribeiro, Helder; Carvalho, Tania; Almeida, Luis; Veiga-Fernandes, Henrique] Fac Med Lisbon, Inst Med Mol, Ave Prof Egas Moniz,Edificio Egas Moniz, P-1649028 Lisbon, Portugal. [Marques, Rute; Eberl, Gerard] Inst Pasteur, Microenvironm & Immun Unit, 25 Rue Docteur Roux, F-75724 Paris, France. [Misic, Ana M.; Bartow-McKenney, Casey; Grice, Elizabeth A.] Univ Penn, Dept Dermatol, Perelman Sch Med, 421 Curie Blvd,1007 Biomed Res Bldg, Philadelphia, PA 19104 USA. [Larson, Denise M.; Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Veiga-Fernandes, Henrique] Champalimaud Ctr Unknown, Champalimaud Res, P-1400038 Lisbon, Portugal. [Marques, Rute] INSERM, U1163, Lab Intestinal Immun, Paris, France. [Marques, Rute] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Marques, Rute] Inst Imagine, Paris, France. [Misic, Ana M.] Univ Penn, Sch Vet Med, Dept Pathobiol, Ctr Host Microbial Interact, Philadelphia, PA 19104 USA. RP Veiga-Fernandes, H (reprint author), Fac Med Lisbon, Inst Med Mol, Ave Prof Egas Moniz,Edificio Egas Moniz, P-1649028 Lisbon, Portugal.; Veiga-Fernandes, H (reprint author), Champalimaud Ctr Unknown, Champalimaud Res, P-1400038 Lisbon, Portugal. EM jhfernandes@medicina.ulisboa.pt FU MEC, Spain; FCT, Portugal; EU [289720]; EMBO [1648]; ERC, EU [647274]; Kenneth Rainin Foundation, US; Crohn's and Colitis Foundation of America, US; Institut Pasteur; ANR, France; NIH NIAMS [R01 AR060873, T32 AR007465]; Morris Animal Foundation [D14CA-404] FX We thank the Histology, Flow Cytometry, Bioimaging and Vivarium services at IMM; Sanjay Jain for providing RetGFP mice. Genentech for providing anti-IL-22 antibody. S.I. was supported by MEC, Spain and FCT, Portugal. B.G.-C. by FP7 (289720), EU. H.V.-F. by EMBO (1648); ERC (647274), EU; Kenneth Rainin Foundation, US; Crohn's and Colitis Foundation of America, US; and FCT, Portugal. G.E. by Institut Pasteur and ANR, France. E.A.G. by NIH NIAMS R01 AR060873. A.M.M. by NIH NIAMS T32 AR007465 and Morris Animal Foundation (D14CA-404). NR 60 TC 13 Z9 13 U1 11 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 21 PY 2016 VL 535 IS 7612 BP 440 EP + DI 10.1038/nature18644 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS1GQ UT WOS:000380344200044 PM 27409807 ER PT J AU Reitman, ML AF Reitman, Marc L. TI Hormone-Replacement Therapy for Melanocyte-Stimulating Hormone Deficiency SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID OBESITY; MUTATIONS; AGONIST; HUMANS C1 [Reitman, Marc L.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Reitman, ML (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. OI Reitman, Marc/0000-0002-0426-9475 NR 10 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 21 PY 2016 VL 375 IS 3 BP 278 EP 279 DI 10.1056/NEJMe1606919 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DS0ZL UT WOS:000380325400014 PM 27468065 ER PT J AU Zhao, HY Fu, Y Glasser, C Andrade, E Mayer, ML Patterson, G Schuck, P AF Zhao, Huaying Fu, Yan Glasser, Carla Andrade, Eric Mayer, Mark L. Patterson, George Schuck, Peter TI Monochromatic Multicomponent Fluorescence Sedimentation Velocity for the Study of High-Affinity Protein Interactions SO ELIFE LA English DT Article ID HIGHER-ORDER ASSEMBLIES; N-TERMINAL DOMAIN; ANALYTICAL ULTRACENTRIFUGATION; DETECTED SEDIMENTATION; SIGNALING COMPLEXES; RECEPTOR HETEROMERS; MULTIPOINT BINDING; MEMBRANE-PROTEINS; T-CELLS; SIZE AB The dynamic assembly of multi-protein complexes underlies fundamental processes in cell biology. A mechanistic understanding of assemblies requires accurate measurement of their stoichiometry, affinity and cooperativity, and frequently consideration of multiple coexisting complexes. Sedimentation velocity analytical ultracentrifugation equipped with fluorescence detection (FDS-SV) allows the characterization of protein complexes free in solution with high size resolution, at concentrations in the nanomolar and picomolar range. Here, we extend the capabilities of FDS-SV with a single excitation wavelength from single-component to multi-component detection using photoswitchable fluorescent proteins (psFPs). We exploit their characteristic quantum yield of photo-switching to imprint spatio-temporal modulations onto the sedimentation signal that reveal different psFP-tagged protein components in the mixture. This novel approach facilitates studies of heterogeneous multi-protein complexes at orders of magnitude lower concentrations and for higher-affinity systems than previously possible. Using this technique we studied high-affinity interactions between the amino-terminal domains of GluA2 and GluA3 AMPA receptors. C1 [Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Fu, Yan; Andrade, Eric; Patterson, George] Natl Inst Biomed Imaging & Bioengn, Sect Biophoton, NIH, Bethesda, MD 20892 USA. [Glasser, Carla; Mayer, Mark L.] NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. EM schuckp@mail.nih.gov FU Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering; National Institute of Child Health and Human Development, at the National Institutes of Health, United States FX We thank Stefan Jakobs and Stefan Hell (Max Planck Institute for Biophysical Chemistry) for providing pQE31-rsEGFP plasmid. This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, and the National Institute of Child Health and Human Development, at the National Institutes of Health, United States. NR 57 TC 1 Z9 1 U1 4 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUL 20 PY 2016 VL 5 AR e17812 DI 10.7554/eLife.17812 PG 49 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DS5ZW UT WOS:000380862500001 ER PT J AU Ramaswamy, V Hielscher, T Mack, SC Lassaletta, A Lin, T Pajtler, KW Jones, DTW Luu, B Cavalli, FMG Aldape, K Remke, M Mynarek, M Rutkowski, S Gururangan, S McLendon, RE Lipp, ES Dunham, C Hukin, J Eisenstat, DD Fulton, D van Landeghem, FKH Santi, M van Veelen, MLC Van Meir, EG Osuka, S Fan, X Muraszko, KM Tirapelli, DPC Oba-Shinjo, SM Marie, SKN Carlotti, CG Lee, JY Rao, AAN Giannini, C Faria, CC Nunes, S Mora, J Hamilton, RL Hauser, P Jabado, N Petrecca, K Jung, S Massimi, L Zollo, M Cinalli, G Bognar, L Klekner, A Hortobagyi, T Leary, S Ermoian, RP Olson, JM Leonard, JR Gardner, C Grajkowska, WA Chambless, LB Cain, J Eberhart, CG Ahsan, S Massimino, M Giangaspero, F Buttarelli, FR Packer, RJ Emery, L Yong, WH Soto, H Liau, LM Everson, R Grossbach, A Shalaby, T Grotzer, M Karajannis, MA Zagzag, D Wheeler, H von Hoff, K Alonso, MM Tuon, T Schuller, U Zitterbart, K Sterba, J Chan, JA Guzman, M Elbabaa, SK Colman, H Dhall, G Fisher, PG Fouladi, M Gajjar, A Goldman, S Hwang, E Kool, M Ladha, H Vera-Bolanos, E Wani, K Lieberman, F Mikkelsen, T Omuro, AM Pollack, IF Prados, M Robins, HI Soffietti, R Wu, J Metellus, P Tabori, U Bartels, U Bouffet, E Hawkins, CE Rutka, JT Dirks, P Pfister, SM Merchant, TE Gilbert, MR Armstrong, TS Korshunov, A Ellison, DW Taylor, MD AF Ramaswamy, Vijay Hielscher, Thomas Mack, Stephen C. Lassaletta, Alvaro Lin, Tong Pajtler, Kristian W. Jones, David T. W. Luu, Betty Cavalli, Florence M. G. Aldape, Kenneth Remke, Marc Mynarek, Martin Rutkowski, Stefan Gururangan, Sridharan McLendon, Roger E. Lipp, Eric S. Dunham, Christopher Hukin, Juliette Eisenstat, David D. Fulton, Dorcas van Landeghem, Frank K. H. Santi, Mariarita van Veelen, Marie-Lise C. Van Meir, Erwin G. Osuka, Satoru Fan, Xing Muraszko, Karin M. Tirapelli, Daniela P. C. Oba-Shinjo, Sueli M. Marie, Suely K. N. Carlotti, Carlos G. Lee, Ji Yeoun Rao, Amulya A. Nageswara Giannini, Caterina Faria, Claudia C. Nunes, Sofia Mora, Jaume Hamilton, Ronald L. Hauser, Peter Jabado, Nada Petrecca, Kevin Jung, Shin Massimi, Luca Zollo, Massimo Cinalli, Giuseppe Bognar, Laszlo Klekner, Almos Hortobagyi, Tibor Leary, Sarah Ermoian, Ralph P. Olson, James M. Leonard, Jeffrey R. Gardner, Corrine Grajkowska, Wieslawa A. Chambless, Lola B. Cain, Jason Eberhart, Charles G. Ahsan, Sama Massimino, Maura Giangaspero, Felice Buttarelli, Francesca R. Packer, Roger J. Emery, Lyndsey Yong, William H. Soto, Horacio Liau, Linda M. Everson, Richard Grossbach, Andrew Shalaby, Tarek Grotzer, Michael Karajannis, Matthias A. Zagzag, David Wheeler, Helen von Hoff, Katja Alonso, Marta M. Tuon, Teresa Schueller, Ulrich Zitterbart, Karel Sterba, Jaroslav Chan, Jennifer A. Guzman, Miguel Elbabaa, Samer K. Colman, Howard Dhall, Girish Fisher, Paul G. Fouladi, Maryam Gajjar, Amar Goldman, Stewart Hwang, Eugene Kool, Marcel Ladha, Harshad Vera-Bolanos, Elizabeth Wani, Khalida Lieberman, Frank Mikkelsen, Tom Omuro, Antonio M. Pollack, Ian F. Prados, Michael Robins, H. Ian Soffietti, Riccardo Wu, Jing Metellus, Phillipe Tabori, Uri Bartels, Ute Bouffet, Eric Hawkins, Cynthia E. Rutka, James T. Dirks, Peter Pfister, Stefan M. Merchant, Thomas E. Gilbert, Mark R. Armstrong, Terri S. Korshunov, Andrey Ellison, David W. Taylor, Michael D. TI Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CONFORMAL RADIATION-THERAPY; NEWLY-DIAGNOSED EPENDYMOMA; PHASE-II TRIAL; BRAIN-TUMORS; PEDIATRIC-PATIENTS; CRANIAL RADIATION; CHILDREN; CHILDHOOD; CHEMOTHERAPY; AGE AB PurposePosterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known.MethodsFour independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses.ResultsMolecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation.ConclusionThe most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence. C1 [Ramaswamy, Vijay; Mack, Stephen C.; Lassaletta, Alvaro; Luu, Betty; Cavalli, Florence M. G.; Tabori, Uri; Bartels, Ute; Bouffet, Eric; Hawkins, Cynthia E.; Rutka, James T.; Dirks, Peter; Taylor, Michael D.] Hosp Sick Children, Toronto, ON, Canada. [Ramaswamy, Vijay; Aldape, Kenneth; Rutka, James T.; Taylor, Michael D.] Univ Toronto, Toronto, ON, Canada. [Aldape, Kenneth] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Dunham, Christopher; Hukin, Juliette] Univ British Columbia, British Columbia Childrens Hosp, Vancouver, BC, Canada. [Hukin, Juliette] Univ British Columbia, Vancouver, BC, Canada. [Eisenstat, David D.; Fulton, Dorcas; van Landeghem, Frank K. H.] Univ Alberta, Edmonton, AB, Canada. [Chan, Jennifer A.] Univ Calgary, Calgary, AB, Canada. [Jabado, Nada; Petrecca, Kevin] McGill Univ, Montreal, PQ, Canada. [Hielscher, Thomas; Pajtler, Kristian W.; Jones, David T. W.; Kool, Marcel; Pfister, Stefan M.; Korshunov, Andrey] German Canc Res Ctr, Heidelberg, Germany. [Pfister, Stefan M.] Univ Heidelberg Hosp, Heidelberg, Germany. [Remke, Marc] Univ Hosp Dusseldorf, Dusseldorf, Germany. [Mynarek, Martin; Rutkowski, Stefan; von Hoff, Katja] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Schueller, Ulrich] Univ Munich, Munich, Germany. [Mack, Stephen C.] Cleveland Clin Fdn, Cleveland, OH USA. [Fouladi, Maryam] Univ Cincinnati, Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Lin, Tong; Gajjar, Amar; Merchant, Thomas E.; Ellison, David W.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Chambless, Lola B.] Vanderbilt Univ Sch Med, Nashville, TN USA. [Gururangan, Sridharan; McLendon, Roger E.; Lipp, Eric S.] Duke Univ, Durham, NC 27706 USA. [Wu, Jing] Univ N Carolina, Chapel Hill, NC USA. [Santi, Mariarita] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Emery, Lyndsey] Hosp Univ Penn, 3400 Spruce St, Philadelphia, PA 19104 USA. [Hamilton, Ronald L.; Pollack, Ian F.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. [Lieberman, Frank] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Van Meir, Erwin G.; Osuka, Satoru] Emory Univ, Atlanta, GA 30322 USA. [Fan, Xing; Muraszko, Karin M.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Mikkelsen, Tom] Henry Ford Hlth Syst, Detroit, MI USA. [Leary, Sarah; Ermoian, Ralph P.; Olson, James M.] Seattle Childrens Hosp, Seattle, WA USA. [Ermoian, Ralph P.; Olson, James M.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Leary, Sarah; Ermoian, Ralph P.; Olson, James M.] Univ Washington, Seattle, WA 98195 USA. [Leonard, Jeffrey R.; Gardner, Corrine] Washington Univ, Sch Med, St Louis, MO USA. [Leonard, Jeffrey R.; Gardner, Corrine] St Louis Childrens Hosp, St Louis, MO 63178 USA. [Guzman, Miguel; Elbabaa, Samer K.] St Louis Univ, Sch Med, St Louis, MO USA. [Eberhart, Charles G.; Ahsan, Sama] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Gilbert, Mark R.] NCI, Bethesda, MD 20892 USA. [Packer, Roger J.; Hwang, Eugene] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Yong, William H.; Soto, Horacio; Liau, Linda M.; Everson, Richard] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Dhall, Girish] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Fisher, Paul G.] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Prados, Michael] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Grossbach, Andrew] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Karajannis, Matthias A.; Zagzag, David] NYU, Langone Med Ctr, New York, NY USA. [Omuro, Antonio M.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Colman, Howard] Univ Utah Hlth Syst, Huntsman Canc Inst, Salt Lake City, UT USA. [Rao, Amulya A. Nageswara; Giannini, Caterina] Mayo Clin, Rochester, MN USA. [Goldman, Stewart] Lurie Childrens Hosp, Chicago, IL USA. [Ladha, Harshad; Vera-Bolanos, Elizabeth; Wani, Khalida; Gilbert, Mark R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Armstrong, Terri S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Robins, H. Ian] Univ Wisconsin, Madison, WI USA. [van Veelen, Marie-Lise C.] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Tirapelli, Daniela P. C.; Oba-Shinjo, Sueli M.; Marie, Suely K. N.; Carlotti, Carlos G.] Univ Sao Paulo, Sao Paulo, Brazil. [Lee, Ji Yeoun] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Jung, Shin] Chonnam Natl Univ, Res Inst Med Sci, Hwasun Gun, Chonnam, South Korea. [Jung, Shin] Chonnam Natl Univ, Hwasun Hosp & Med Sch, Hwasun Gun, Chonnam, South Korea. [Faria, Claudia C.] Hosp Santa Maria, Ctr Hosp Lisboa Norte, Lisbon, Portugal. [Nunes, Sofia] Inst Portugues Oncol Francisco Gentil, Lisbon, Portugal. [Mora, Jaume] Hosp San Juan Dios, Barcelona, Spain. [Alonso, Marta M.] Univ Hosp Navarra, Pamplona, Spain. [Tuon, Teresa] Complejo Hosp Navarra, Navarra, Spain. [Hauser, Peter] Semmelweis Univ, Budapest, Hungary. [Bognar, Laszlo; Klekner, Almos; Hortobagyi, Tibor] Univ Debrecen, Debrecen, Hungary. [Massimi, Luca] Catholic Univ, Sch Med, Rome, Italy. [Buttarelli, Francesca R.] Univ Roma La Sapienza, Rome, Italy. [Zollo, Massimo; Cinalli, Giuseppe] Univ Naples Federico II, I-80138 Naples, Italy. [Cinalli, Giuseppe] Osped Santobono Pausilipon, Naples, Italy. [Massimino, Maura] Fdn Ist Ricovero & Cura Carattere Sci IRCCS, Ist Nazl Tumori, Milan, Italy. [Giangaspero, Felice] Univ Roma La Sapienza, Policlin Umberto 1, Pozzilli, Italy. [Giangaspero, Felice] IRCCS Neuromed, Pozzilli, Italy. [Soffietti, Riccardo] Univ Turin, Turin, Italy. [Grajkowska, Wieslawa A.] Childrens Mem Hlth Inst, Warsaw, Poland. [Cain, Jason] Hudson Inst Med Res, Clayton, Vic, Australia. [Wheeler, Helen] Univ Sydney, Kolling Inst Med Res, Sydney, NSW, Australia. [Shalaby, Tarek; Grotzer, Michael] Univ Childrens Hosp Zurich, Zurich, Switzerland. [Zitterbart, Karel; Sterba, Jaroslav] Masaryk Univ, Brno, Czech Republic. [Metellus, Phillipe] Ctr Hosp Clairval, Marseille, France. RP Taylor, MD (reprint author), Div Neurosurg, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM mdtaylor@sickkids.ca RI Oba-Shinjo, Sueli /C-4017-2012; Carlotti, Carlos/C-1608-2012; massimino, maura/K-7310-2016; Tunon, Teresa/B-2525-2017; OI Carlotti, Carlos/0000-0002-7055-0564; massimino, maura/0000-0002-5506-2001; Tunon, Teresa/0000-0001-6589-1084; Dunham, Christopher/0000-0002-6244-0584; Karajannis, Matthias/0000-0002-7151-6528 FU Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children; University of Toronto; Pediatric Brain Tumor Foundation; Rally Foundation; National Institutes of Health (NIH) [R01CA159859, R01CA148699]; Canadian Institutes of Health Research (CIHR); CIHR; Alberta Innovates-Health Solutions Clinical Fellowship; Collaborative Ependymoma Research Network (CERN) Foundation fellowship; Alex's Lemonade Stand Young Investigator Award; b.r.a.i.n.child; Mildred Scheel Cancer Foundation; Deutsche Kinderkrebsstiftung; YU Langone Human Specimen Resource Center; Laura and Isaac Perlmutter Cancer Center; Clinical and Translational Science Institute (CTSI); Cancer Center Support Grant [P30CA016087]; National Center for the Advancement of Translational Science (NCATS) [UL 1 TR000038]; NIH; Making Headway Foundation; Hungarian Brain Research Program [KTIA_13_NAP-A-V/3]; Janos Bolyai Scholarship of the Hungarian Academy of Sciences; Faculty of Medicine, Masaryk University; NIH [R01 CA163722, NS096236]; St Baldrick's Foundation; Cure Childhood Cancer Foundation; CERN Foundation; [TAMOP-4.2.2.A-11/1/KONV-2012-0025] FX M.D.T. is supported by funds from the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto and operating funds from the Pediatric Brain Tumor Foundation, Meagan's Walk, the Rally Foundation, the National Institutes of Health (NIH; Grants No. R01CA159859 and R01CA148699), and the Canadian Institutes of Health Research (CIHR). V.R. is supported by a CIHR fellowship, an Alberta Innovates-Health Solutions Clinical Fellowship, a Collaborative Ependymoma Research Network (CERN) Foundation fellowship, and an Alex's Lemonade Stand Young Investigator Award. E.B. and V.R. acknowledge support from b.r.a.i.n.child. S.G., R.E.M., and D.B. are supported by the Pediatric Brain Tumor Foundation. M.R. is supported by a fellowship from the Mildred Scheel Cancer Foundation. S.M.P. is supported by a grant from the Deutsche Kinderkrebsstiftung. M.A.K. and D.Z. are supported by the NYU Langone Human Specimen Resource Center, Laura and Isaac Perlmutter Cancer Center, and Clinical and Translational Science Institute (CTSI), which were partially supported by the Cancer Center Support Grant P30CA016087 and a grant from the National Center for the Advancement of Translational Science (NCATS) (UL 1 TR000038), NIH, and grants from The Making Headway Foundation. A.K. was supported by the Hungarian Brain Research Program (Grant No. KTIA_13_NAP-A-V/3), the TAMOP-4.2.2.A-11/1/KONV-2012-0025 project, and Janos Bolyai Scholarship of the Hungarian Academy of Sciences. K.Z. acknowledges the support of an Institutional Research Project grant to junior researchers from the Faculty of Medicine, Masaryk University. E.V.M. is funded by NIH Grants No. R01 CA163722 and NS096236, St Baldrick's Foundation, and the Cure Childhood Cancer Foundation. M.D.T., V.R., K.A., T.S.A., and M.R.G. are supported by the CERN Foundation. NR 31 TC 5 Z9 6 U1 6 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2016 VL 34 IS 21 BP 2468 EP + DI 10.1200/JCO.2015.65.7825 PG 23 WC Oncology SC Oncology GA DT5BZ UT WOS:000381497000006 PM 27269943 ER PT J AU Mazzulli, JR Zunke, F Tsunemi, T Toker, NJ Jeon, S Burbulla, LF Patnaik, S Sidransky, E Marugan, JJ Sue, CM Krainc, D AF Mazzulli, Joseph R. Zunke, Friederike Tsunemi, Taiji Toker, Nicholas J. Jeon, Sohee Burbulla, Lena F. Patnaik, Samarjit Sidransky, Ellen Marugan, Juan J. Sue, Carolyn M. Krainc, Dimitri TI Activation of beta-Glucocerebrosidase Reduces Pathological alpha-Synuclein and Restores Lysosomal Function in Parkinson's Patient Midbrain Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE alpha-synuclein; glucocerebrosidase; induced pluripotent stem cells; lysosomes; Parkinson's disease; synucleinopathy ID GAUCHER-DISEASE; DOPAMINE NEURONS; LEWY BODIES; MOUSE MODEL; DYSFUNCTION; AGGREGATION; MUTATIONS; INHIBITION; DEFECTS; CELLS AB Parkinson's disease (PD) is characterized by the accumulation of alpha-synuclein (alpha-syn) within Lewy body inclusions in the nervous system. There are currently no disease-modifying therapies capable of reducing alpha-syn inclusions in PD. Recent data has indicated that loss-of-function mutations in the GBA1 gene that encodes lysosomal beta-glucocerebrosidase (GCase) represent an important risk factor for PD, and can lead to alpha-syn accumulation. Here we use a small-molecule modulator of GCase to determine whether GCase activation within lysosomes can reduce alpha-syn levels and ameliorate downstream toxicity. Using induced pluripotent stem cell (iPSC)-derived human midbrain dopamine (DA) neurons from synucleinopathy patients with different PD-linked mutations, wefind that a non-inhibitory small molecule modulator of GCase specifically enhanced activity within lysosomal compartments. This resulted in reduction of GCase substrates and clearance of pathological alpha-syn, regardless of the disease causing mutations. Importantly, the reduction of alpha-syn was sufficient to reverse downstream cellular pathologies induced by alpha-syn, including perturbations in hydrolase maturation and lysosomal dysfunction. These results indicate that enhancement of a single lysosomal hydrolase, GCase, can effectively reduce alpha-syn and provide therapeutic benefit in human midbrain neurons. This suggests that GCase activators may prove beneficial as treatments for PD and related synucleinopathies. C1 [Mazzulli, Joseph R.; Tsunemi, Taiji; Burbulla, Lena F.; Krainc, Dimitri] Massachusetts Gen Hosp, Harvard Med Sch, MassGen Inst Neurodegenerat, Dept Neurol, Charlestown, MA 02129 USA. [Mazzulli, Joseph R.; Zunke, Friederike; Tsunemi, Taiji; Toker, Nicholas J.; Jeon, Sohee; Burbulla, Lena F.; Krainc, Dimitri] Northwestern Univ, Feinberg Sch Med, Ken & Ruth Davee Dept Neurol, 303 East Chicago Ave,Ward 12-140, Chicago, IL 60611 USA. [Patnaik, Samarjit; Marugan, Juan J.] NIH, Dept Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Sue, Carolyn M.] Royal North Shore Hosp, Kolling Inst Med Res, Dept Neurogenet, St Leonards, NSW 2065, Australia. [Sue, Carolyn M.] Univ Sydney, St Leonards, NSW 2065, Australia. RP Mazzulli, JR; Krainc, D (reprint author), Northwestern Univ, Feinberg Sch Med, Ken & Ruth Davee Dept Neurol, 303 East Chicago Ave,Ward 12-140, Chicago, IL 60611 USA. EM jmazzulli@northwestern.edu; krainc@northwestern.edu FU Human Embryonic and Induced Pluripotent Stem Cell Facility at Northwestern University; NIH [P30 NS081774]; Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]; Lipidomics Core in the South Carolina Lipidomics and Pathobiology Center of Biomedical Research Excellence, Department Biochemistry, Medical University of South Carolina [P20 RR017677]; German Academic Exchange Service (DAAD); Intramural Research Programs of the National Human Genome Research Institute; Intramural Research Program of the National Center for Advancing Translational Sciences of the National Institutes of Health; NHMRC Practitioner Fellowship [1008433]; National Institute of Neurological Disorders and Stroke [R01NS092823, R01NS076054, U24NS078338]; PDNSW Association FX This work was supported in part by the Human Embryonic and Induced Pluripotent Stem Cell Facility at Northwestern University and NIH core support Grant P30 NS081774; lipid measurements were supported in part by the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313) and the Lipidomics Core in the South Carolina Lipidomics and Pathobiology Center of Biomedical Research Excellence, Department Biochemistry, Medical University of South Carolina (P20 RR017677); L.F.B. was supported by a fellowship within the postdoctoral program of the German Academic Exchange Service (DAAD); E.S. was supported by the Intramural Research Programs of the National Human Genome Research Institute; S.P. and J.J.M. by the Intramural Research Program of the National Center for Advancing Translational Sciences, both of the National Institutes of Health; C.M.S. by the NHMRC Practitioner Fellowship (1008433); National Institute of Neurological Disorders and Stroke Grants R01NS092823 (J.R.M.), R01NS076054, U24NS078338 (D.K.); and the PDNSW Association (C.M.S.). We thank Kana Hamada and Haris Dzaferbegovic for excellent technical assistance, Nick Blair and Ernst Wolvetang for advice and characterization of PARK9 iPSC line, R. Jaenisch (MIT) for generously providing the A53T alpha-syn iPSC lines, and Johannes Aerts (University of Leiden) for generously providing the anti-glucocerebrosidase antibody (8E4). NR 48 TC 10 Z9 10 U1 6 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 20 PY 2016 VL 36 IS 29 BP 7693 EP 7706 DI 10.1523/JNEUROSCI.0628-16.2016 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DU6AX UT WOS:000382296300013 PM 27445146 ER PT J AU Lee, HJ Weitz, AJ Bernal-Casas, D Duffy, BA Choy, M Kravitz, AV Kreitzer, AC Lee, JH AF Lee, Hyun Joo Weitz, Andrew J. Bernal-Casas, David Duffy, Ben A. Choy, ManKin Kravitz, Alexxai V. Kreitzer, Anatol C. Lee, Jin Hyung TI Activation of Direct and Indirect Pathway Medium Spiny Neurons Drives Distinct Brain-wide Responses SO NEURON LA English DT Article ID BASAL GANGLIA CIRCUITRY; ELECTRICAL-STIMULATION; OPTOGENETIC CONTROL; PROJECTION NEURONS; GENE-EXPRESSION; FUNCTIONAL MRI; FMRI; CORTEX; CONNECTIVITY; NETWORK AB A central theory of basal ganglia function is that striatal neurons expressing the D1 and D2 dopamine receptors exert opposing brain-wide influences. However, the causal influence of each population has never been measured at the whole-brain scale. Here, we selectively stimulated D1 or D2 receptor-expressing neurons while visualizing whole-brain activity with fMRI. Excitation of either inhibitory population evoked robust positive BOLD signals within striatum, while downstream regions exhibited significantly different and generally opposing responses consistent with-though not easily predicted from-contemporary models of basal ganglia function. Importantly, positive and negative signals within the striatum, thalamus, GPi, and STN were all associated with increases and decreases in single-unit activity, respectively. These findings provide direct evidence for the opposing influence of D1 and D2 receptor-expressing striatal neurons on brain-wide circuitry and extend the interpretability of fMRI studies by defining cell-type-specific contributions to the BOLD signal. C1 [Lee, Hyun Joo; Weitz, Andrew J.; Bernal-Casas, David; Duffy, Ben A.; Choy, ManKin; Lee, Jin Hyung] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Weitz, Andrew J.; Lee, Jin Hyung] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Kravitz, Alexxai V.] NIDDK, NIH, Bethesda, MD 20892 USA. [Kravitz, Alexxai V.; Kreitzer, Anatol C.] Univ Calif San Francisco, Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA. [Lee, Jin Hyung] Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA. [Lee, Jin Hyung] Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA. RP Lee, JH (reprint author), Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA.; Lee, JH (reprint author), Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.; Lee, JH (reprint author), Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA.; Lee, JH (reprint author), Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA. EM ljinhy@stanford.edu FU NIH/NIBIB [R00EB008738]; Okawa Foundation; NIH [DP2OD007265]; NSF CAREER [1056008]; Alfred P. Sloan Research Fellowship; NIH/NINDS [R01NS091461] FX This work was supported by the NIH/NIBIB R00 Award (R00EB008738), Okawa Foundation Research Grant Award, NIH Director's New Innovator Award (DP2OD007265), the NSF CAREER Award (1056008), the Alfred P. Sloan Research Fellowship, and the NIH/NINDS R01 (R01NS091461). NR 67 TC 4 Z9 4 U1 9 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUL 20 PY 2016 VL 91 IS 2 BP 412 EP 424 DI 10.1016/j.neuron.2016.06.010 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DU7LH UT WOS:000382395200018 PM 27373834 ER PT J AU Diallo, M Diarra, B Sanogo, M Togo, ACG Somboro, AM Diallo, MH Traore, B Maiga, M Kone, Y Tounkara, K Sarro, YDS Baya, B Goita, D Kassambara, H Dembele, BPP Siddiqui, S Murphy, RL Dao, S Diallo, S Tounkara, A Niang, M AF Diallo, Mamadou Diarra, Bassirou Sanogo, Moumine Togo, Antieme C. G. Somboro, Anou M. Diallo, Mariam H. Traore, Brehima Maiga, Mamoudou Kone, Younoussa Tounkara, Karim Sarro, Yeya Dit Sadio Baya, Bocar Goita, Drissa Kassambara, Hamadoun Dembele, Bindongo P. P. Siddiqui, Sophia Murphy, Robert L. Dao, Sounkalo Diallo, Souleymane Tounkara, Anatole Niang, Mamadou TI Molecular identification of Mycobacterium bovis from cattle and human host in Mali: expanded genetic diversity SO BMC VETERINARY RESEARCH LA English DT Article DE Bovine tuberculosis; Frequency; Spoligotyping; Mali ID TUBERCULOSIS; EPIDEMIOLOGY; INFECTION; TANZANIA; AFRICA AB Background: Bovine tuberculosis (BTB) is a contagious, debilitating human and animal disease caused by Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex. The study objective were to estimate the frequency of BTB, examine genetic diversity of the M. bovis population in cattle from five regions in Mali and to determine whether M. bovis is involved in active tuberculosis (TB) in humans. Samples from suspected lesions on cattle at the slaughterhouses were collected. Mycobacterial smear, culture confirmation, and spoligotyping were used for diagnosis and species identification. Mycobacterium DNA from TB patients was spoligotyped to identify M. bovis. Results: In total, 675 cattle have been examined for lesions in the five regions of Mali. Out of 675 cattle, 79 specimens presented lesions and then examined for the presence of M. bovis. Thus, 19 (24.1 %) were identified as M. bovis; eight (10.1 %) were non-tuberculous Mycobacterium (NTM). Nineteen spoligotype patterns were identified among 79 samples with five novel patterns. One case of M. bovis (spoligotype pattern SB0300) was identified among 67 TB patients. Conclusion: This study estimates a relatively true proportion of BTB in the regions of Mali and reveals new spoligotype patterns. C1 [Diallo, Mamadou; Kone, Younoussa; Tounkara, Karim; Niang, Mamadou] Cent Vet Lab, Bamako, Mali. [Diarra, Bassirou; Sanogo, Moumine; Togo, Antieme C. G.; Somboro, Anou M.; Diallo, Mariam H.; Traore, Brehima; Maiga, Mamoudou; Sarro, Yeya Dit Sadio; Baya, Bocar; Goita, Drissa; Kassambara, Hamadoun; Dembele, Bindongo P. P.; Dao, Sounkalo; Diallo, Souleymane; Tounkara, Anatole] Univ Sci Tech & Technol Bamako, SEREFO, Bamako, Mali. [Siddiqui, Sophia] NIH, Div Clin Res, Bldg 10, Bethesda, MD 20892 USA. [Murphy, Robert L.] Northwestern Univ, Chicago, IL 60611 USA. RP Diarra, B (reprint author), Univ Sci Tech & Technol Bamako, SEREFO, Bamako, Mali. EM bdiarra@icermali.org OI Traore, Brehima/0000-0001-9075-9157 FU World Bank through Programme Maladie Infectieuse [PMI PMI-23/LCV]; le programme d'appui aux services agricoles et aux organisations paysannes (PASAOP); Division of Clinical Research (DCR) of NIAID/NIH; NIH [5D43TW007995, 5UM1AI69471] FX This study was funded by World Bank through Programme Maladie Infectieuse (PMI PMI-23/LCV) and le programme d'appui aux services agricoles et aux organisations paysannes (PASAOP) and by the Division of Clinical Research (DCR) of NIAID/NIH. This work was also partially supported by NIH grants 5D43TW007995 and 5UM1AI69471. NR 23 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1746-6148 J9 BMC VET RES JI BMC Vet. Res. PD JUL 20 PY 2016 VL 12 AR 145 DI 10.1186/s12917-016-0768-7 PG 9 WC Veterinary Sciences SC Veterinary Sciences GA DR9YD UT WOS:000380251200001 PM 27439708 ER PT J AU Cho, HS Schotte, F Dashdorj, N Kyndt, J Henning, R Anfinrud, PA AF Cho, Hyun Sun Schotte, Friedrich Dashdorj, Naranbaatar Kyndt, John Henning, Robert Anfinrud, Philip A. TI Picosecond Photobiology: Watching a Signaling Protein Function in Real Time via Time-Resolved Small- and Wide-Angle X-ray Scattering SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PHOTOACTIVE YELLOW PROTEIN; GLOBAL CONFORMATIONAL-CHANGE; FREE-ELECTRON LASER; STRUCTURAL DYNAMICS; ECTOTHIORHODOSPIRA-HALOPHILA; LAUE CRYSTALLOGRAPHY; PHOTOCYCLE; SPECTROSCOPY; MYOGLOBIN; LIGHT AB The capacity to respond to environmental changes is crucial to an organism's survival. Halorhodospira halophila is a photosynthetic bacterium that swims away from blue light, presumably in an effort to evade photons energetic enough to be genetically harmful. The protein responsible for this response is believed to be photoactive yellow protein (PYP), whose chromophore photoisomerizes from trans to cis in the presence of blue light. We investigated the complete PYP photocycle by acquiring time-resolved small and wide-angle X-ray scattering patterns (SAXS/WAXS) over 10 decades of time spanning from 100 ps to 1 s. Using a sequential model, global analysis of the time-dependent scattering differences recovered four intermediates (pR(0)/pR(1), pR(2), pB(0), pB(1)), the first three of which can be assigned to prior time-resolved crystal structures. The 1.8 ms pB(0) to pB(1) transition produces the PYP signaling state, whose radius of gyration (R-g = 16.6 angstrom) is significantly larger than that for the ground state (R-g = 14.7 angstrom) and is therefore inaccessible to time-resolved protein crystallography. The shape of the signaling state, reconstructed using GASBOR, is highly anisotropic and entails significant elongation of the long axis of the protein. This structural change is consistent with unfolding of the 25 residue N-terminal domain, which exposes the beta-scaffold of this sensory protein to a potential binding partner. This mechanistically detailed description of the complete PYP photocycle, made possible by time-resolved crystal and solution studies, provides a framework for understanding signal transduction in proteins and for assessing and validating theoretical/computational approaches in protein biophysics. C1 [Cho, Hyun Sun; Schotte, Friedrich; Dashdorj, Naranbaatar; Anfinrud, Philip A.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Kyndt, John] Bellevue Univ, Coll Sci & Technol, Bellevue, NE 68005 USA. [Henning, Robert] Univ Chicago, Ctr Adv Radiat Sources, Chicago, IL 60637 USA. [Dashdorj, Naranbaatar] Onom Fdn, Ulaanbaatar, Mongol Peo Rep. RP Anfinrud, PA (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM anfinrud@nih.gov FU National Center for Research Resources from National Institutes of Health [5P41RR007707]; National Institute of General Medical Sciences from National Institutes of Health [8P41GM103543]; U.S. DOE [DE-AC02-06CH11357]; NIH/NIDDK; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We thank Gerhard Hummer and Jurgen Kofinger for helpful discussions and Bernard Howder, Jr. for machining many of the components required for this study. Structures in several figures were generated using VMD : http://www.ks.uiuc.edu/Research/vmd/). Use of the BioCARS Sector 14 was supported by grants from the National Center for Research Resources (5P41RR007707) and the National Institute of General Medical Sciences (8P41GM103543) from the National Institutes of Health. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under contract no. DE-AC02-06CH11357. The time-resolved setup at Sector 14 was funded in part through a collaboration with Philip Anfinrud (NIH/NIDDK). This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 47 TC 0 Z9 0 U1 26 U2 33 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 20 PY 2016 VL 138 IS 28 BP 8815 EP 8823 DI 10.1021/jacs.6b03565 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA DS0OC UT WOS:000380295600029 PM 27305463 ER PT J AU Schmidt, T Situ, AJ Ulmer, TS AF Schmidt, Thomas Situ, Alan J. Ulmer, Tobias S. TI Structural and thermodynamic basis of proline-induced transmembrane complex stabilization SO SCIENTIFIC REPORTS LA English DT Article ID MEMBRANE-PROTEIN; NMR; EVOLUTION; RESIDUES; SUBSTITUTIONS; PROPENSITY; REFINEMENT; HELICES; POLAR AB In membrane proteins, proline-mediated helix kinks are indispensable for the tight packing of transmembrane (TM) helices. However, kinks invariably affect numerous interhelical interactions, questioning the acceptance of proline substitutions and evolutionary origin of kinks. Here, we present the structural and thermodynamic basis of proline-induced integrin alpha IIb beta 3 TM complex stabilization to understand the introduction of proline kinks in membrane proteins. In phospholipid bicelles, the A711P substitution in the center of the beta 3 TM helix changes the direction of adjacent helix segments to form a 35 +/- 2 degrees angle and predominantly repacks the segment in the inner membrane leaflet due to a swivel movement. This swivel repacks hydrophobic and electrostatic interhelical contacts within intracellular lipids, resulting in an overall TM complex stabilization of -0.82 +/- 0.01 kcal/mol. Thus, proline substitutions can directly stabilize membrane proteins and such substitutions are proposed to follow the structural template of integrin alpha IIb beta 3(A711P). C1 [Ulmer, Tobias S.] Univ Southern Calif, Keck Sch Med, Dept Biochem & Mol Biol, 1501 San Pablo St, Los Angeles, CA 90033 USA. Univ Southern Calif, Keck Sch Med, Zilkha Neurogenet Inst, 1501 San Pablo St, Los Angeles, CA 90033 USA. [Schmidt, Thomas] NIDDK, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RP Ulmer, TS (reprint author), Univ Southern Calif, Keck Sch Med, Dept Biochem & Mol Biol, 1501 San Pablo St, Los Angeles, CA 90033 USA. EM tulmer@usc.edu FU American Heart Association [15GRNT23200010] FX This work was supported by American Heart Association grant 15GRNT23200010. NR 33 TC 1 Z9 1 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 20 PY 2016 VL 6 AR 29809 DI 10.1038/srep29809 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR5DI UT WOS:000379922800001 PM 27436065 ER PT J AU Fay, MP Brittain, EH AF Fay, Michael P. Brittain, Erica H. TI Finite sample pointwise confidence intervals for a survival distribution with right-censored data SO STATISTICS IN MEDICINE LA English DT Article DE beta product confidence procedure; exact test; Kaplan-Meier estimator; mid p-value; survival analysis ID DISCRETE-DISTRIBUTIONS AB We review and develop pointwise confidence intervals for a survival distribution with right-censored data for small samples, assuming only independence of censoring and survival. When there is no censoring, at each fixed time point, the problem reduces to making inferences about a binomial parameter. In this case, the recently developed beta product confidence procedure (BPCP) gives the standard exact central binomial confidence intervals of Clopper and Pearson. Additionally, the BPCP has been shown to be exact (gives guaranteed coverage at the nominal level) for progressive type II censoring and has been shown by simulation to be exact for general independent right censoring. In this paper, we modify the BPCP to create a mid-p' version, which reduces to the mid-p confidence interval for a binomial parameter when there is no censoring. We perform extensive simulations on both the standard and mid-p BPCP using a method of moments implementation that enforces monotonicity over time. All simulated scenarios suggest that the standard BPCP is exact. The mid-p BPCP, like other mid-p confidence intervals, has simulated coverage closer to the nominal level but may not be exact for all survival times, especially in very low censoring scenarios. In contrast, the two asymptotically-based approximations have lower than nominal coverage in many scenarios. This poor coverage is due to the extreme inflation of the lower error rates, although the upper limits are very conservative. Both the standard and the mid-p BPCP methods are available in our R package. Published 2016. This article is US Government work and is in the public domain in the USA. C1 [Fay, Michael P.; Brittain, Erica H.] NIAID, 5601 Fishers Lane,MSC 9820, Bethesda, MD 20892 USA. RP Fay, MP (reprint author), NIAID, 5601 Fishers Lane,MSC 9820, Bethesda, MD 20892 USA. EM mfay@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 FU Intramural NIH HHS [Z99 AI999999] NR 23 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUL 20 PY 2016 VL 35 IS 16 BP 2726 EP 2740 DI 10.1002/sim.6905 PG 15 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DP5PJ UT WOS:000378549200004 PM 26891706 ER PT J AU Chen, L Weinberg, CR Chen, JB AF Chen, Lu Weinberg, Clarice R. Chen, Jinbo TI Using family members to augment genetic case-control studies of a life-threatening disease SO STATISTICS IN MEDICINE LA English DT Article DE case-control study; family genetic data; non-ignorable missingness; retrospective maximum likelihood; survival bias ID HARDY-WEINBERG EQUILIBRIUM; ASSOCIATIONS; DESIGNS AB Survival bias is difficult to detect and adjust for in case-control genetic association studies but can invalidate findings when only surviving cases are studied and survival is associated with the genetic variants under study. Here, we propose a design where one genotypes genetically informative family members (such as offspring, parents, and spouses) of deceased cases and incorporates that surrogate genetic information into a retrospective maximum likelihood analysis. We show that inclusion of genotype data from first-degree relatives permits unbiased estimation of genotype association parameters. We derive closed-form maximum likelihood estimates for association parameters under the widely used log-additive and dominant association models. Our proposed design not only permits a valid analysis but also enhances statistical power by augmenting the sample with indirectly studied individuals. Gene variants associated with poor prognosis can also be identified under this design. We provide simulation results to assess performance of the methods. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Chen, Lu; Chen, Jinbo] Univ Penn, Sch Med, Dept Biostat & Epidemiol, 203 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Weinberg, Clarice R.] Natl Inst Environm Hlth, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Chen, L (reprint author), Univ Penn, Sch Med, Dept Biostat & Epidemiol, 203 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM chenlu6@mail.med.upenn.edu FU NIH [ES016626/ES020811]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES040007]; [FAS 0703856] FX We thank Dr. David Umbach for his useful comments. This research was supported in part by the NIH grants ES016626/ES020811 (for LC and JC) and Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, under project number Z01 ES040007 (for CRW) and by Susan G. Komen for the Cure (grant FAS 0703856). NR 18 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUL 20 PY 2016 VL 35 IS 16 BP 2815 EP 2830 DI 10.1002/sim.6888 PG 16 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DP5PJ UT WOS:000378549200010 PM 26866629 ER PT J AU Huang, YT Cai, TX Kim, E AF Huang, Yen-Tsung Cai, Tianxi Kim, Eunhee TI Integrative genomic testing of cancer survival using semiparametric linear transformation models SO STATISTICS IN MEDICINE LA English DT Article DE integrative genomics; linear transformation model; mediation analysis; survival analysis; variance component test ID FAILURE TIME DATA; GENE-EXPRESSION; DNA METHYLATION; REGRESSION-MODELS; COMPLEX DISEASES; JOINT ANALYSIS; CENSORED-DATA; GLIOBLASTOMA; MEDIATION; ASSOCIATION AB The wide availability of multi-dimensional genomic data has spurred increasing interests in integrating multi-platform genomic data. Integrative analysis of cancer genome landscape can potentially lead to deeper understanding of the biological process of cancer. We integrate epigenetics (DNA methylation and microRNA expression) and gene expression data in tumor genome to delineate the association between different aspects of the biological processes and brain tumor survival. To model the association, we employ a flexible semiparametric linear transformation model that incorporates both the main effects of these genomic measures as well as the possible interactions among them. We develop variance component tests to examine different coordinated effects by testing various subsets of model coefficients for the genomic markers. A Monte Carlo perturbation procedure is constructed to approximate the null distribution of the proposed test statistics. We further propose omnibus testing procedures to synthesize information from fitting various parsimonious sub-models to improve power. Simulation results suggest that our proposed testing procedures maintain proper size under the null and outperform standard score tests. We further illustrate the utility of our procedure in two genomic analyses for survival of glioblastoma multiforme patients. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Huang, Yen-Tsung] Brown Univ, Dept Epidemiol, 121 South Main St Box G-S121-2, Providence, RI 02912 USA. [Huang, Yen-Tsung] Brown Univ, Dept Biostat, 121 South Main St Box G-S121-2, Providence, RI 02912 USA. [Cai, Tianxi] Harvard Univ, Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. [Kim, Eunhee] NINDS, Off Biostat, NIH, 10 Ctr Dr,Bldg 10,Rm 5N230, Bethesda, MD 20892 USA. RP Huang, YT (reprint author), Brown Univ, Dept Epidemiol, 121 South Main St Box G-S121-2, Providence, RI 02912 USA.; Huang, YT (reprint author), Brown Univ, Dept Biostat, 121 South Main St Box G-S121-2, Providence, RI 02912 USA. EM Yen-Tsung_Huang@brown.edu FU National Institutes of Health [R03CA182937, R01AG048825] FX The authors are grateful to the editor, the associate editor and two anonymous referees for their insightful comments that improved the presentation of the paper. This study is supported by National Institutes of Health grants R03CA182937 and R01AG048825. NR 34 TC 0 Z9 0 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUL 20 PY 2016 VL 35 IS 16 BP 2831 EP 2844 DI 10.1002/sim.6900 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DP5PJ UT WOS:000378549200011 PM 26887583 ER PT J AU Zhang, Z Liu, L Gomez-Casal, R Wang, XH Hayashi, R Appella, E Kopelovich, L DeLeo, AB AF Zhang, Zhan Liu, Ling Gomez-Casal, Roberto Wang, Xinhui Hayashi, Ryo Appella, Ettore Kopelovich, Levy DeLeo, Albert B. TI Targeting cancer stem cells with p53 modulators SO ONCOTARGET LA English DT Article DE CP-31398; PRIMA-1; cancer stem cells; P53 vaccine; T cells ID TUMOR-SUPPRESSOR FUNCTION; ALDEHYDE DEHYDROGENASE 1; HSP90 ATPASE ACTIVITY; BREAST-CANCER; MUTANT P53; RETINOIC ACID; CP-31398; ANTIGEN; PRIMA-1; MARKER AB Cancer stem cells (CSC) typically over-express aldehyde dehydrogenase (ALDH). Thus, ALDH(bright) tumor cells represent targets for developing novel cancer prevention/treatment interventions. Loss of p53 function is a common genetic event during cancer development wherein small molecular weight compounds (SMWC) that restore p53 function and reverse tumor growth have been identified. Here, we focused on two widely studied p53 SMWC, CP-31398 and PRIMA-1, to target ALDHbright CSC in human breast, endometrial and pancreas carcinoma cell lines expressing mutant or wild type (WT) p53. CP-31398 and PRIMA-1 significantly reduced CSC content and sphere formation by these cell lines in vitro. In addition, these agents were more effective in vitro against CSC compared to cisplatin and gemcitabine, two often-used chemotherapeutic agents. We also tested a combinatorial treatment in methylcholantrene (MCA)-treated mice consisting of p53 SMWC and p53-based vaccines. Yet using survival end-point analysis, no increased efficacy in the presence of either p53 SMWC alone or with vaccine compared to vaccine alone was observed. These results may be due, in part, to the presence of immune cells, such as activated lymphocytes expressing WT p53 at levels comparable to some tumor cells, wherein further increase of p53 expression by p53 SMWC may alter survival of these immune cells and negatively impact an effective immune response. Continuous exposure of mice to MCA may have also interfered with the action of these p53 SMWC, including potential direct interaction with MCA. Nonetheless, the effect of p53 SMWC on CSC and cancer treatment remains of great interest. C1 [Zhang, Zhan; Liu, Ling] Zhengzhou Univ, Affiliated Hosp 3, Dept Obstet & Gynecol, Zhengzhou, Henan, Peoples R China. [Liu, Ling; Wang, Xinhui] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02115 USA. [Gomez-Casal, Roberto; DeLeo, Albert B.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Gomez-Casal, Roberto; DeLeo, Albert B.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. [Hayashi, Ryo; Appella, Ettore] NCI, Bethesda, MD 20892 USA. [Kopelovich, Levy] Weill Cornell Med Coll, Dept Med, New York, NY USA. RP Wang, XH (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02115 USA. EM xwang30@mgh.harvard.edu FU NCI [CN-433008]; Massachusetts General Hospital ECOR Deliberative Interim Support Funding [NCI R21 CA181851]; China Scholarship Council (CSC) [201407040027] FX Funded by NCI contract CN-433008 (A.B.D.), Massachusetts General Hospital ECOR Deliberative Interim Support Funding (X.W.), NCI R21 CA181851 (X.W.) and China Scholarship Council (CSC No. 201407040027) (L.L.). NR 44 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 19 PY 2016 VL 7 IS 29 BP 45079 EP 45093 DI 10.18632/oncotarget.8650 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8SX UT WOS:000385402300020 PM 27074569 ER PT J AU Wang, DR Qian, XL Rajaram, M Durkin, ME Lowy, DR AF Wang, Dunrui Qian, Xiaolan Rajaram, Megha Durkin, Marian E. Lowy, Douglas R. TI DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers SO ONCOTARGET LA English DT Article DE RhoGAP; tumor suppressor; bioinformatics; DLC genes; TCGA ID GTPASE-ACTIVATING PROTEIN; TUMOR-SUPPRESSOR GENE; HEPATOCELLULAR-CARCINOMA; LUNG-CANCER; CELL-GROWTH; RHO-GTPASES; TRANSFORMATION; INHIBITION; EXPRESSION; GENOMICS AB The RHO family of RAS-related GTPases in tumors may be activated by reduced levels of RHO GTPase accelerating proteins (GAPs). One common mechanism is decreased expression of one or more members of the Deleted in Liver Cancer (DLC) family of Rho-GAPs, which comprises three closely related genes (DLC1, DLC2, and DLC3) that are down-regulated in a wide range of malignancies. Here we have studied their comparative biological activity in cultured cells and used publicly available datasets to examine their mRNA expression patterns in normal and cancer tissues, and to explore their relationship to cancer phenotypes and survival outcomes. In The Cancer Genome Atlas (TCGA) database, DLC1 expression predominated in normal lung, breast, and liver, but not in colorectum. Conversely, reduced DLC1 expression predominated in lung squamous cell carcinoma (LSC), lung adenocarcinoma (LAD), breast cancer, and hepatocellular carcinoma (HCC), but not in colorectal cancer. Reduced DLC1 expression was frequently associated with promoter methylation in LSC and LAD, while DLC1 copy number loss was frequent in HCC. DLC1 expression was higher in TCGA LAD patients who remained cancer-free, while low DLC1 had a poorer prognosis than low DLC2 or low DLC3 in a more completely annotated database. The poorest prognosis was associated with low expression of both DLC1 and DLC2 (P < 0.0001). In cultured cells, the three genes induced a similar reduction of Rho-GTP and cell migration. We conclude that DLC1 is the predominant family member expressed in several normal tissues, and its expression is preferentially reduced in common cancers at these sites. C1 [Wang, Dunrui; Qian, Xiaolan; Rajaram, Megha; Durkin, Marian E.; Lowy, Douglas R.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rajaram, Megha] BioTek Instruments Inc, Winooski, VT 05404 USA. RP Lowy, DR (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM LowyD@mail.nih.gov FU Intramural Research Program of Center for Cancer Research, National Cancer Institute, NIH FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH NR 41 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 19 PY 2016 VL 7 IS 29 BP 45144 EP 45157 DI 10.18632/oncotarget.9266 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8SX UT WOS:000385402300025 PM 27174913 ER PT J AU Leigh, R Christensen, S Campbell, BCV Marks, MP Albers, GW Lansberg, MG AF Leigh, Richard Christensen, Soren Campbell, Bruce C. V. Marks, Michael P. Albers, Gregory W. Lansberg, Maarten G. CA DEFUSE 2 Investigators TI Pretreatment blood-brain barrier disruption and post-endovascular intracranial hemorrhage SO NEUROLOGY LA English DT Article ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; INTRAVENOUS T-PA; IMAGING SELECTION; CEREBRAL BLOOD; THERAPY; TRANSFORMATION; PERMEABILITY; MRI; THROMBOLYSIS AB Objective: This study sought to confirm the relationship between the degree of blood-brain barrier (BBB) damage and the severity of intracranial hemorrhage (ICH) in a population of patients who received endovascular therapy. Methods: The degree of BBB disruption on pretreatment MRI scans was analyzed, blinded to follow-up data, in the DEFUSE 2 cohort in which patients had endovascular therapy within 12 hours of stroke onset. BBB disruption was compared with ICH grade previously established by the DEFUSE 2 core lab. A prespecified threshold for predicting parenchymal hematoma (PH) was tested. Results: Of the 108 patients in the DEFUSE 2 trial, 100 had adequate imaging and outcome data and were included in this study; 24 developed PH. Increasing amounts of BBB disruption on pretreatment MRIs was associated with increasing severity of ICH grade (p = 0.004). BBB disruption on the pretreatment scan was associated with PH (p = 0.020) with an odds ratio for developing PH of 1.69 for each 10% increase in BBB disruption (95% confidence interval 1.09-2.64), although a reliably predictive threshold was not identified. Conclusions: The amount of BBB disruption on pretreatment MRI is associated with the severity of ICH after acute intervention. This relationship has now been identified in patients receiving IV, endovascular, and combined therapies. Further study is needed to determine its role in guiding treatment. C1 [Leigh, Richard] NINDS, Neuro Vasc Brain Imaging Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Christensen, Soren; Albers, Gregory W.; Lansberg, Maarten G.] Stanford Univ, Stanford Stroke Ctr, Dept Neurol & Neurol Sci, Palo Alto, CA 94304 USA. [Campbell, Bruce C. V.] Univ Melbourne, Royal Melbourne Hosp, Dept Med & Neurol, Melbourne, Vic 3010, Australia. [Marks, Michael P.] Stanford Univ, Med Ctr, Dept Radiol, Stanford, CA 94305 USA. RP Leigh, R (reprint author), NINDS, Neuro Vasc Brain Imaging Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM richard.leigh@nih.gov FU Intramural Program of NIH, NINDS; National Institute for Neurological Disorders and Stroke [R01 NS03932505, K23 NS051372]; National Health and Medical Research Council of Australia FX Dr. Leigh is supported by the Intramural Program of NIH, NINDS. Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2 (DEFUSE 2) was funded by grants from the National Institute for Neurological Disorders and Stroke (R01 NS03932505 to Dr. Albers and K23 NS051372 to Dr. Lansberg). Dr. Campbell reports funding of the National Health and Medical Research Council of Australia. NR 22 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 19 PY 2016 VL 87 IS 3 BP 263 EP 269 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DT4SQ UT WOS:000381471600010 PM 27316247 ER PT J AU Speake, C Pichugin, A Sahu, T Malkov, V Morrison, R Pei, Y Juompan, L Milman, N Zarling, S Anderson, C Wong-Madden, S Wendler, J Ishizuka, A MacMillen, ZW Garcia, V Kappe, SHI Krzych, U Duffy, PE AF Speake, Cate Pichugin, Alexander Sahu, Tejram Malkov, Vlad Morrison, Robert Pei, Ying Juompan, Laure Milman, Neta Zarling, Stasya Anderson, Charles Wong-Madden, Sharon Wendler, Jason Ishizuka, Andrew MacMillen, Zachary W. Garcia, Valentino Kappe, Stefan H. I. Krzych, Urszula Duffy, Patrick E. TI Identification of Novel Pre-Erythrocytic Malaria Antigen Candidates for Combination Vaccines with Circumsporozoite Protein SO PLOS ONE LA English DT Article ID PLASMODIUM-BERGHEI MALARIA; PROBE LEVEL DATA; CD8(+) T-CELLS; NAIVE ADULTS; IMMUNE-RESPONSES; IRRADIATED SPOROZOITES; PROTECTIVE IMMUNITY; FALCIPARUM-MALARIA; STERILE IMMUNITY; LIVER STAGES AB Malaria vaccine development has been hampered by the limited availability of antigens identified through conventional discovery approaches, and improvements are needed to enhance the efficacy of the leading vaccine candidate RTS, S that targets the circumsporozoite protein (CSP) of the infective sporozoite. Here we report a transcriptome-based approach to identify novel pre-erythrocytic vaccine antigens that could potentially be used in combination with CSP. We hypothesized that stage-specific upregulated genes would enrich for protective vaccine targets, and used tiling microarray to identify P. falciparum genes transcribed at higher levels during liver stage versus sporozoite or blood stages of development. We prepared DNA vaccines for 21 genes using the predicted orthologues in P. yoelii and P. berghei and tested their efficacy using different delivery methods against pre-erythrocytic malaria in rodent models. In our primary screen using P. yoelii in BALB/c mice, we found that 16 antigens significantly reduced liver stage parasite burden. In our confirmatory screen using P. berghei in C57Bl/6 mice, we confirmed 6 antigens that were protective in both models. Two antigens, when combined with CSP, provided significantly greater protection than CSP alone in both models. Based on the observations reported here, transcriptional patterns of Plasmodium genes can be useful in identifying novel pre-erythrocytic antigens that induce protective immunity alone or in combination with CSP. C1 [Speake, Cate; Malkov, Vlad; Pei, Ying; Milman, Neta; Wendler, Jason; Ishizuka, Andrew; MacMillen, Zachary W.; Garcia, Valentino; Kappe, Stefan H. I.] Seattle Biomed Res Inst, 4 Nickerson St, Seattle, WA 98109 USA. [Pichugin, Alexander; Juompan, Laure; Zarling, Stasya; Krzych, Urszula] Walter Reed Army Inst Res, Dept Cellular Immunol, Silver Spring, MD USA. [Sahu, Tejram; Morrison, Robert; Anderson, Charles; Wong-Madden, Sharon; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Duffy, PE (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM duffype@niaid.nih.gov FU PATH Malaria Vaccine Initiative; Intramural Research Program of NIAID, NIH; Military Infectious Diseases Research Program of Walter Reed Army Institute of Research FX The work was funded in part by the PATH Malaria Vaccine Initiative, by the Intramural Research Program of NIAID, NIH and the Military Infectious Diseases Research Program of Walter Reed Army Institute of Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 1 Z9 1 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 19 PY 2016 VL 11 IS 7 AR e0159449 DI 10.1371/journal.pone.0159449 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR8TG UT WOS:000380169600053 PM 27434123 ER PT J AU Mark, DB Federspiel, JJ Cowper, PA Anstrom, KJ Hoffmann, U Patel, MR Davidson-Ray, L Daniels, MR Cooper, LS Knight, JD Lee, KL Douglas, PS AF Mark, Daniel B. Federspiel, Jerome J. Cowper, Patricia A. Anstrom, Kevin J. Hoffmann, Udo Patel, Manesh R. Davidson-Ray, Linda Daniels, Melanie R. Cooper, Lawton S. Knight, J. David Lee, Kerry L. Douglas, Pamela S. CA PROMISE Investigators TI Economic Outcomes With Anatomical Versus Functional Diagnostic Testing for Coronary Artery Disease SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ANGIOGRAPHY; METAANALYSIS; ACCURACY; ECHOCARDIOGRAPHY; MANAGEMENT; ANGINA AB Background: PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) found that initial use of at least 64-slice multidetector computed tomography angiography (CTA) versus functional diagnostic testing strategies did not improve clinical outcomes in stable symptomatic patients with suspected coronary artery disease (CAD) requiring noninvasive testing. Objective: To conduct an economic analysis for PROMISE (a major secondary aim of the study). Design: Prospective economic study from the U.S. perspective. Comparisons were made according to the intention-to-treat principle, and CIs were calculated using bootstrap methods. (ClinicalTrials.gov: NCT01174550) Setting: 190 U.S. centers. Patients: 9649 U.S. patients enrolled in PROMISE between July 2010 and September 2013. Median follow-up was 25 months. Measurements: Technical costs of the initial (outpatient) testing strategy were estimated from Premier Research Database data. Hospital-based costs were estimated using hospital bills and Medicare cost-charge ratios. Physician fees were taken from the Medicare Physician Fee Schedule. Costs were expressed in 2014 U.S. dollars, discounted at 3% annually, and estimated out to 3 years using inverse probability weighting methods. Results: The mean initial testing costs were $174 for exercise electrocardiography; $404 for CTA; $501 to $514 for pharmacologic and exercise stress echocardiography, respectively; and $946 to $1132 for exercise and pharmacologic stress nuclear testing, respectively. Mean costs at 90 days were $2494 for the CTA strategy versus $2240 for the functional strategy (mean difference, $254 [95% CI, -$634 to $906]). The difference was associated with more revascularizations and catheterizations (4.25 per 100 patients) with CTA use. After 90 days, the mean cost difference between the groups out to 3 years remained small. Limitation: Cost weights for test strategies were obtained from sources outside PROMISE. Conclusion: Computed tomography angiography and functional diagnostic testing strategies in patients with suspected CAD have similar costs through 3 years of follow-up. C1 Duke Univ, Med Ctr, Duke Clin Res Inst, Outcomes Res Grp, Durham, NC USA. Duke Univ, Durham, NC USA. Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Cooper, Lawton S.] NHLBI, RKL2 BG RM 10108,6701 Rockledge Dr, Bethesda, MD 20817 USA. [Mark, Daniel B.; Federspiel, Jerome J.; Cowper, Patricia A.; Anstrom, Kevin J.; Patel, Manesh R.; Davidson-Ray, Linda; Daniels, Melanie R.; Knight, J. David; Lee, Kerry L.; Douglas, Pamela S.] Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. [Hoffmann, Udo] Radiol Associates, 55 Fruit St, Boston, MA 02114 USA. RP Mark, DB (reprint author), Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. OI Picard, Michael/0000-0002-9264-3243 FU National Heart, Lung, and Blood Institute FX National Heart, Lung, and Blood Institute. NR 13 TC 6 Z9 6 U1 1 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 19 PY 2016 VL 165 IS 2 BP 94 EP + DI 10.7326/M15-2639 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA DS2GY UT WOS:000380583100016 PM 27214597 ER PT J AU Zhao, R Grunke, SD Keralapurath, MM Yetman, MJ Lam, A Lee, TC Sousounis, K Jiang, YY Swing, DA Tessarollo, L Ji, DY Jankowsky, JL AF Zhao, Rong Grunke, Stacy D. Keralapurath, Madhusudhanan M. Yetman, Michael J. Lam, Alexander Lee, Tang-Cheng Sousounis, Konstantinos Jiang, Yongying Swing, Deborah A. Tessarollo, Lino Ji, Daoyun Jankowsky, Joanna L. TI Impaired Recall of Positional Memory following Chemogenetic Disruption of Place Field Stability SO CELL REPORTS LA English DT Article ID MEDIAL ENTORHINAL CORTEX; GATED ION CHANNELS; SPATIAL MEMORY; RETROSPLENIAL CORTEX; P-GLYCOPROTEIN; UNIT-ACTIVITY; HIPPOCAMPUS; INACTIVATION; IVERMECTIN; CELLS AB The neural network of the temporal lobe is thought to provide a cognitive map of our surroundings. Functional analysis of this network has been hampered by coarse tools that often result in collateral damage to other circuits. We developed a chemogenetic system to temporally control electrical input into the hippocampus. When entorhinal input to the perforant path was acutely silenced, hippocampal firing patterns became destabilized and underwent extensive remapping. We also found that spatial memory acquired prior to neural silencing was impaired by loss of input through the perforant path. Together, our experiments show that manipulation of entorhinal activity destabilizes spatial coding and disrupts spatial memory. Moreover, we introduce a chemogenetic model for non-invasive neuronal silencing that offers multiple advantages over existing strategies in this setting. C1 [Zhao, Rong; Grunke, Stacy D.; Keralapurath, Madhusudhanan M.; Yetman, Michael J.; Lam, Alexander; Lee, Tang-Cheng; Sousounis, Konstantinos; Ji, Daoyun; Jankowsky, Joanna L.] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. [Ji, Daoyun] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Jankowsky, Joanna L.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Jankowsky, Joanna L.] Baylor Coll Med, Dept Neurosurg, Houston, TX 77030 USA. [Jankowsky, Joanna L.] Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA. [Lam, Alexander] Rice Univ, Dept Cognit Sci, Houston, TX 77251 USA. [Jiang, Yongying] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77054 USA. [Swing, Deborah A.; Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Ji, DY; Jankowsky, JL (reprint author), Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA.; Ji, DY (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.; Jankowsky, JL (reprint author), Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA.; Jankowsky, JL (reprint author), Baylor Coll Med, Dept Neurosurg, Houston, TX 77030 USA.; Jankowsky, JL (reprint author), Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA. EM dji@bcm.edu; jankowsk@bcm.edu OI Sousounis, Konstantinos/0000-0002-5577-6207 FU NIH Director's New Innovator Award [DP2 OD001734, R21 MH101583, T32 AG000183]; Bright-Focus Foundation postdoctoral fellowship [A2015016F]; Baylor College of Medicine; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Henry Lester for initially harnessing cys-loop receptors for neuronal silencing, Timothy Lynagh and Joseph Lynch for sharing their optimized F207A/A288G GlyCl cDNA, Roy Sillitoe for expert guidance on cerebellar anatomy, Mark Mayford and Karsten Baumgartel for sharing the Nop-tTA line, Hunter Allen for assistance screening founder lines, and Bryan Song and Rebecca Corrigan for excellent care of the animal colony. This work was funded by an NIH Director's New Innovator Award DP2 OD001734 (J.L.J.), R21 MH101583 (J.L.J.), T32 AG000183 (support for S.D.G. and M.J.Y.), Bright-Focus Foundation postdoctoral fellowship A2015016F (S.D.G.), a gift from the Gillson Longenbaugh Foundation, and seed funds from Baylor College of Medicine (J.L.J.). D.A.S. and L.T. were supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 53 TC 5 Z9 5 U1 2 U2 3 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 JUL 19 PY 2016 VL 16 IS 3 BP 793 EP 804 DI 10.1016/j.celrep.2016.06.032 PG 12 WC Cell Biology SC Cell Biology GA DS0CY UT WOS:000380264200018 PM 27373150 ER PT J AU Gunier, RB Nuckols, JR Whitehead, TP Colt, JS Deziel, NC Metayer, C Reynolds, P Ward, MH AF Gunier, Robert B. Nuckols, John R. Whitehead, Todd P. Colt, Joanne S. Deziel, Nicole C. Metayer, Catherine Reynolds, Peggy Ward, Mary H. TI Temporal Trends of Insecticide Concentrations in Carpet Dust in California from 2001 to 2006 SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID IN-HOUSE DUST; PESTICIDE CONCENTRATIONS; RESIDENTIAL EXPOSURE; FARMWORKER CHILDREN; PRESCHOOL-CHILDREN; HOMES; ORGANOPHOSPHATES; ORGANOCHLORINES; CHLORPYRIFOS; PYRETHROIDS AB Active ingredients in residential and agricultural insecticides have changed over time, due in part to regulatory restrictions. Few studies have evaluated how changes in active ingredients have impacted insecticide levels measured in.homes. We measured concentrations of insecticides in one carpet dust sample from each of 434 homes in California from 2001 to 2006. Analytes included four insecticides sold for indoor home use during our study period (carbaryl, cypermethrin, permethrin, and propoxur) and four that are no longer sold for indoor use including dichlorodiphenyltrichloroethylene (DDT, removed from the market in 1972), chlordane (1988), chlorpyrifos (2001), and diazinon (2004). We considered other potential determinants of concentrations of insecticides in carpet dust, such as home and garden use, occupational exposure; and nearby agricultural applications. We calculated the percentage change in the concentration of each insecticide per year, adjusting for significant determinants. In adjusted models, concentrations of insecticides in carpet dust decreased for three of four insecticides no longer sold for residential use: chlordane (-15% per year), chlorpyrifos (-31%), diazinon (-48%), and propoxur (-34%), which is currently sold for residential use but with increased restrictions since 1997. Concentrations of other insecticides sold for indoor use (carbaryl, cypermethrin, and permethrin) and DDT did not change over time in our study population. C1 [Gunier, Robert B.; Whitehead, Todd P.; Metayer, Catherine] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94704 USA. [Nuckols, John R.] Colorado State Univ, Environm Hlth Sci, Ft Collins, CO 80523 USA. [Nuckols, John R.] JRN Environm Hlth Sci, North Bethesda, MD USA. [Colt, Joanne S.; Deziel, Nicole C.; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Deziel, Nicole C.] Yale Sch Publ Hlth, New Haven, CT 06520 USA. [Reynolds, Peggy] Canc Prevent Inst Calif, Berkeley, CA 94538 USA. RP Gunier, RB (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94704 USA. EM gunier@berkeley.edu FU National Institute of Environmental Health Sciences [R01ES09137, P42-ES04705]; National Cancer Institute [5R01CA092683, R01CA92674] FX This research was supported by the National Institute of Environmental Health Sciences, grants R01ES09137 (P. Buffler, UCB, PI) and P42-ES04705 (P. Buffler, UCB, PI), the National Cancer Institute intramural research program (M. Ward, PI), and grant numbers 5R01CA092683 (J.R. Nuckols, CSU, PI) and R01CA92674 (P. Reynolds, CPIC, PI). This research could not have been conducted without the strong support from our clinical collaborators, participating hospitals, and the families of study participants. The opinions given by the authors are not necessarily those of the funding agencies. NR 41 TC 0 Z9 0 U1 11 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD JUL 19 PY 2016 VL 50 IS 14 BP 7761 EP 7769 DI 10.1021/acs.est.6b00252 PG 9 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA DS0OD UT WOS:000380295700055 PM 27341453 ER PT J AU Gieseck, RL Ramalingam, TR Hart, KM Vannella, KM Cantu, DA Lu, WY Ferreira-Gonzalez, S Forbes, SJ Vallier, L Wynn, TA AF Gieseck, Richard L., III Ramalingam, Thirumalai R. Hart, Kevin M. Vannella, Kevin M. Cantu, David A. Lu, Wei-Yu Ferreira-Gonzalez, Sofia Forbes, Stuart J. Vallier, Ludovic Wynn, Thomas A. TI Interleukin-13 Activates Distinct Cellular Pathways Leading to Ductular Reaction, Steatosis, and Fibrosis SO IMMUNITY LA English DT Article ID SEVERE ATOPIC-DERMATITIS; HEPATIC STELLATE CELLS; STEM-CELLS; EPITHELIAL INJURY; PROGENITOR CELLS; GROWTH-FACTOR; DOUBLE-BLIND; LIVER; IL-13; MICE AB Fibroproliferative diseases are driven by dysregulated tissue repair responses and are a major cause of morbidity and mortality because they affect nearly every organ system. Type 2 cytokine responses are critically involved in tissue repair; however, the mechanisms that regulate beneficial regeneration versus pathological fibrosis are not well understood. Here, we have shown that the type 2 effector cytokine interleukin-13 simultaneously, yet independently, directed hepatic fibrosis and the compensatory proliferation of hepatocytes and biliary cells in progressive models of liver disease induced by interleukin-13 overexpression or after infection with Schistosoma mansoni. Using transgenic mice with interleukin-13 signaling genetically disrupted in hepatocytes, cholangiocytes, or resident tissue fibroblasts, we have revealed direct and distinct roles for interleukin-13 in fibrosis, steatosis, cholestasis, and ductular reaction. Together, these studies show that these mechanisms are simultaneously controlled but distinctly regulated by interleukin-13 signaling. Thus, it may be possible to promote interleukin-13-dependent hepatobiliary expansion without generating pathological fibrosis. C1 [Gieseck, Richard L., III; Ramalingam, Thirumalai R.; Hart, Kevin M.; Vannella, Kevin M.; Cantu, David A.; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20852 USA. [Gieseck, Richard L., III; Vallier, Ludovic] Univ Cambridge, Dept Surg, Anne McLaren Lab, MRC,Wellcome Trust,Stem Cell Inst, Cambridge CB2 0SZ, England. [Lu, Wei-Yu; Ferreira-Gonzalez, Sofia; Forbes, Stuart J.] Univ Edinburgh, MRC, Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland. [Vallier, Ludovic] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20852 USA. EM twynn@niaid.nih.gov OI Gieseck, Richard/0000-0003-0200-581X FU Intramural Research Program of the NIH, National Institute of Allergy and Infectious Disease; ERC; Cambridge Hospitals National Institute for Health Research Biomedical Research Center; UKRMP Hub; Medical Research Council FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Disease. L.V. is funded by the ERC starting grant Relieve IMDs and the Cambridge Hospitals National Institute for Health Research Biomedical Research Center. S.J.F. is funded by the UKRMP Hub and Medical Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Frank Brombacher for sharing the IL-4R alpha-floxed mice. NR 53 TC 5 Z9 5 U1 4 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUL 19 PY 2016 VL 45 IS 1 BP 145 EP 158 DI 10.1016/j.immuni.2016.06.009 PG 14 WC Immunology SC Immunology GA DS4KC UT WOS:000380749000017 PM 27421703 ER PT J AU Woytschak, J Keller, N Krieg, C Impellizzieri, D Thompson, RW Wynn, TA Zinkernagel, AS Boyman, O AF Woytschak, Janine Keller, Nadia Krieg, Carsten Impellizzieri, Daniela Thompson, Robert W. Wynn, Thomas A. Zinkernagel, Annelies S. Boyman, Onur TI Type 2 Interleukin-4 Receptor Signaling in Neutrophils Antagonizes Their Expansion and Migration during Infection and Inflammation SO IMMUNITY LA English DT Article ID ATOPIC-DERMATITIS; IN-VIVO; ALLERGIC INFLAMMATION; ANTIBODY COMPLEXES; IMMUNE-RESPONSES; MYELOID CELLS; IL-4; ACTIVATION; INNATE; MECHANISMS AB Neutrophils are the first immune cells recruited to sites of inflammation and infection. However, patients with allergic disorders such as atopic dermatitis show a paucity of skin neutrophils and are prone to bacterial skin infections, suggesting that allergic inflammation curtails neutrophil responses. Here we have shown that the type 2 cell signature cytokine interleukin-4 (IL-4) hampers neutrophil expansion and migration by antagonizing granulocyte colony-stimulating factor (G-CSF) and chemokine receptor-mediated signals. Cutaneous bacterial infection in mice was exacerbated by IL-4 signaling and improved with IL-4 inhibition, each outcome inversely correlating with neutrophil migration to skin. Likewise, systemic bacterial infection was worsened by heightened IL-4 activity, with IL-4 restricting G-CSF-induced neutrophil expansion and migration to tissues by affecting CXCR2-CXCR4 chemokine signaling in neutrophils. These effects were dependent on IL-4 acting through type 2 IL-4 receptors on neutrophils. Thus, targeting IL-4 might be beneficial in neutropenic conditions with increased susceptibility to bacterial infections. C1 [Woytschak, Janine; Impellizzieri, Daniela; Boyman, Onur] Univ Zurich, Univ Zurich Hosp, Dept Immunol, CH-8091 Zurich, Switzerland. [Keller, Nadia; Zinkernagel, Annelies S.] Univ Zurich, Univ Zurich Hosp, Dept Infect Dis, CH-8091 Zurich, Switzerland. [Krieg, Carsten] Univ Zurich, Inst Expt Immunol, CH-8057 Zurich, Switzerland. [Thompson, Robert W.; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Program Barrier Immun & Repair, Lab Parasit Dis,NIH, Bethesda, MD 20892 USA. RP Boyman, O (reprint author), Univ Zurich, Univ Zurich Hosp, Dept Immunol, CH-8091 Zurich, Switzerland. EM onur.boyman@uzh.ch RI Infektiologie, USZ/A-6921-2011; Zinkernagel, Annelies/F-1780-2017; OI Boyman, Onur/0000-0001-8279-5545 FU Swiss National Science Foundation [PP00P3-128421, PP00P3-150751, 310030-146295]; University of Zurich; Candoc fellowship of University of Zurich; Hochspezialisierte Medizin Schwerpunkt Immunologie (HSM-2-Immunologie) FX We thank Daniel Legler and the members of the O.B. laboratory for helpful discussions and critical reading of the manuscript. We thank Emerita Ammann Meier for excellent technical assistance and Sandra Seyfferth for help with typing the manuscript. This study was funded by Swiss National Science Foundation grants PP00P3-128421, PP00P3-150751 (both to O.B.), and 310030-146295 (to A.S.Z.), a grant of University of Zurich (to O.B.), a Candoc fellowship of University of Zurich (to J.W.), and by Hochspezialisierte Medizin Schwerpunkt Immunologie (HSM-2-Immunologie; to O.B.). NR 52 TC 1 Z9 1 U1 8 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUL 19 PY 2016 VL 45 IS 1 BP 172 EP 184 DI 10.1016/j.immuni.2016.06.025 PG 13 WC Immunology SC Immunology GA DS4KC UT WOS:000380749000019 PM 27438770 ER PT J AU Presman, DM Ganguly, S Schiltz, RL Johnson, TA Karpova, TS Hager, GL AF Presman, Diego M. Ganguly, Sourav Schiltz, R. Louis Johnson, Thomas A. Karpova, Tatiana S. Hager, Gordon L. TI DNA binding triggers tetramerization of the glucocorticoid receptor in live cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE glucocorticoid receptor; steroid receptors; dimer; tetramer; number and brightness ID LIGAND-SPECIFIC DYNAMICS; LIVING CELLS; CHROMATIN ACCESSIBILITY; ANDROGEN RECEPTOR; TRANSCRIPTION; DOMAIN; DIMER; DIMERIZATION; COMPLEX; ELEMENT AB Transcription factors dynamically bind to chromatin and are essential for the regulation of genes. Although a large percentage of these proteins appear to self-associate to form dimers or higher order oligomers, the stoichiometry of DNA-bound transcription factors has been poorly characterized in vivo. The glucocorticoid receptor (GR) is a ligand-regulated transcription factor widely believed to act as a dimer or a monomer. Using a unique set of imaging techniques coupled with a cell line containing an array of DNA binding elements, we show that GR is predominantly a tetramer when bound to its target DNA. We find that DNA binding triggers an interdomain allosteric regulation within the GR, leading to tetramerization. We therefore propose that dynamic changes in GR stoichiometry represent a previously unidentified level of regulation in steroid receptor activation. Quaternary structure analysis of other members of the steroid receptor family (estrogen, androgen, and progesterone receptors) reveals variation in oligomerization states among this family of transcription factors. Because GR's oligomerization state has been implicated in therapy outcome, our findings open new doors to the rational design of novel GR ligands and redefine the quaternary structure of steroid receptors. C1 [Presman, Diego M.; Ganguly, Sourav; Schiltz, R. Louis; Johnson, Thomas A.; Karpova, Tatiana S.; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Ganguly, Sourav] Univ Calif Berkeley, Li Ka Shing Ctr, Berkeley, CA 94720 USA. RP Presman, DM; Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM presmandm@mail.nih.gov; hagerg@exchange.nih.gov OI Presman, Diego/0000-0003-4515-8058 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Myong-Hee Sung, Erin Swinstead, Ido Goldstein, Pablo Ariel, Tom Misteli, Dan Larson, and Valeria Levi for critical reading of the manuscript. We also thank Grzegorz Piszczek for technical assistance with the fluorometer and Tatsuya Morisaki and Davide Mazza for assembly of the HiLO scope. This research was supported by grants from the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 45 TC 2 Z9 2 U1 5 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 19 PY 2016 VL 113 IS 29 BP 8236 EP 8241 DI 10.1073/pnas.1606774113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR9NX UT WOS:000380224500071 PM 27382178 ER PT J AU Richard, AC Peters, JE Lee, JC Vahedi, G Schaffer, AA Siegel, RM Lyons, PA Smith, KGC AF Richard, Arianne C. Peters, James E. Lee, James C. Vahedi, Golnaz Schaeffer, Alejandro A. Siegel, Richard M. Lyons, Paul A. Smith, Kenneth G. C. TI Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network SO GENOME MEDICINE LA English DT Article DE TNF superfamily; Autoimmunity; Autoinflammation; Genomics; eQTL; Gene set analysis; GWAS; Genetics ID TUMOR-NECROSIS-FACTOR; SYSTEMIC-LUPUS-ERYTHEMATOSUS; INFLAMMATORY-BOWEL-DISEASE; PRIMARY BILIARY-CIRRHOSIS; GENE SET ANALYSIS; WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; CROHNS-DISEASE; LYMPHOPROLIFERATIVE SYNDROME; SUSCEPTIBILITY LOCI AB Background: Tumour necrosis factor (TNF) superfamily cytokines and their receptors regulate diverse immune system functions through a common set of signalling pathways. Genetic variants in and expression of individual TNF superfamily cytokines, receptors and signalling proteins have been associated with autoimmune and inflammatory diseases, but their interconnected biology has been largely unexplored. Methods: We took a hypothesis-driven approach using available genome-wide datasets to identify genetic variants regulating gene expression in the TNF superfamily cytokine signalling network and the association of these variants with autoimmune and autoinflammatory disease. Using paired gene expression and genetic data, we identified genetic variants associated with gene expression, expression quantitative trait loci (eQTLs), in four peripheral blood cell subsets. We then examined whether eQTLs were dependent on gene expression level or the presence of active enhancer chromatin marks. Using these eQTLs as genetic markers of the TNF superfamily signalling network, we performed targeted gene set association analysis in eight autoimmune and autoinflammatory disease genome-wide association studies. Results: Comparison of TNF superfamily network gene expression and regulatory variants across four leucocyte subsets revealed patterns that differed between cell types. eQTLs for genes in this network were not dependent on absolute gene expression levels and were not enriched for chromatin marks of active enhancers. By examining autoimmune disease risk variants among our eQTLs, we found that risk alleles can be associated with either increased or decreased expression of co-stimulatory TNF superfamily cytokines, receptors or downstream signalling molecules. Gene set disease association analysis revealed that eQTLs for genes in the TNF superfamily pathway were associated with six of the eight autoimmune and autoinflammatory diseases examined, demonstrating associations beyond single genome-wide significant hits. Conclusions: This systematic analysis of the influence of regulatory genetic variants in the TNF superfamily network reveals widespread and diverse roles for these cytokines in susceptibility to a number of immune-mediated diseases. C1 [Richard, Arianne C.; Peters, James E.; Lee, James C.; Lyons, Paul A.; Smith, Kenneth G. C.] Univ Cambridge, Dept Med, Box 139,Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0XY, England. [Richard, Arianne C.; Peters, James E.; Lee, James C.; Lyons, Paul A.; Smith, Kenneth G. C.] Univ Cambridge, Cambridge Inst Med Res, Box 139,Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0XY, England. [Richard, Arianne C.; Siegel, Richard M.] NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Vahedi, Golnaz] Univ Penn, Perelman Sch Med, Inst Immunol, Dept Genet, Philadelphia, PA 19104 USA. [Schaeffer, Alejandro A.] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Smith, KGC (reprint author), Univ Cambridge, Dept Med, Box 139,Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0XY, England.; Smith, KGC (reprint author), Univ Cambridge, Cambridge Inst Med Res, Box 139,Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0XY, England. EM kgcs2@cam.ac.uk FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Library of Medicine (NLM) of the NIH; Wellcome Trust [080327/Z/06/Z, 087007/Z/08/Z, 094227/Z/10/Z]; Medical Research Council [G0400929]; National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre; NIH-Oxford-Cambridge Scholars Program; Wellcome Trust Clinical PhD Programme; Wellcome Trust Strategic Award [079895] FX This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Library of Medicine (NLM) of the NIH, the Wellcome Trust (080327/Z/06/Z, 087007/Z/08/Z and 094227/Z/10/Z), the Medical Research Council (G0400929) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. KGCS is an NIHR Senior Investigator. ACR was funded by the NIH-Oxford-Cambridge Scholars Program. JEP and JCL were funded by the Wellcome Trust Clinical PhD Programme. The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (079895). NR 84 TC 1 Z9 1 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD JUL 19 PY 2016 VL 8 AR 76 DI 10.1186/s13073-016-0329-5 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA DR9IG UT WOS:000380209700001 PM 27435189 ER PT J AU Compton, WM Volkow, ND AF Compton, Wilson M. Volkow, Nora D. TI Improving Outcomes for Persons With Opioid Use Disorders Buprenorphine Implants to Improve Adherence and Access to Care SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CHRONIC PAIN; INTERVENTION C1 [Compton, Wilson M.; Volkow, Nora D.] NIDA, 6001 Execut Blvd,MSC 9581, Bethesda, MD 20892 USA. RP Compton, WM (reprint author), NIDA, 6001 Execut Blvd,MSC 9581, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov NR 11 TC 0 Z9 0 U1 5 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 19 PY 2016 VL 316 IS 3 BP 277 EP 279 DI 10.1001/jama.2016.8897 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DR3LN UT WOS:000379804800014 PM 27434440 ER PT J AU Menke, A Casagrande, S Cowie, CC AF Menke, Andy Casagrande, Sarah Cowie, Catherine C. TI Prevalence of Diabetes in Adolescents Aged 12 to 19 Years in the United States, 2005-2014 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID TYPE-2; YOUTH C1 [Menke, Andy; Casagrande, Sarah] Social & Sci Syst, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. [Cowie, Catherine C.] NIDDK, NIH, Bethesda, MD USA. RP Menke, A (reprint author), Social & Sci Syst, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. EM amenke@s-3.com FU PHS HHS [GS10F0381L] NR 6 TC 3 Z9 3 U1 3 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 19 PY 2016 VL 316 IS 3 BP 344 EP 345 DI 10.1001/jama.2016.8544 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DR3LN UT WOS:000379804800023 PM 27434447 ER PT J AU Frise, R Bradley, K van Doremalen, N Galiano, M Elderfield, RA Stilwell, P Ashcroft, JW Fernandez-Alonso, M Miah, S Lackenby, A Roberts, KL Donnelly, CA Barclay, WS AF Frise, Rebecca Bradley, Konrad van Doremalen, Neeltje Galiano, Monica Elderfield, Ruth A. Stilwell, Peter Ashcroft, Jonathan W. Fernandez-Alonso, Mirian Miah, Shahjahan Lackenby, Angie Roberts, Kim L. Donnelly, Christl A. Barclay, Wendy S. TI Contact transmission of influenza virus between ferrets imposes a looser bottleneck than respiratory droplet transmission allowing propagation of antiviral resistance SO SCIENTIFIC REPORTS LA English DT Article ID A VIRUS; MAMMALIAN ADAPTATION; AEROSOL TRANSMISSION; IN-VIVO; INFECTION; MUTATIONS; DIVERSITY; SELECTION; HUMANS; MODEL AB Influenza viruses cause annual seasonal epidemics and occasional pandemics. It is important to elucidate the stringency of bottlenecks during transmission to shed light on mechanisms that underlie the evolution and propagation of antigenic drift, host range switching or drug resistance. The virus spreads between people by different routes, including through the air in droplets and aerosols, and by direct contact. By housing ferrets under different conditions, it is possible to mimic various routes of transmission. Here, we inoculated donor animals with a mixture of two viruses whose genomes differed by one or two reverse engineered synonymous mutations, and measured the transmission of the mixture to exposed sentinel animals. Transmission through the air imposed a tight bottleneck since most recipient animals became infected by only one virus. In contrast, a direct contact transmission chain propagated a mixture of viruses suggesting the dose transferred by this route was higher. From animals with a mixed infection of viruses that were resistant and sensitive to the antiviral drug oseltamivir, resistance was propagated through contact transmission but not by air. These data imply that transmission events with a looser bottleneck can propagate minority variants and may be an important route for influenza evolution. C1 [Frise, Rebecca; Bradley, Konrad; van Doremalen, Neeltje; Elderfield, Ruth A.; Stilwell, Peter; Ashcroft, Jonathan W.; Roberts, Kim L.; Barclay, Wendy S.] Imperial Coll London, Fac Med, Div Infect Dis, Norfolk Pl, London W2 1PG, England. [Galiano, Monica; Fernandez-Alonso, Mirian; Miah, Shahjahan; Lackenby, Angie] Publ Hlth England, London, England. [Donnelly, Christl A.] Imperial Coll London, Fac Med, Sch Publ Hlth, MRC Ctr Outbreak Anal & Modelling,Dept Infect Dis, London, England. [van Doremalen, Neeltje] NIAID, Virus Ecol Unit, Virol Lab, Rocky Mt Labs,NIH, 903 South 4th St, Hamilton, MT 59840 USA. [Stilwell, Peter] Univ Exeter, Environm & Sustainabil Inst, Penryn, England. [Ashcroft, Jonathan W.] Univ Cambridge, Addenbrookes Hosp, Dept Med, Div Gastroenterol & Hepatol, Cambridge, England. [Fernandez-Alonso, Mirian] Univ Navarra, Sch Med, E-31080 Pamplona, Spain. [Roberts, Kim L.] Trinity Coll Dublin, Sch Genet & Microbiol, Moyne Inst Prevent Med, Dept Microbiol, Dublin, Ireland. RP Barclay, WS (reprint author), Imperial Coll London, Fac Med, Div Infect Dis, Norfolk Pl, London W2 1PG, England. EM w.barclay@imperial.ac.uk RI Fernandez-Alonso, Mirian/Q-4471-2016 OI Fernandez-Alonso, Mirian/0000-0001-8047-2734 FU Wellcome Trust [087039/Z/08Z]; Medical Research Council UK [G0600504]; NC3Rs grant [NC/K00042X/1]; UK Medical Research Council; European Union Seventh Framework Programme [FP7] [nu278433-PREDEMICS]; National Institute for Health Research Health Protection Research Unit (NIHR HPRU)) in Modelling Methodology at Imperial College London; Public Health England (PHE) FX Jason Long for critical reviews of the manuscript. The authors thank staff at Imperial College Central Biological Services for their expert help. Aisling Vaughan for help with plaque picking. KB, JA, RF, NvD and KR were supported by Wellcome Trust programme grant (087039/Z/08Z), and Medical Research Council UK grant G0600504. RE was supported by NC3Rs grant NC/K00042X/1. CAD thanks the UK Medical Research Council for Centre funding and the European Union Seventh Framework Programme [FP7/2007-2013] for funding under Grant Agreement nu278433-PREDEMICS. The research was funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU)) in Modelling Methodology at Imperial College London in partnership with Public Health England (PHE). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. NR 49 TC 0 Z9 0 U1 7 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 19 PY 2016 VL 6 AR 29793 DI 10.1038/srep29793 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR3XO UT WOS:000379836200001 PM 27430528 ER PT J AU Huang, ZB Wang, HY Wang, JK Zhao, MQ Sun, NN Sun, FF Shen, JX Zhang, HY Xia, KK Chen, DJ Gao, M Hammer, RP Liu, QR Xi, ZX Fan, XG Wu, J AF Huang, Zebing Wang, Haiyan Wang, Jingke Zhao, Mengqin Sun, Nana Sun, Fangfang Shen, Jianxin Zhang, Haiying Xia, Kunkun Chen, Dejie Gao, Ming Hammer, Ronald P. Liu, Qingrong Xi, Zhengxiong Fan, Xuegong Wu, Jie TI Cannabinoid receptor subtype 2 (CB2R) agonist, GW405833 reduces agonist-induced Ca2+ oscillations in mouse pancreatic acinar cells SO SCIENTIFIC REPORTS LA English DT Article ID AMP SIGNALING CASCADE; INOSITOL TRISPHOSPHATE; SELECTIVE LIGANDS; INSULIN-SECRETION; NEUROPATHIC PAIN; MICE; ACTIVATION; RELEASE; CB1; TRANSDUCTION AB Emerging evidence demonstrates that the blockade of intracellular Ca2+ signals may protect pancreatic acinar cells against Ca2+ overload, intracellular protease activation, and necrosis. The activation of cannabinoid receptor subtype 2 (CB2R) prevents acinar cell pathogenesis in animal models of acute pancreatitis. However, whether CB(2)Rs modulate intracellular Ca2+ signals in pancreatic acinar cells is largely unknown. We evaluated the roles of CB2R agonist, GW405833 (GW) in agonist-induced Ca2+ oscillations in pancreatic acinar cells using multiple experimental approaches with acute dissociated pancreatic acinar cells prepared from wild type, CB1R-knockout (KO), and CB2R-KO mice. Immunohistochemical labeling revealed that CB2R protein was expressed in mouse pancreatic acinar cells. Electrophysiological experiments showed that activation of CB(2)Rs by GW reduced acetylcholine (ACh)-, but not cholecystokinin (CCK)-induced Ca2+ oscillations in a concentration-dependent manner; this inhibition was prevented by a selective CB2R antagonist, AM630, or was absent in CB2R-KO but not CB1R-KO mice. In addition, GW eliminated L-arginine-induced enhancement of Ca2+ oscillations, pancreatic amylase, and pulmonary myeloperoxidase. Collectively, we provide novel evidence that activation of CB(2)Rs eliminates ACh-induced Ca2+ oscillations and L-arginine-induced enhancement of Ca2+ signaling in mouse pancreatic acinar cells, which suggests a potential cellular mechanism of CB2R-mediated protection in acute pancreatitis. C1 [Huang, Zebing; Fan, Xuegong; Wu, Jie] Cent S Univ, Xiangya Hosp, Dept Infect Dis, Changsha 410008, Hunan, Peoples R China. [Huang, Zebing; Fan, Xuegong; Wu, Jie] Key Lab Viral Hepatitis, Changsha, Hunan, Peoples R China. [Huang, Zebing; Xia, Kunkun; Chen, Dejie; Gao, Ming; Wu, Jie] St Josephs Hosp, Barrow Neurol Inst, Dept Neurol, Phoenix, AZ 85013 USA. [Huang, Zebing; Xia, Kunkun; Chen, Dejie; Gao, Ming; Wu, Jie] St Josephs Hosp, Barrow Neurol Inst, Dept Neurobiol, Phoenix, AZ 85013 USA. [Wang, Haiyan; Wang, Jingke; Zhao, Mengqin; Sun, Nana; Sun, Fangfang; Shen, Jianxin; Wu, Jie] Shantou Univ, Dept Physiol, Coll Med, Shantou 515041, Guangdong, Peoples R China. [Zhang, Haiying; Liu, Qingrong; Xi, Zhengxiong] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Hammer, Ronald P.; Wu, Jie] Univ Arizona, Dept Basic Med Sci, Coll Med, Phoenix, AZ 85004 USA. [Hammer, Ronald P.] Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85721 USA. [Hammer, Ronald P.] Univ Arizona, Coll Med, Dept Psychiat, Tucson, AZ 85721 USA. [Wang, Jingke] Lishui Peoples Hosp, Dept Lab Med, Lishui 323000, Zhejiang, Peoples R China. [Xia, Kunkun] Zhengzhou Univ, Dept Gen Surg, Affiliated Hosp 1, Zhengzhou 450052, Henan, Peoples R China. [Chen, Dejie] Yun Fu Peoples Hosp, Dept Neurol, Yun Fu 527300, Guangdong, Peoples R China. RP Wu, J (reprint author), Cent S Univ, Xiangya Hosp, Dept Infect Dis, Changsha 410008, Hunan, Peoples R China.; Wu, J (reprint author), Key Lab Viral Hepatitis, Changsha, Hunan, Peoples R China.; Wu, J (reprint author), St Josephs Hosp, Barrow Neurol Inst, Dept Neurol, Phoenix, AZ 85013 USA.; Wu, J (reprint author), St Josephs Hosp, Barrow Neurol Inst, Dept Neurobiol, Phoenix, AZ 85013 USA.; Wu, J (reprint author), Shantou Univ, Dept Physiol, Coll Med, Shantou 515041, Guangdong, Peoples R China.; Wu, J (reprint author), Univ Arizona, Dept Basic Med Sci, Coll Med, Phoenix, AZ 85004 USA. EM jie.wu@dignityhealth.org FU Seed Fund of Shangtou University Medical College; Guangdong Science and Technology Foundation FX Part of this work was supported by a Seed Fund of Shangtou University Medical College and by Guangdong Science and Technology Foundation (HYW). Authors thank the editor in Barrow Neurological Institute Publication Department for her assistance for editing the English. NR 41 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 19 PY 2016 VL 6 AR 29757 DI 10.1038/srep29757 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR4DE UT WOS:000379850900001 PM 27432473 ER PT J AU Ikeda, K Ueda, T Yamasaki, N Nakata, Y Sera, Y Nagamachi, A Miyama, T Kobayashi, H Takubo, K Kanai, A Oda, H Wolff, L Honda, Z Ichinohe, T Matsubara, A Suda, T Inaba, T Honda, H AF Ikeda, Kenichiro Ueda, Takeshi Yamasaki, Norimasa Nakata, Yuichiro Sera, Yasuyuki Nagamachi, Akiko Miyama, Takahiko Kobayashi, Hiroshi Takubo, Keiyo Kanai, Akinori Oda, Hideaki Wolff, Linda Honda, Zen-ichiro Ichinohe, Tatsuo Matsubara, Akio Suda, Toshio Inaba, Toshiya Honda, Hiroaki TI Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency SO SCIENTIFIC REPORTS LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; REPRESSIVE COMPLEX 2; POLYCOMB-GROUP PROTEINS; STEM-CELLS; MYELOID MALIGNANCIES; BONE-MARROW; NEOPLASMS; CHROMATIN; GENE; DIFFERENTIATION AB Polycomb repressive complex 2 (PRC2) participates in transcriptional repression through methylation of histone H3K27. The WD-repeat protein embryonic ectoderm development (EED) is a non-catalytic but an essential component of PRC2 and its mutations were identified in hematopoietic malignancies. To clarify the role(s) of EED in adult hematopoiesis and leukemogenesis, we generated Eed conditional knockout (Eed(Delta/Delta)) mice. Eed(Delta/Delta) mice died in a short period with rapid decrease of hematopoietic cells. Hematopoietic stem/progenitor cells (HSPCs) were markedly decreased with impaired bone marrow (BM) repopulation ability. Cell cycle analysis of HSPCs demonstrated increased S-phase fraction coupled with suppressed G0/G1 entry. Genes encoding cell adhesion molecules are significantly enriched in Eed(Delta/Delta) HSPCs, and consistently, Eed(Delta/Delta) HSPCs exhibited increased attachment to a major extracellular matrix component, fibronectin. Thus, EED deficiency increases proliferation on one side but promotes quiescence possibly by enhanced adhesion to the hematopoietic niche on the other, and these conflicting events would lead to abnormal differentiation and functional defect of Eed(Delta/Delta) HSPCs. In addition, Eed haploinsufficiency induced hematopoietic dysplasia, and Eed heterozygous mice were susceptible to malignant transformation and developed leukemia in cooperation with Evi1 overexpression. Our results demonstrated differentiation stage-specific and dose-dependent roles of EED in normal hematopoiesis and leukemogenesis. C1 [Ikeda, Kenichiro; Ueda, Takeshi; Yamasaki, Norimasa; Nakata, Yuichiro; Sera, Yasuyuki; Honda, Hiroaki] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Dis Model, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. [Ikeda, Kenichiro; Matsubara, Akio] Hiroshima Univ, Inst Biomed & Hlth Sci, Dept Urol, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. [Nagamachi, Akiko; Kanai, Akinori; Inaba, Toshiya] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Mol Oncol, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. [Miyama, Takahiko; Ichinohe, Tatsuo] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Hematol & Oncol, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. [Kobayashi, Hiroshi; Takubo, Keiyo] Natl Ctr Global Hlth & Med, Res Inst, Dept Stem Cell Biol, Shinjuku Ku, 1-21-1 Toyama, Tokyo 1628655, Japan. [Oda, Hideaki] Tokyo Womens Med Univ, Dept Pathol, Shinjuku Ku, 8-1 Kawada Cho, Tokyo 1628666, Japan. [Wolff, Linda] NCI, Ctr Canc Res, Cellular Oncol Lab, Bethesda, MD USA. [Honda, Zen-ichiro] Ochanomizu Univ, Hlth Care Ctr, Bunkyo Ku, 2-1-1 Otsuka, Tokyo 1128611, Japan. [Honda, Zen-ichiro] Ochanomizu Univ, Hlth Care Ctr, Grad Sch Humanities & Sci, Inst Environm Sci Human Life,Bunkyo Ku, 2-1-1 Otsuka, Tokyo 1128611, Japan. [Suda, Toshio] Natl Univ Singapore, Ctr Translat Med, Canc Sci Inst Singapore, 14 Med Dr 12-01, Singapore 117599, Singapore. RP Honda, H (reprint author), Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Dis Model, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. EM hhonda@hiroshima-u.ac.jp FU Ministry of Education, Science and Culture of Japan FX We thank Yuki Sakai, Sawako Ogata, Kaoru Wada, and Rika Tai for assistance with animal care, mouse genotyping, and molecular experiments. We also thank the RIKEN BioResource Center for providing us with B6-Tg(CAG-FLPe) 36 mice (RBRC01834). This work was partly supported by a Grant-in-Aid from the Ministry of Education, Science and Culture of Japan. NR 42 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 19 PY 2016 VL 6 AR 29454 DI 10.1038/srep29454 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR4AB UT WOS:000379842700001 PM 27432459 ER PT J AU Kancharla, K Weissman, G Elagha, AA Kancherla, K Samineni, S Hill, PC Boyce, S Fuisz, AR AF Kancharla, Krishna Weissman, Gaby Elagha, Abdalla A. Kancherla, Kalyan Samineni, Swetha Hill, Peter C. Boyce, Steven Fuisz, Anthon R. TI Scar quantification by cardiovascular magnetic resonance as an independent predictor of long-term survival in patients with ischemic heart failure treated by coronary artery bypass graft surgery SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Cardiovascular magnetic resonance; Scar; Ischemic cardiomyopathy; CABG; Mortality ID LATE GADOLINIUM ENHANCEMENT; MYOCARDIAL-INFARCTION; MEDICAL THERAPY; NONISCHEMIC CARDIOMYOPATHY; SURGICAL REVASCULARIZATION; VENTRICULAR-ARRHYTHMIAS; CONTRAST; DISEASE; EXTENT; SIZE AB Background: Scar burden by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is associated with functional recovery after coronary artery bypass surgery (CABG). There is limited data on long-term mortality after CABG based on left ventricular (LV) scar burden. Methods: Patients who underwent LGE CMR between January 2003 and February 2010 within 1 month prior to CABG were included. A standard 16 segment model was used for scar quantification. A score of 1 for no scar, 2 for <= 50 % and 3 for > 50 % transmurality was assigned for each segment. LV scar score (LVSS) defined as the sum of segment scores divided by 16. All-cause mortality was ascertained by social security death index. Results: One hundred ninety-six patients met the inclusion criteria. 185 CMR studies were available. History of prior MI was present in 64 % and prior CABG in 5.4 % of patients. Scar was present in 72 % of patients and median LVEF was 38 %. Over a median follow up of 8.3 years, there were 64 deaths (34.6 %). There was no statistically significant difference in mortality between Scar and No-scar groups (37 % versus 29 %). In the group with scar, a lower scar burden (defined either < 4 segments with scar or based on LVSS) was independently associated with increased survival. Conclusion: In patients undergoing surgical revascularization, scar burden is negatively associated with survival in patients with scar. However, there is no difference in survival based on presence or absence of scar alone. CMR prior to CABG adds additional prognostic information. C1 [Kancharla, Krishna] Mayo Clin, Dept Cardiol, Rochester, MN 55905 USA. [Weissman, Gaby] MedStar Washington Hosp Ctr, Div Cardiol, MedStar Heart & Vasc Inst, Washington, DC USA. [Weissman, Gaby; Boyce, Steven] Georgetown Univ, Washington, DC USA. [Elagha, Abdalla A.] Cairo Univ Hosp, Dept Cardiol, Cairo, Egypt. [Elagha, Abdalla A.] NHLBI, Translat Med Branch, Bldg 10, Bethesda, MD 20892 USA. [Kancherla, Kalyan] MedStar Hlth Res Inst, Washington, DC USA. [Kancherla, Kalyan] Howard Univ Hosp, Washington, DC USA. [Samineni, Swetha] Mayo Clin Hlth Syst, Austin, MN USA. [Hill, Peter C.; Boyce, Steven] MedStar Washington Hosp Ctr, MedStar Heart & Vasc Inst, Dept Cardiac Surg, Washington, DC USA. [Fuisz, Anthon R.] Westchester Med Ctr, Div Cardiol, Valhalla, NY USA. RP Kancharla, K (reprint author), Mayo Clin, Dept Cardiol, Rochester, MN 55905 USA. EM krish.kancharla@gmail.com NR 29 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JUL 18 PY 2016 VL 18 AR 45 DI 10.1186/s12968-016-0265-y PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DT3KH UT WOS:000381379200001 PM 27430331 ER PT J AU Tang, Q Billington, N Krementsova, EB Bookwalter, CS Lord, M Trybus, KM AF Tang, Qing Billington, Neil Krementsova, Elena B. Bookwalter, Carol S. Lord, Matthew Trybus, Kathleen M. TI A single-headed fission yeast myosin V transports actin in a tropomyosin-dependent manner SO JOURNAL OF CELL BIOLOGY LA English DT Article ID CONTRACTILE RING; SCHIZOSACCHAROMYCES-POMBE; TAIL DOMAIN; IN-VITRO; F-ACTIN; BINDING SITE; CELL-FUSION; CYTOKINESIS; MICROTUBULES; CABLES AB Myo51, a class V myosin in fission yeast, localizes to and assists in the assembly of the contractile ring, a conserved eukaryotic actomyosin structure that facilitates cytokinesis. Rng8 and Rng9 are binding partners that dictate the cellular localization and function of Myo51. Myo51 was expressed in insect cells in the presence or absence of Rng8/9. Surprisingly, electron microscopy of negatively stained images and hydrodynamic measurements showed that Myo51 is single headed, unlike most class V myosins. When Myo51-Rng8/9 was bound to actin-tropomyosin, two attachment sites were observed: the typical ATP-dependent motor domain attachment and a novel ATP-independent binding of the tail mediated by Rng8/9. A modified motility assay showed that this additional binding site anchors Myo51-Rng8/9 so that it can cross-link and slide actin-tropomyosin filaments relative to one another, functions that may explain the role of this motor in contractile ring assembly. C1 [Tang, Qing; Krementsova, Elena B.; Bookwalter, Carol S.; Lord, Matthew; Trybus, Kathleen M.] Univ Vermont, Dept Physiol & Mol Biophys, Burlington, VT 05405 USA. [Billington, Neil] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Trybus, KM (reprint author), Univ Vermont, Dept Physiol & Mol Biophys, Burlington, VT 05405 USA. EM kathleen.trybus@uvm.edu FU National Institutes of Health [GM097193, GM078097, P20GM103449] FX This work was supported by National Institutes of Health grant GM097193 to M. Lord and GM078097 to K. M. Trybus. Mass spectrometry protein identification of expressed protein bands was performed by the Vermont Genetics Network Core Facility, which is supported by National Institutes of Health Institutional Development Award P20GM103449. NR 45 TC 0 Z9 0 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUL 18 PY 2016 VL 214 IS 2 BP 167 EP 179 DI 10.1083/jcb.201511102 PG 13 WC Cell Biology SC Cell Biology GA DS5OJ UT WOS:000380831300008 PM 27432898 ER PT J AU Mitchell, S Gao, J Hallett, M Voon, V AF Mitchell, Simon Gao, Jennifer Hallett, Mark Voon, Valerie TI The Role of Social Novelty in Risk Seeking and Exploratory Behavior: Implications for Addictions SO PLOS ONE LA English DT Article ID SENSATION-SEEKING; DRUG-USE; DOPAMINE; ADOLESCENTS; IMPULSIVITY; STIMULI; ALCOHOL; MEMORY; MODEL AB Novelty preference or sensation seeking is associated with disorders of addiction and predicts rodent compulsive drug use and adolescent binge drinking in humans. Novelty has also been shown to influence choice in the context of uncertainty and reward processing. Here we introduce a novel or familiar neutral face stimuli and investigate its influence on risk-taking choices in healthy volunteers. We focus on behavioural outcomes and imaging correlates to the prime that might predict risk seeking. We hypothesized that subjects would be more risk seeking following a novel relative to familiar stimulus. We adapted a risk-taking task involving acceptance or rejection of a 50: 50 choice of gain or loss that was preceded by a familiar (pre-test familiarization) or novel face prime. Neutral expression faces of males and females were used as primes. Twenty-four subjects were first tested behaviourally and then 18 scanned using a different variant of the same task under functional MRI. We show enhanced risk taking to both gain and loss anticipation following novel relative to familiar images and particularly for the low gain condition. Greater risk taking behaviour and selfreported exploratory behaviours was predicted by greater right ventral putaminal activity to novel versus familiar contexts. Social novelty appears to have a contextually enhancing effect on augmenting risky choices possibly mediated via ventral putaminal dopaminergic activity. Our findings link the observation that novelty preference and sensation seeking are important traits predicting the initiation and maintenance of risky behaviours, including substance and behavioural addictions. C1 [Mitchell, Simon; Voon, Valerie] Univ Cambridge, Dept Psychiat, Cambridge, England. [Mitchell, Simon; Voon, Valerie] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge, England. [Gao, Jennifer; Hallett, Mark] NINDS, NIH, Human Motor Control Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Gao, Jennifer] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Voon, Valerie] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England. RP Voon, V (reprint author), Univ Cambridge, Dept Psychiat, Cambridge, England.; Voon, V (reprint author), Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge, England.; Voon, V (reprint author), Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England. EM vv247@cam.ac.uk FU NIH [Z01 NS002669]; Wellcome Trust [093705/Z/10/Z]; National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This study was funded by an internal NIH grant (Z01 NS002669). Valerie Voon was funded by a Wellcome Trust Intermediate Fellowship (093705/Z/10/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; VV is a Wellcome Trust Intermediate Fellow in Clinical Neurosciences (093705/Z/10/Z). The study was conducted at, and supported by, the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 26 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 18 PY 2016 VL 11 IS 7 AR e0158947 DI 10.1371/journal.pone.0158947 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR8TD UT WOS:000380169300026 PM 27427940 ER PT J AU Anson, ER Bigelow, RT Carey, JP Xue, QL Studenski, S Schubert, MC Weber, KP Agrawal, Y AF Anson, Eric R. Bigelow, Robin T. Carey, John P. Xue, Quan-Li Studenski, Stephanie Schubert, Michael C. Weber, Konrad P. Agrawal, Yuri TI Aging Increases Compensatory Saccade Amplitude in the Video Head Impulse Test SO FRONTIERS IN NEUROLOGY LA English DT Article DE VOR; compensatory saccades; healthy aging; head impulse test; vestibular ID UNILATERAL VESTIBULAR DEAFFERENTATION; VESTIBULOOCULAR REFLEX FUNCTION; CATCH-UP SACCADES; GAZE STABILIZATION; SENSORY EPITHELIA; EYE-MOVEMENTS; QUICK PHASES; VOR GAIN; AGE; OCULOGRAPHY AB Objective: Rotational vestibular function declines with age resulting in saccades as a compensatory mechanism to improve impaired gaze stability. Small reductions in rotational vestibulo-ocular reflex (VOR) gain that would be considered clinically normal have been associated with compensatory saccades. We evaluated whether compensatory saccade characteristics varied as a function of age, independent of semicircular canal function as quantified by VOR gain. Methods: Horizontal VOR gain was measured in 243 participants age 27-93 from the Baltimore Longitudinal Study of Aging using video head impulse testing. Latency and amplitude of the first saccade (either covert-occurring during head impulse, or overt-occurring following head impulse) were measured for head impulses with compensatory saccades (n = 2230 head impulses). The relationship between age and saccade latency, as well as the relationship between age and saccade amplitude, were evaluated using regression analyses adjusting for VOR gain, gender, and race. Results: Older adults (mean age 75.9) made significantly larger compensatory saccades relative to younger adults (mean age 45.0). In analyses adjusted for VOR gain, there was a significant association between age and amplitude of the first compensatory covert saccade (beta = 0.015, p = 0.008). In analyses adjusted for VOR gain, there was a significant association between age and amplitude of the first compensatory overt saccade (beta = 0.02, p < 0.001). Compensatory saccade latencies did not vary significantly by age. Conclusion: We observed that aging increases the compensatory catch-up saccade amplitude in healthy adults after controlling for VOR gain. Size of compensatory saccades may be useful in addition to VOR gain for characterizing vestibular function in aging adults. C1 [Anson, Eric R.; Bigelow, Robin T.; Carey, John P.; Schubert, Michael C.; Agrawal, Yuri] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. [Xue, Quan-Li] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Xue, Quan-Li] Johns Hopkins Med Inst, Ctr Aging & Hlth, Baltimore, MD 21205 USA. [Studenski, Stephanie] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. [Weber, Konrad P.] Univ Zurich, Univ Zurich Hosp, Dept Neurol, Zurich, Switzerland. [Weber, Konrad P.] Univ Zurich, Univ Zurich Hosp, Dept Ophthalmol, Zurich, Switzerland. RP Anson, ER (reprint author), Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. EM eanson1@jhmi.edu FU NIDCD [K23 DC013056, T32 DC000023] FX The study was supported in part by NIDCD K23 DC013056 and NIDCD T32 DC000023. NR 41 TC 1 Z9 1 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PD JUL 18 PY 2016 VL 7 AR 113 DI 10.3389/fneur.2016.00113 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DR3NQ UT WOS:000379810300001 PM 27486430 ER PT J AU Pei, WH Xu, LS Varshney, GK Carrington, B Bishop, K Jones, M Huang, SC Idol, J Pretorius, PR Beirl, A Schimmenti, LA Kindt, KS Sood, R Burgess, SM AF Pei, Wuhong Xu, Lisha Varshney, Gaurav K. Carrington, Blake Bishop, Kevin Jones, MaryPat Huang, Sunny C. Idol, Jennifer Pretorius, Pamela R. Beirl, Alisha Schimmenti, Lisa A. Kindt, Katie S. Sood, Raman Burgess, Shawn M. TI Additive reductions in zebrafish PRPS1 activity result in a spectrum of deficiencies modeling several human PRPS1-associated diseases SO SCIENTIFIC REPORTS LA English DT Article ID PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE; CELL-PROLIFERATION; MYCOPHENOLIC-ACID; HEARING-LOSS; MUTATIONS; GENE; REGENERATION; DEAFNESS; REPLACEMENT; CHILDHOOD AB Phosphoribosyl pyrophosphate synthetase-1 (PRPS1) is a key enzyme in nucleotide biosynthesis, and mutations in PRPS1 are found in several human diseases including nonsyndromic sensorineural deafness, Charcot-Marie-Tooth disease-5, and Arts Syndrome. We utilized zebrafish as a model to confirm that mutations in PRPS1 result in phenotypic deficiencies in zebrafish similar to those in the associated human diseases. We found two paralogs in zebrafish, prps1a and prps1b and characterized each paralogous mutant individually as well as the double mutant fish. Zebrafish prps1a mutants and prps1a; prps1b double mutants showed similar morphological phenotypes with increasingly severe phenotypes as the number of mutant alleles increased. Phenotypes included smaller eyes and reduced hair cell numbers, consistent with the optic atrophy and hearing impairment observed in human patients. The double mutant also showed abnormal development of primary motor neurons, hair cell innervation, and reduced leukocytes, consistent with the neuropathy and recurrent infection of the human patients possessing the most severe reductions of PRPS1 activity. Further analyses indicated the phenotypes were associated with a prolonged cell cycle likely resulting from reduced nucleotide synthesis and energy production in the mutant embryos. We further demonstrated the phenotypes were caused by delays in the tissues most highly expressing the prps1 genes. C1 [Pei, Wuhong; Xu, Lisha; Varshney, Gaurav K.; Carrington, Blake; Bishop, Kevin; Huang, Sunny C.; Idol, Jennifer; Sood, Raman; Burgess, Shawn M.] NHGRI, Translat & Funct Genom Branch, Bethesda, MD 20892 USA. [Jones, MaryPat] NHGRI, Canc Genet & Comparat Genom Branch, Bethesda, MD 20892 USA. [Pretorius, Pamela R.] Hanover Coll, Dept Biol, Hanover, IN 47243 USA. [Beirl, Alisha; Kindt, Katie S.] Natl Inst Deafness & Other Commun Disorders, Sect Sensory Cell Dev & Funct, Bethesda, MD 20892 USA. [Schimmenti, Lisa A.] Mayo Clin, Dept Otorhinolaryngol, Rochester, MN 55905 USA. [Schimmenti, Lisa A.] Mayo Clin, Dept Clin Genom, Rochester, MN 55905 USA. RP Burgess, SM (reprint author), NHGRI, Translat & Funct Genom Branch, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov OI Varshney, Gaurav K./0000-0002-0429-1904 FU Intramural Research Program of the National Human Genome Research Institute [ZIAHG200386-05]; National Eye Institute [EY019267]; National Institute of Dental and Craniofacial Research MinnCResT Training Grant [T32DE07288, T90DE022732] FX We would like to thank Dustin Prebilic, Colin Huck, and their team members at Charles Rivers for animal husbandry; Haigen Huang and Shou Lin for in vitro fertilization of the prps1a viral mutant; Sahlee Sabala from Department of Laboratory Medicine at NIH for Wright Giemsa staining of the blood smear slides; Stephen Wincovitch from NHGRI Cytogenetics and Microscopy Core for assistance in imaging; the members of the Burgess Laboratory for helpful discussions. This research was supported by the Intramural Research Program of the National Human Genome Research Institute (ZIAHG200386-05), the National Eye Institute (EY019267 to L.A.S.), and the National Institute of Dental and Craniofacial Research MinnCResT Training Grant (T32DE07288, T90DE022732 to P.R.P.). NR 46 TC 0 Z9 0 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 18 PY 2016 VL 6 AR 29946 DI 10.1038/srep29946 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR2CV UT WOS:000379713500002 PM 27425195 ER PT J AU Bandiera, FC Assari, S Livaudais-Toman, J Perez-Stable, EJ AF Bandiera, Frank C. Assari, Shervin Livaudais-Toman, Jennifer Perez-Stable, Eliseo J. TI Latino and Black smokers in the Health and Retirement Study are more likely to quit: the role of light smoking SO TOBACCO INDUCED DISEASES LA English DT Article DE Latinos; Smoking cessation; Older persons ID INVOLUNTARY JOB LOSS; CESSATION; PREDICTORS; ADULTS AB Background: Older persons are more vulnerable to tobacco mortality and less likely to make quit attempts. Less is known, however, about the role of race and ethnicity on quit rates in the U.S. Using a nationally representative data source of older adults in U.S., we aimed to study racial and ethnic differences in smoking cessation rates. Methods: We used data from all waves of the Health and Retirement Study (HRS) between 1992-2012. The HRS is a longitudinal nationally representative survey of adults over the age of 50 in the United States. We followed current smokers at baseline (year 1992) until time to first quit. Race/ethnicity was the main predictor; gender, age, education, marital status, count of chronic medical conditions, depressive symptoms, and drinking at baseline were control variables. Cox regression was used for analysis of time to quit. Results: Hazard ratios of quitting during the first ten (Hazard ratio = 1.51, p < 0.05) and 20 years (Hazard ratio = 1.46, p < 0.05) were larger for Latinos over the age of 50 compared to Whites. In addition, hazard ratios of quitting during the first 20 years (Hazard ratio = 1.19, p < 0.05) were larger for Blacks over the age of 50 compared to Whites. These findings were partially explained by cigarette consumption intensity, such that Latinos were lighter smokers and therefore more likely to quit than Whites. Conclusion: Latinos and Blacks were more likely than Whites to quit smoking cigarettes within 20 years. However, this finding may be explained by cigarette consumption intensity. C1 [Bandiera, Frank C.] Univ Texas Dallas, Sch Publ Hlth, Dallas Reg Campus,6011 Harry Hines Blvd V8-112, Dallas, TX 75390 USA. [Bandiera, Frank C.] Univ Texas Southwestern, Harold C Simmons Canc Ctr, 6011 Harry Hines Blvd V8-112, Dallas, TX 75390 USA. [Assari, Shervin] Univ Michigan, Sch Med, Dept Psychiat, 4250 Plymouth Rd, Ann Arbor, MI 48109 USA. [Assari, Shervin] Univ Michigan, Ctr Res Ethn Culture & Hlth, Sch Publ Hlth, 4250 Plymouth Rd, Ann Arbor, MI 48109 USA. [Livaudais-Toman, Jennifer] Univ Calif San Francisco, Div Gen Internal Med, 3333 Calif St, San Francisco, CA 94143 USA. [Perez-Stable, Eliseo J.] Nat Inst Minor Hlth & Hlth Dispar, NIH, 6707 Democracy Blvd,Suite 800, Bethesda, MD 20892 USA. RP Bandiera, FC (reprint author), Univ Texas Dallas, Sch Publ Hlth, Dallas Reg Campus,6011 Harry Hines Blvd V8-112, Dallas, TX 75390 USA.; Bandiera, FC (reprint author), Univ Texas Southwestern, Harold C Simmons Canc Ctr, 6011 Harry Hines Blvd V8-112, Dallas, TX 75390 USA. EM Frank.Bandiera@UTSouthwestern.edu NR 17 TC 1 Z9 1 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1617-9625 J9 TOB INDUC DIS JI Tob. Induc. Dis. PD JUL 18 PY 2016 VL 14 AR 23 DI 10.1186/s12971-016-0090-y PG 6 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA DR4GH UT WOS:000379859100001 PM 27436994 ER PT J AU Ullah, I Kabir, F Iqbal, M Gottsch, CBS Naeem, MA Assir, MZ Khan, SN Akram, J Riazuddin, S Ayyagari, R Hejtmancik, JF Riazuddin, SA AF Ullah, Inayat Kabir, Firoz Iqbal, Muhammad Gottsch, Clare Brooks S. Naeem, Muhammad Asif Assir, Muhammad Zaman Khan, Shaheen N. Akram, Javed Riazuddin, Sheikh Ayyagari, Radha Hejtmancik, J. Fielding Riazuddin, S. Amer TI Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases SO MOLECULAR VISION LA English DT Article ID LEBER CONGENITAL AMAUROSIS; GENOTYPE-PHENOTYPE CORRELATION; COMPREHENSIVE MOLECULAR DIAGNOSIS; HOMOZYGOUS MISSENSE MUTATION; ONSET RETINAL DEGENERATION; ROD CGMP PHOSPHODIESTERASE; SPLICE-SITE MUTATION; PAKISTANI FAMILIES; DOMINANT MUTATION; GENETIC-ANALYSIS AB Purpose: To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous familial cases. Methods: Seven large familial cases with multiple individuals diagnosed with retinitis pigmentosa were included in the study. Affected individuals in these families underwent ophthalmic examinations to document the symptoms and confirm the initial diagnosis. Blood samples were collected from all participating members, and genomic DNA was extracted. An exclusion analysis with microsatellite markers spanning the TULP1 locus on chromosome 6p was performed, and two-point logarithm of odds (LOD) scores were calculated. All coding exons along with the exon-intron boundaries of TULP1 were sequenced bidirectionally. We constructed a single nucleotide polymorphism (SNP) haplotype for the four familial cases harboring the K489R allele and estimated the likelihood of a founder effect. Results: The ophthalmic examinations of the affected individuals in these familial cases were suggestive of RP. Exclusion analyses confirmed linkage to chromosome 6p harboring TULP1 with positive two-point LOD scores. Subsequent Sanger sequencing identified the single base pair substitution in exon14, c.1466A>G (p.K489R), in four families. Additionally, we identified a two-base deletion in exon 4, c.286_287delGA (p.E96Gfs77*); a homozygous splice site variant in intron 14, c.1495+4A>C; and a novel missense variation in exon 15, c.1561C>T (p.P521S). All mutations segregated with the disease phenotype in the respective families and were absent in ethnically matched control chromosomes. Haplotype analysis suggested (p<10(-6)) that affected individuals inherited the causal mutation from a common ancestor. Conclusions: Pathogenic mutations in TULP1 are responsible for the RP phenotype in seven familial cases with a common ancestral mutation responsible for the disease phenotype in four of the seven families. C1 [Ullah, Inayat; Iqbal, Muhammad; Naeem, Muhammad Asif; Khan, Shaheen N.; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Kabir, Firoz; Gottsch, Clare Brooks S.; Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, 600 N Wolfe Street,Maumenee 840, Baltimore, MD 21287 USA. [Assir, Muhammad Zaman; Akram, Javed; Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. [Assir, Muhammad Zaman; Akram, Javed; Riazuddin, Sheikh] Shaheed Zulfiqar Ali Bhutto Med Univ, Natl Ctr Genet Dis, Islamabad, Pakistan. [Ayyagari, Radha] Univ Calif San Diego, Shiley Eye Inst, San Diego, CA 92103 USA. [Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Riazuddin, SA (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, 600 N Wolfe Street,Maumenee 840, Baltimore, MD 21287 USA. EM riazuddin@jhmi.edu FU Higher Education Commission, Islamabad, Pakistan; National Eye Institute [R01EY021237-01] FX We are thankful to all family members for their participation in this study. This study was supported in part by the Higher Education Commission, Islamabad, Pakistan (SR), and by the National Eye Institute Grant R01EY021237-01 (RA and SAR). NR 116 TC 0 Z9 0 U1 1 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUL 16 PY 2016 VL 22 BP 797 EP 815 PG 19 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA DX7KG UT WOS:000384565200001 PM 27440997 ER PT J AU Paz-Soldan, VA Bauer, KM Lenhart, A Lopez, JJC Elder, JP Scott, TW McCall, PJ Kochel, TJ Morrison, AC AF Paz-Soldan, Valerie A. Bauer, Karin M. Lenhart, Audrey Lopez, Jhonny J. Cordova Elder, John P. Scott, Thomas W. McCall, Philip J. Kochel, Tadeusz J. Morrison, Amy C. TI Experiences with insecticide-treated curtains: a qualitative study in Iquitos, Peru SO BMC PUBLIC HEALTH LA English DT Article DE Dengue; Insecticide treated curtains (ITC); Peru; Qualitative ID AEDES-AEGYPTI DIPTERA; DENGUE VIRUS; DETERMINANTS; TRANSMISSION; ACCEPTABILITY; PATTERNS; COVERAGE; VECTORS; MEXICO; NETS AB Background: Dengue is an arthropod-borne viral disease responsible for approximately 400 million infections annually; the only available method of prevention is vector control. It has been previously demonstrated that insecticide treated curtains (ITCs) can lower dengue vector infestations in and around houses. As part of a larger trial examining whether ITCs could reduce dengue transmission in Iquitos, Peru, the objective of this study was to characterize the participants' experience with the ITCs using qualitative methods. Methods: Knowledge, attitudes, and practices (KAP) surveys (at baseline, and 9 and 27 months post-ITC distribution, with n = 593, 595 and 511, respectively), focus group discussions (at 6 and 12 months post-ITC distribution, with n = 18 and 33, respectively), and 11 one-on-one interviews (at 12 months post-distribution) were conducted with 605 participants who received ITCs as part of a cluster-randomized trial. Results: Focus groups at 6 months post-ITC distribution revealed that individuals had observed their ITCs to function for approximately 3 months, after which they reported the ITCs were no longer working. Follow up revealed that the ITCs required re-treatment with insecticide at approximately 1 year post-distribution. Over half (55.3 %, n = 329) of participants at 9 months post-ITC distribution and over a third (34.8 %, n = 177) at 27 months post-ITC distribution reported perceiving a decrease in the number of mosquitoes in their home. The percentage of participants who would recommend ITCs to their family or friends in the future remained high throughout the study (94.3 %, n = 561 at 9 months and 94.6 %, n = 488 at 27 months post-distribution). When asked why, participants reported that ITCs were effective at reducing mosquitoes (81.6 and 37.8 %, at 9 and 27 months respectively), that they prevent dengue (5.7 and 51.2 %, at 9 and 27 months), that they are "beautiful" (5.9 and 3.1 %), as well as other reasons (6.9 and 2.5 %). Conclusion: ITCs have substantial potential for long term dengue vector control because they are liked by users, both for their perceived effectiveness and for aesthetic reasons, and because they require little proactive behavioral effort on the part of the users. Our results highlight the importance of gathering process (as opposed to outcome) data during vector control studies, without which researchers would not have become aware that the ITCs had lost effectiveness early in the trial. C1 [Paz-Soldan, Valerie A.; Bauer, Karin M.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Global Community Hlth & Behav Sci, 1440 Canal St,Suite 2200, New Orleans, LA 70118 USA. [Paz-Soldan, Valerie A.] Univ Peruana Cayetano Heredia, Fac Salud Publ & Adm, Lima, Peru. [Lenhart, Audrey] US Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Entomol Branch, Atlanta, GA USA. [Lopez, Jhonny J. Cordova; McCall, Philip J.] Univ Liverpool Liverpool Sch Trop Med, Dept Vector Biol, Liverpool, Merseyside, England. [Elder, John P.] San Diego State Univ, Grad Sch Publ Hlth, Div Hlth Promot & Behav Sci, San Diego, CA 92182 USA. [Scott, Thomas W.; Morrison, Amy C.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Scott, Thomas W.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Kochel, Tadeusz J.] Naval Med Res Ctr, Virol Dept, Silver Spring, MD USA. RP Paz-Soldan, VA (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Global Community Hlth & Behav Sci, 1440 Canal St,Suite 2200, New Orleans, LA 70118 USA.; Paz-Soldan, VA (reprint author), Univ Peruana Cayetano Heredia, Fac Salud Publ & Adm, Lima, Peru. EM vpazsold@tulane.edu FU Wellcome Trust [WT085714MA]; U.S. National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID) [R01 AI069341-01]; NIH/NIAID [P01 AI098670]; Armed Forces Health Surveillance Center Global Emerging Infections Systems Research Program [847705.82000.25GB.B0016]; Military Infectious Disease Research Program [S0263_10_LI, S0216_09_LI]; Fogarty International Center [K01 TW008414-01A1]; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security; Fogarty International Center; National Institutes of Health FX This research was supported by funding from the Wellcome Trust (WT085714MA), the U.S. National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID) award number R01 AI069341-01, the NIH/NIAID award number P01 AI098670, the Armed Forces Health Surveillance Center Global Emerging Infections Systems Research Program (847705.82000.25GB.B0016), and the Military Infectious Disease Research Program (S0263_10_LI and S0216_09_LI). VPS received supported from the Fogarty International Center, award number K01 TW008414-01A1. TWS received support from the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 49 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD JUL 16 PY 2016 VL 16 AR 582 DI 10.1186/s12889-016-3191-x PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DR2CK UT WOS:000379712400003 PM 27422403 ER PT J AU Nagy, A Xu, YF Bauchan, GR Shelton, DR Nou, XW AF Nagy, Attila Xu, Yunfeng Bauchan, Gary R. Shelton, Daniel R. Nou, Xiangwu TI Aggregative adherence fimbriae I (AAF/I) mediate colonization of fresh produce and abiotic surface by Shiga toxigenic enteroaggregative Escherichia coli O104:H4 SO INTERNATIONAL JOURNAL OF FOOD MICROBIOLOGY LA English DT Article DE Enteroaggregative E. coli; E. coli O104:H4; Aggregative adherence fimbriae; Fresh produce; Aggregation; Colonization; Biofilms ID HEMOLYTIC-UREMIC SYNDROME; BIOFILM FORMATION; MICROTITER-PLATE; OUTBREAK; O104/H4; GERMANY; ATTACHMENT; INFECTION; ADHESION; STRAINS AB The Shiga toxigenic Escherichia coli O104:H4 isolated during the 2011 European outbreak expresses Shiga toxin 2a and possess virulence genes associated with the enteroaggregative E. coli (EAEC) pathotype. It produces plasmid encoded aggregative adherence fimbriae I (AAF/I) which mediate cell aggregation and biofilm formation in human intestine and promote Shiga-toxin adsorption, but it is not clear whether the AAF/I fimbriae are involved in the colonization and biofilm formation on food and environmental matrices such as the surface of fresh produce. We deleted the gene encoding for the AAF/I fimbriae main subunit (AggA) from an outbreak associated E. coli O104:H4 strain, and evaluated the role of AAF/I fimbriae in the adherence and colonization of E. coli O104:H4 to spinach and abiotic surfaces. The deletion of aggA did not affect the adherence of E. coli O104:H4 to these surfaces. However, it severely diminished the colonization and biofilm formation of E. coli O104:H4 on these surfaces. Strong aggregation and biofilm formation on spinach and abiotic surfaces were observed with the wild type strain but not the isogenic aggA deletion mutant, suggesting that AAF/I fimbriae play a crucial role in persistence of O104:H4 cells outside of the intestines of host species, such as on the surface of fresh produce. Published by Elsevier B.V. C1 [Nagy, Attila; Xu, Yunfeng; Bauchan, Gary R.; Shelton, Daniel R.; Nou, Xiangwu] ARS, Environm Microbial & Food Safety Lab, Electron & Confocal Microscopy Unit, USDA, Beltsville, MD 20705 USA. [Nagy, Attila] NIAID, NIH, Vaccine Res Ctr, Gaithersburg, MD 20878 USA. RP Nou, XW (reprint author), ARS, Environm Microbial & Food Safety Lab, Electron & Confocal Microscopy Unit, USDA, Beltsville, MD 20705 USA. EM xiangwu.nou@ars.usda.gov FU China Scholarship Council FX The authors thank Michigan State University EHEC Stock Center for providing E. coli O104:H4 strain TW16133, and Yale University E. coli Genetic Stock Center for providing pKD78 used in this study. Y. Xu is a pre-doctoral visiting student from Northwest A&F University, China, and is supported by China Scholarship Council. NR 25 TC 3 Z9 3 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1605 EI 1879-3460 J9 INT J FOOD MICROBIOL JI Int. J. Food Microbiol. PD JUL 16 PY 2016 VL 229 BP 44 EP 51 DI 10.1016/j.ijfoodmicro.2016.04.007 PG 8 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA DO6XR UT WOS:000377927300006 PM 27099984 ER PT J AU Gulati, R Feuer, EJ Etzioni, R AF Gulati, Roman Feuer, Eric J. Etzioni, Ruth TI Conditions for Valid Empirical Estimates of Cancer Overdiagnosis in Randomized Trials and Population Studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bias; early detection of cancer; mass screening; mathematical model; overdiagnosis; randomized clinical trial ID PROSTATE-SPECIFIC ANTIGEN; INVASIVE BREAST-CANCER; LEAD-TIME MODELS; SOJOURN TIME; FOLLOW-UP; SCREENING MAMMOGRAPHY; MORTALITY; SENSITIVITY; AGE; ERSPC AB Cancer overdiagnosis is frequently estimated using the excess incidence in a screened group relative to that in an unscreened group. However, conditions for unbiased estimation are poorly understood. We developed a mathematical framework to project the effects of screening on the incidence of relevant cancers-that is, cancers that would present clinically without screening. Screening advances the date of diagnosis for a fraction of preclinical relevant cancers. Which diagnoses are advanced and by how much depends on the preclinical detectable period, test sensitivity, and screening patterns. Using the model, we projected incidence in common trial designs and population settings and compared excess incidence with true overdiagnosis. In trials with no control arm screening, unbiased estimates are available using cumulative incidence if the screen arm stops screening and using annual incidence if the screen arm continues screening. In both designs, unbiased estimation requires waiting until screening stabilizes plus the maximum preclinical period. In continued-screen trials and population settings, excess cumulative incidence is persistently biased. We investigated this bias in published estimates from the European Randomized Study of Screening for Prostate Cancer after 9-13 years. In conclusion, no trial or population setting automatically permits unbiased estimation of overdiagnosis; sufficient follow-up and appropriate analysis remain crucial. C1 [Gulati, Roman; Etzioni, Ruth] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,M2-B230,POB 19024, Seattle, WA 98109 USA. [Feuer, Eric J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Gulati, R (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,M2-B230,POB 19024, Seattle, WA 98109 USA. EM rgulati@fredhutch.org FU National Cancer Institute at the National Institutes of Health [R01 CA192402, U01 CA199338] FX This work was supported by the National Cancer Institute at the National Institutes of Health (grants R01 CA192402 and U01 CA199338). NR 39 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 2016 VL 184 IS 2 BP 140 EP 147 DI 10.1093/aje/kwv342 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DV7FK UT WOS:000383101500007 PM 27358266 ER PT J AU Limou, S Taverner, AM Winkler, CA AF Limou, Sophie Taverner, Andrew M. Winkler, Cheryl A. TI Ferret: a user-friendly Java tool to extract data from the 1000 Genomes Project SO BIOINFORMATICS LA English DT Article ID GENETIC-VARIATION AB The 1000 Genomes (1KG) Project provides a near-comprehensive resource on human genetic variation in worldwide reference populations. 1KG variants can be accessed through a browser and through the raw and annotated data that are regularly released on an ftp server. We developed Ferret, a user-friendly Java tool, to easily extract genetic variation information from these large and complex data files. From a locus, gene(s) or SNP(s) of interest, Ferret retrieves genotype data for 1KG SNPs and indels, and computes allelic frequencies for 1KG populations and optionally, for the Exome Sequencing Project populations. By converting the 1KG data into files that can be imported into popular pre-existing tools (e.g. PLINK and HaploView), Ferret offers a straightforward way, even for non-bioinformatics specialists, to manipulate, explore and merge 1KG data with the user's dataset, as well as visualize linkage disequilibrium pattern, infer haplotypes and design tagSNPs. C1 [Limou, Sophie; Taverner, Andrew M.; Winkler, Cheryl A.] NCI, Mol Genet Epidemiol Sect, Basic Res Lab, Basic Sci Program,Leidos Biomed Res Inc,Frederick, Frederick, MD 21702 USA. [Taverner, Andrew M.] Princeton Univ, Quantitat & Computat Biol Program, Princeton, NJ 08544 USA. RP Limou, S (reprint author), NCI, Mol Genet Epidemiol Sect, Basic Res Lab, Basic Sci Program,Leidos Biomed Res Inc,Frederick, Frederick, MD 21702 USA. EM ferret@nih.gov NR 10 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUL 15 PY 2016 VL 32 IS 14 BP 2224 EP 2226 DI 10.1093/bioinformatics/btw147 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA DT1SZ UT WOS:000381263700026 PM 27153588 ER PT J AU Zhang, YL Fox, JT Park, YU Elliott, G Rai, G Cai, ML Sakamuru, S Huang, RL Xia, MH Lee, K Jeon, MH Mathew, BP Park, HD Edelmann, W Park, CY Hong, SY Maloney, D Myung, K AF Zhang, Yongliang Fox, Jennifer T. Park, Young-Un Elliott, Gene Rai, Ganesha Cai, Mengli Sakamuru, Srilatha Huang, Ruili Xia, Menghang Lee, Kyeryoung Jeon, Min Ho Mathew, Bijoy P. Park, Hee Dong Edelmann, Winfried Park, Chan Young Hong, Sung You Maloney, David Myung, Kyungjae TI A Novel Chemotherapeutic Agent to Treat Tumors with DNA Mismatch Repair Deficiencies SO CANCER RESEARCH LA English DT Article ID COLORECTAL-CANCER; DAMAGE RESPONSE; LYNCH SYNDROME; BAICALEIN; CELLS; MSH2; SUSCEPTIBILITY; SCUTELLARIA; MECHANISMS; STABILITY AB Impairing the division of cancer cells with genotoxic small molecules has been a primary goal to develop chemotherapeutic agents. However, DNA mismatch repair (MMR)-deficient cancer cells are resistant to most conventional chemotherapeutic agents. Here we have identified baicalein as a small molecule that selectively kills MutS alpha-deficient cancer cells. Baicalein binds preferentially to mismatched DNA and induces a DNA damage response in a MMR-dependent manner. In MutS alpha-proficient cells, baicalein binds to MutS alpha to dissociate CHK2 from MutS alpha leading to S-phase arrest and cell survival. In contrast, continued replication in the presence of baicalein in MutS alpha-deficient cells results in a high number of DNA double-strand breaks and ultimately leads to apoptosis. Consistently, baicalein specifically shrinks MutS alpha-deficient xenograft tumors and inhibits the growth of AOM-DSS-induced colon tumors in colon-specific MSH2 knockout mice. Collectively, baicalein offers the potential of an improved treatment option for patients with tumors with a DNA MMR deficiency. (C)2016 AACR. C1 [Zhang, Yongliang; Fox, Jennifer T.; Myung, Kyungjae] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Park, Young-Un; Mathew, Bijoy P.; Hong, Sung You; Myung, Kyungjae] Inst Basic Sci, Ctr Genom Integr, Ulsan 68979, South Korea. [Park, Young-Un; Park, Chan Young; Myung, Kyungjae] Ulsan Natl Inst Sci & Technol, Sch Life Sci, Dept Biol Sci, Ulsan, South Korea. [Elliott, Gene] NHGRI, Transgen Mouse Core, NIH, Bethesda, MD 20892 USA. [Rai, Ganesha; Sakamuru, Srilatha; Huang, Ruili; Xia, Menghang; Maloney, David] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Cai, Mengli] NIDDK, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. [Lee, Kyeryoung; Edelmann, Winfried] Albert Einstein Coll Med, Michael F Price Ctr, New York, NY USA. [Jeon, Min Ho; Mathew, Bijoy P.; Hong, Sung You] Ulsan Natl Inst Sci & Technol, Sch Energy & Chem Engn, Ulsan, South Korea. [Park, Hee Dong] LG Life Sci Ltd, Inst Drug Discovery Res & Dev, Daejeon, South Korea. RP Myung, K (reprint author), Inst Basic Sci, UNIST Gil 50, Ulsan 68979, South Korea. EM kmyung@ibs.re.kr RI Hong, Sung You/G-2323-2011; Mathew, Bijoy/Q-7906-2016 OI Hong, Sung You/0000-0002-5785-4475; Mathew, Bijoy/0000-0002-6060-4936 FU Intramural NIH HHS [ZIA HG200376-04, Z99 HG999999, ZIA HG200376-01, ZIA HG200376-02, ZIA HG200376-03]; NCI NIH HHS [R01 CA076329] NR 35 TC 0 Z9 0 U1 3 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2016 VL 76 IS 14 BP 4183 EP 4191 DI 10.1158/0008-5472.CAN-15-2974 PG 9 WC Oncology SC Oncology GA DS9NY UT WOS:000381111400016 PM 27262172 ER PT J AU Yamada, K Uchiyama, A Uehara, A Perera, B Ogino, S Yokoyama, Y Takeuchi, Y Udey, MC Ishikawa, O Motegi, SI AF Yamada, Kazuya Uchiyama, Akihiko Uehara, Akihito Perera, Buddhini Ogino, Sachiko Yokoyama, Yoko Takeuchi, Yuko Udey, Mark C. Ishikawa, Osamu Motegi, Sei-ichiro TI MFG-E8 Drives Melanoma Growth by Stimulating Mesenchymal Stromal Cell-Induced Angiogenesis and M2 Polarization of Tumor-Associated Macrophages SO CANCER RESEARCH LA English DT Article ID STEM-CELLS; BONE-MARROW; FACTOR-VIII; IN-VIVO; MILK; NEOVASCULARIZATION; TRANSPLANTATION; IDENTIFICATION; ENDOTHELIN-1; RECRUITMENT AB Secretion of the powerful angiogenic factor MFG-E8 by pericytes can bypass the therapeutic effects of anti-VEGF therapy, but the mechanisms by which MFG-E8 acts are not fully understood. In this study, we investigated how this factor acts to promote the growth of melanomas that express it. We found that mouse bone marrow-derived mesenchymal stromal cells (MSC) expressed a substantial amount of MFG-E8. To assess its expression from this cell type, we implanted melanoma cells and MSC derived from wild type (WT) or MFG-E8 deficient [knockout (KO)] into mice and monitored tumor growth. Tumor growth and M2 macrophages were each attenuated in subjects coimplanted with KO-MSC compared with WT-MSC. In both xenograft tumors and clinical specimens of melanoma, we found that MFG-E8 expression was heightened near blood vessels where MSC could be found. Through in vitro assays, we confirmed that WT-MSC-conditioned medium was more potent at inducing M2 macrophage polarization, compared with KO-MSC-conditioned medium. VEGF and ET-1 expression in KO-MSC was significantly lower than in WT-MSC, correlating in vivo with reduced tumor growth and numbers of pericytes and M2 macrophages within tumors. Overall, our results suggested that MFG-E8 acts at two levels, by increasing VEGF and ET-1 expression in MSC and by enhancing M2 polarization of macrophages, to increase tumor angiogenesis. (C)2016 AACR. C1 [Yamada, Kazuya; Uchiyama, Akihiko; Uehara, Akihito; Perera, Buddhini; Ogino, Sachiko; Yokoyama, Yoko; Takeuchi, Yuko; Ishikawa, Osamu; Motegi, Sei-ichiro] Gunma Univ, Grad Sch Med, Dept Dermatol, 3-39-22 Showa, Maebashi, Gunma 3718511, Japan. [Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Motegi, SI (reprint author), Gunma Univ, Grad Sch Med, Dept Dermatol, 3-39-22 Showa, Maebashi, Gunma 3718511, Japan. EM smotegi@gunma-u.ac.jp OI Ishikawa, Osamu/0000-0002-7655-0610 FU Intramural NIH HHS [Z01 SC003669-18, Z01 SC003669-19, Z99 CA999999] NR 44 TC 5 Z9 6 U1 6 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2016 VL 76 IS 14 BP 4283 EP 4292 DI 10.1158/0008-5472.CAN-15-2812 PG 10 WC Oncology SC Oncology GA DS9NY UT WOS:000381111400025 PM 27197197 ER PT J AU Coghill, AE Bu, W Nguyen, H Hsu, WL Yu, KJ Lou, PJ Wang, CP Chen, CJ Hildesheim, A Cohen, JI AF Coghill, Anna E. Bu, Wei Hanh Nguyen Hsu, Wan-Lun Yu, Kelly J. Lou, Pei-Jen Wang, Cheng-Ping Chen, Chien-Jen Hildesheim, Allan Cohen, Jeffrey I. TI High Levels of Antibody that Neutralize B-cell Infection of Epstein-Barr Virus and that Bind EBV gp350 Are Associated with a Lower Risk of Nasopharyngeal Carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID HPV-16/18 AS04-ADJUVANTED VACCINE; COSTA-RICA VACCINE; EPITHELIAL-CELLS; MEMBRANE ANTIGEN; DOUBLE-BLIND; GLYCOPROTEIN; MONONUCLEOSIS; EFFICACY; TAIWAN; TRIAL AB Purpose: Elevated IgA antibodies indicative of ongoing exposure to Epstein-Barr virus (EBV) are high-risk biomarkers for nasopharyngeal carcinoma (NPC), an EBV-related epithelial tumor. However, protective biomarkers that limit exposure to the virus have not been defined. We evaluated whether antibodies that can neutralize EBV infection by targeting glycoproteins involved in viral cell entry, including EBV vaccine candidate glycoprotein 350 (gp350), were associated with lower NPC risk. Experimental Design: In a prospective cohort of 2,557 individuals from 358 high-risk NPC multiplex families in Taiwan, we identified 21 incident NPC cases and 50 disease-free controls. To complement data from high-risk families, we further identified 30 prevalent NPC cases and 50 healthy controls from the general Taiwanese population. We quantified EBV-neutralizing antibody, antibodies against EBV glycoproteins involved in B-cell and epithelial cell entry, and anti-EBNA1 IgA, a high-risk NPC biomarker. Results: EBV-neutralizing antibodies blocking B-cell infection and anti-gp350 antibodies were present at significantly higher levels in disease-free controls compared with incident NPC cases (P < 0.03). Family members with both low EBV-neutralizing potential and elevated EBNA1 IgA had a 7-fold increased risk of NPC (95% CI, 1.9-28.7). Neutralizing antibodies against epithelial cell infection did not differ between incident cases and disease-free controls. Anti-glycoprotein antibody levels measured at diagnosis (prevalent NPC) were significantly higher than levels measured prior to diagnosis (P < 0.01). Conclusions: Elevated titers of EBV-neutralizing antibody and anti-gp350 antibody were low-risk biomarkers for NPC. These data suggest that a vaccine that induces potent EBV gp350 and B-cell-neutralizing antibodies could reduce the risk of EBV-related cancers such as NPC. (C) 2016 AACR. C1 [Coghill, Anna E.; Yu, Kelly J.; Hildesheim, Allan] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bu, Wei; Hanh Nguyen; Cohen, Jeffrey I.] NIAID, Infect Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hsu, Wan-Lun; Chen, Chien-Jen] Natl Taiwan Univ, Grad Inst Epidemiol, Coll Publ Hlth, Taipei, Taiwan. [Hsu, Wan-Lun; Chen, Chien-Jen] Acad Sinica, Genom Res Ctr, Taipei, Taiwan. [Yu, Kelly J.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Lou, Pei-Jen; Wang, Cheng-Ping] Natl Taiwan Univ Hosp, Dept Otolaryngol, Taipei, Taiwan. [Coghill, Anna E.; Lou, Pei-Jen; Wang, Cheng-Ping] Coll Med, Taipei, Taiwan. RP Coghill, AE (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20892 USA. EM anna.coghill@nih.gov FU Intramural Research Program of the NCI; National Institute of Allergy and Infectious Diseases at the NIH FX This research was supported by the Intramural Research Program of the NCI and the National Institute of Allergy and Infectious Diseases at the NIH. NR 46 TC 1 Z9 1 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2016 VL 22 IS 14 BP 3451 EP 3457 DI 10.1158/1078-0432.CCR-15-2299 PG 7 WC Oncology SC Oncology GA DS9ON UT WOS:000381113000006 PM 26920891 ER PT J AU Satoh, K Zhang, LS Zhang, YQ Chelluri, R Boufraqech, M Nilubol, N Patel, D Shen, M Kebebew, E AF Satoh, Kei Zhang, Lisa Zhang, Yaqin Chelluri, Raju Boufraqech, Myriem Nilubol, Naris Patel, Dhaval Shen, Min Kebebew, Electron TI Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID TARGETING MITOCHONDRIA; CLINICAL MANAGEMENT; CANCER-THERAPY; OVARIAN-CANCER; BETA-CATENIN; CELLS; INHIBITION; METABOLISM; MUTATIONS; PATHWAY AB Purpose: Adrenocortical carcinoma (ACC) is a rare and aggressive cancer, and no current effective therapy is available for locally advanced and metastatic ACC. Drug repurposing is an emerging approach for identifying new indications for existing drugs, especially for rare cancers such as ACC. The objective of this study was to use quantitative high-throughput screening to identify agents with antineoplastic activity against ACC. Experimental Design: A screening of 4,292 compounds was performed on three ACC cell lines: BD140A, SW-13, and NCI-H295R. Results: Twenty-one active compounds were identified, with an efficacy of >80% in all three cell lines. Of these, niclosamide showed higher efficacy and lower IC50 than established anti-ACC drugs. We then validated niclosamide-inhibited cellular proliferation in all three ACC cell lines. Next, we investigated the mechanism by which niclosamide inhibited ACC cell proliferation, and found that it induced caspase-dependent apoptosis and G(1) cell-cycle arrest. Niclosamide also decreased cellular migration and reduced the level of mediators of epithelial-to-mesenchymal transition, such as N-cadherin and vimentin. Furthermore, niclosamide treatment resulted in decreased expression of beta-catenin. We also evaluated the effect of niclosamide on energy metabolism in ACC cell lines and found it resulted in mitochondrial uncoupling. Niclosamide treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Conclusions: Our findings suggest that niclosamide has anti-ACC activity through its inhibition of multiple altered cellular pathways and cellular metabolism in ACC. Our results provide a preclinical rationale for evaluating niclosamide therapy in a clinical trial for ACC. (C)2016 AACR. C1 [Satoh, Kei; Zhang, Lisa; Boufraqech, Myriem; Nilubol, Naris; Patel, Dhaval; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Satoh, Kei] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Zhang, Yaqin; Shen, Min] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Chelluri, Raju] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov OI Patel, Dhaval/0000-0002-5744-568X FU intramural research program of the Center for Cancer Research, National Cancer Institute; National Center for Advancing Translational Sciences intramural program, NIH [Z1B HG200319-08]; NIH Medical Research Scholars Program; NIH FX This work was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Center for Advancing Translational Sciences intramural program Z1B HG200319-08, NIH, and the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Newport Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. NR 40 TC 3 Z9 3 U1 3 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2016 VL 22 IS 14 BP 3458 EP 3466 DI 10.1158/1078-0432.CCR-15-2256 PG 9 WC Oncology SC Oncology GA DS9ON UT WOS:000381113000007 PM 26873959 ER PT J AU Palanichamy, K Thirumoorthy, K Kanji, S Gordon, N Singh, R Jacob, JR Sebastian, N Litzenberg, KT Patel, D Bassett, E Ramasubramanian, B Lautenschlaeger, T Fischer, SM Ray-Chaudhury, A Chakravarti, A AF Palanichamy, Kamalakannan Thirumoorthy, Krishnan Kanji, Suman Gordon, Nicolaus Singh, Rajbir Jacob, John R. Sebastian, Nikhil Litzenberg, Kevin T. Patel, Disha Bassett, Emily Ramasubramanian, Brinda Lautenschlaeger, Tim Fischer, Steven M. Ray-Chaudhury, Abhik Chakravarti, Arnab TI Methionine and Kynurenine Activate Oncogenic Kinases in Glioblastoma, and Methionine Deprivation Compromises Proliferation SO CLINICAL CANCER RESEARCH LA English DT Article ID ARYL-HYDROCARBON RECEPTOR; METHYLTHIOADENOSINE PHOSPHORYLASE; C-11-METHIONINE PET; TUMOR XENOGRAFTS; GRADE GLIOMAS; CELL-CULTURE; T-CELLS; CANCER; METABOLOMICS; PATHWAY AB Purpose: We employed a metabolomics-based approach with the goal to better understand the molecular signatures of glioblastoma cells and tissues, with an aim toward identifying potential targetable biomarkers for developing more effective and novel therapies. Experimental Design: We used liquid chromatography coupled with mass spectrometry (LC-MS/Q-TOF and LC-MS/QQQ) for the discovery and validation of metabolites from primary and established glioblastoma cells, glioblastoma tissues, and normal human astrocytes. Results: We identified tryptophan, methionine, kynurenine, and 5-methylthioadenosine as differentially regulated metabolites (DRM) in glioblastoma cells compared with normal human astrocytes (NHAs). Unlike NHAs, glioblastoma cells depend on dietary methionine for proliferation, colony formation, survival, and to maintain a deregulated methylome (SAM: SAH ratio). In methylthioadenosine phosphorylase (MTAP)-deficient glioblas-toma cells, expression of MTAP transgene did not alter methionine dependency, but compromised tumor growth in vivo. We discovered that a lack of the kynurenine-metabolizing enzymes kynurenine monooxygenase and/or kynureninase promotes the accumulation of kynurenine, which triggers immune evasion in glioblastoma cells. In silico analysis of the identified DRMs mapped the activation of key oncogenic kinases that promotes tumorigenesis in glioblastoma. We validated this result by demonstrating that the exogenous addition of DRMs to glioblastoma cells in vitro results in oncogene activation as well as the simultaneous downregulation of Ser/Thr phosphatase PP2A. Conclusions: We have connected a four-metabolite signature, implicated in the methionine and kynurenine pathways, to the promotion and maintenance of glioblastoma. Together, our data suggest that these metabolites and their respective metabolic pathways serve as potential therapeutic targets for glioblastoma. (C)2016 AACR. C1 [Palanichamy, Kamalakannan; Thirumoorthy, Krishnan; Kanji, Suman; Gordon, Nicolaus; Singh, Rajbir; Jacob, John R.; Sebastian, Nikhil; Litzenberg, Kevin T.; Patel, Disha; Bassett, Emily; Ramasubramanian, Brinda; Lautenschlaeger, Tim; Chakravarti, Arnab] Ohio State Univ, Coll Med, James Canc Hosp, Dept Radiat Oncol, Columbus, OH USA. [Palanichamy, Kamalakannan; Thirumoorthy, Krishnan; Kanji, Suman; Gordon, Nicolaus; Singh, Rajbir; Jacob, John R.; Sebastian, Nikhil; Litzenberg, Kevin T.; Patel, Disha; Bassett, Emily; Ramasubramanian, Brinda; Lautenschlaeger, Tim; Chakravarti, Arnab] Ohio State Univ, Coll Med, Solove Res Inst, Columbus, OH USA. [Palanichamy, Kamalakannan; Thirumoorthy, Krishnan; Kanji, Suman; Gordon, Nicolaus; Singh, Rajbir; Jacob, John R.; Sebastian, Nikhil; Litzenberg, Kevin T.; Patel, Disha; Bassett, Emily; Ramasubramanian, Brinda; Lautenschlaeger, Tim; Chakravarti, Arnab] Ctr Comprehens Canc, Wiseman Hall 385E,410 W 12th Ave, Columbus, OH 43210 USA. [Thirumoorthy, Krishnan] VIT Univ, Sch Adv Sci, Environm Analyt Chem Div, Vellore, Tamil Nadu, India. [Fischer, Steven M.] Agilent Technol, Segment Marketing Life Sci Res, Santa Clara, CA USA. [Ray-Chaudhury, Abhik] NINDS, Neuropathol Unit, Surg Neurol Branch, NIH, Bethesda, MD USA. RP Palanichamy, K (reprint author), Ctr Comprehens Canc, Wiseman Hall 385E,410 W 12th Ave, Columbus, OH 43210 USA.; Palanichamy, K (reprint author), Ohio State Univ, Coll Med, Dept Radiat Oncol, Wiseman Hall 385E,410 W 12th Ave, Columbus, OH 43210 USA. EM Kamalakannan.palanichamy@osumc.edu FU NIH/NCI [R01CA108633, RC2CA148190]; Brain Tumor Funders Collaborative Group; Arthur G. James Comprehensive Cancer Center FX This work was supported by NIH/NCI awards R01CA108633, RC2CA148190, The Brain Tumor Funders Collaborative Group, and The Arthur G. James Comprehensive Cancer Center. NR 50 TC 3 Z9 3 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2016 VL 22 IS 14 BP 3513 EP 3523 DI 10.1158/1078-0432.CCR-15-2308 PG 11 WC Oncology SC Oncology GA DS9ON UT WOS:000381113000012 PM 26936918 ER PT J AU Vo, KT Edwards, JV Epling, CL Sinclair, E Hawkins, DS Grier, HE Janeway, KA Barnette, P Mcllvaine, E Krailo, MD Barkauskas, DA Matthay, KK Womer, RB Gorlick, RG Lessnick, SL Mackall, CL DuBois, SG AF Vo, Kieuhoa T. Edwards, Jeremy V. Epling, C. Lorrie Sinclair, Elizabeth Hawkins, Douglas S. Grier, Holcombe E. Janeway, Katherine A. Barnette, Phillip Mcllvaine, Elizabeth Krailo, Mark D. Barkauskas, Donald A. Matthay, Katherine K. Womer, Richard B. Gorlick, Richard G. Lessnick, Stephen L. Mackall, Crystal L. DuBois, Steven G. TI Impact of Two Measures of Micrometastatic Disease on Clinical Outcomes in Patients with Newly Diagnosed Ewing Sarcoma: A Report from the Children's Oncology Group SO CLINICAL CANCER RESEARCH LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; CIRCULATING TUMOR-CELLS; BONE-MARROW; GROWTH-FACTOR; RT-PCR; RECEPTOR ANTIBODY; PERIPHERAL-BLOOD; FLOW-CYTOMETRY; PHASE-II; EXPRESSION AB Purpose: Flow cytometry and RT-PCR can detect occult Ewing sarcoma cells in the blood and bone marrow. These techniques were used to evaluate the prognostic significance of micrometastatic disease in Ewing sarcoma. Experimental Design: Newly diagnosed patients with Ewing sarcoma were enrolled on two prospective multicenter studies. In the flow cytometry cohort, patients were defined as "positive" for bone marrow micrometastatic disease if their CD99(+)/CD45(-) values were above the upper limit in 22 control patients. In the PCR cohort, RT-PCR on blood or bone marrow samples classified the patients as "positive" or "negative" for EWSR1/FLI1 translocations. The association between micrometastatic disease burden with clinical features and outcome was assessed. Coexpression of insulin-like growth factor-1 receptor (IGF-1R) on detected tumor cells was performed in a subset of flow cytometry samples. Results: The median total bone marrow CD99(+)CD45(-) percent was 0.0012%(range0%-1.10%) in the flow cytometry cohort, with 14 of 109 (12.8%) of Ewing sarcoma patients defined as "positive." In the PCR cohort, 19.6%(44/225) patients were "positive" for any EWSR1/FLI1 translocation in blood or bone marrow. There were no differences in baseline clinical features or event-free or overall survival between patients classified as "positive" versus "negative" by either method. CD99(+)CD45(-) cells had significantly higher IGF-1R expression compared with CD45(+) hematopoietic cells (mean geometric mean fluorescence intensity 982.7 vs. 190.9; P < 0.001). Conclusions: The detection of micrometastatic disease at initial diagnosis by flow cytometry or RT-PCR is not associated with outcome in newly diagnosed patients with Ewing sarcoma. Flow cytometry provides a tool to characterize occult micrometastatic tumor cells for proteins of interest. (C) 2016 AACR. C1 [Vo, Kieuhoa T.; Matthay, Katherine K.; DuBois, Steven G.] Univ Calif San Francisco, Sch Med, Dept Pediat, UCSF Benioff Childrens Hosp, San Francisco, CA 94143 USA. [Edwards, Jeremy V.] Walter Reed Army Med Ctr, Dept Pediat, Washington, DC 20307 USA. [Epling, C. Lorrie; Sinclair, Elizabeth] Univ Calif San Francisco, Sch Med, UCSF Benioff Childrens Hosp, Div Expt Med,Core Immunol Lab, San Francisco, CA USA. [Hawkins, Douglas S.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle Childrens Hosp, Div Hematol Oncol, Seattle, WA 98195 USA. [Grier, Holcombe E.; Janeway, Katherine A.] Harvard Med Sch, Dana Farber Boston Childrens Canc & Blood Disords, Boston, MA USA. [Barnette, Phillip] Univ Utah, Huntsman Canc Inst, Ctr Childrens Canc Res, Dept Pediat Hematol Oncol, Salt Lake City, UT USA. [Mcllvaine, Elizabeth; Krailo, Mark D.; Barkauskas, Donald A.] Univ Southern Calif, Keck Sch Med, Dept Preventat Med, Los Angeles, CA 90033 USA. [Womer, Richard B.] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Gorlick, Richard G.] Albert Einstein Coll Med, Childrens Hosp Montefiore, Div Pediat Hematol Oncol, Bronx, NY 10467 USA. [Lessnick, Stephen L.] Ohio State Univ, Ctr Childhood Canc & Blood Disorders, Nationwide Childrens Hosp, Columbus, OH 43210 USA. [Lessnick, Stephen L.] Ohio State Univ, Div Hematol Oncol & BMT, Columbus, OH 43210 USA. [Mackall, Crystal L.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP DuBois, SG (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 3, Boston, MA 02215 USA. EM steven_dubois@dfci.harvard.edu FU NIH [K23 CA154530, P30AI027763]; NIH Intramural Research Program; Alex's Lemonade Stand Foundation; Frank A. Campini Foundation; Hope Street Kids; Sarcoma Foundation of America; CureSearch for Children's Cancer; John M. Gilbertson Foundation; Daniel P. Sullivan Fund; WWWW (QuadW) Foundation; Children's Oncology Group grants [U10CA180886, U10CA180899, U10CA098543, U10CA098413] FX This work was supported in part by the NIH grant K23 CA154530 (to S.G. DuBois); NIH Intramural Research Program (to C.L. Mackall); NIH grant P30AI027763 to the UCSF-GIVI Center for AIDS Research (UCSF Flow Cytometry Core Laboratory); Alex's Lemonade Stand Foundation (to K.T. Vo, K.K. Matthay, and S.G. DuBois); Frank A. Campini Foundation (to K.K. Matthay and S.G. DuBois); Hope Street Kids (to S.G. DuBois); Sarcoma Foundation of America (to S.G. DuBois); CureSearch for Children's Cancer (to S.G. DuBois); John M. Gilbertson Foundation (to D.S. Hawkins); Daniel P. Sullivan Fund (to R.B. Womer); WWWW (QuadW) Foundation (to M.D. Krailo and D.A. Barkauskas); Children's Oncology Group grants (U10CA180886, U10CA180899, U10CA098543, and U10CA098413). NR 27 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2016 VL 22 IS 14 BP 3643 EP 3650 DI 10.1158/1078-0432.CCR-15-2516 PG 8 WC Oncology SC Oncology GA DS9ON UT WOS:000381113000023 PM 26861456 ER PT J AU Srivastava, AK Hollingshead, MG Weiner, J Navas, T Evrard, YA Khin, SA Ji, JJ Zhang, YP Borgel, S Pfister, TD Kinders, RJ Bottaro, DP Linehan, WM Tomaszewski, JE Doroshow, JH Parchment, RE AF Srivastava, Apurva K. Hollingshead, Melinda G. Weiner, Jennifer Navas, Tony Evrard, Yvonne A. Khin, Sonny A. Ji, Jiuping Jay Zhang, Yiping Borgel, Suzanne Pfister, Thomas D. Kinders, Robert J. Bottaro, Donald P. Linehan, W. Marston Tomaszewski, Joseph E. Doroshow, James H. Parchment, Ralph E. TI Pharmacodynamic Response of the MET/HGF Receptor to Small-Molecule Tyrosine Kinase Inhibitors Examined with Validated, Fit-for-Clinic Immunoassays SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; GROWTH-FACTOR-RECEPTOR; ADP-RIBOSE POLYMERASE; TIVANTINIB ARQ 197; C-MET; DOUBLE-BLIND; ADVANCED MALIGNANCIES; MONOCLONAL-ANTIBODY; CYTOTOXIC ACTIVITY; ANTITUMOR-ACTIVITY AB Purpose: Rational development of targeted MET inhibitors for cancer treatment requires a quantitative understanding of target pharmacodynamics, including molecular target engagement, mechanism of action, and duration of effect. Experimental Design: Sandwich immunoassays and specimen handling procedures were developed and validated for quantifying full-length MET and its key phosphospecies (pMET) in core tumor biopsies. MET was captured using an antibody to the extracellular domain and then probed using antibodies to its C-terminus (full-length) and epitopes containing pY1234/1235, pY1235, and pY1356. Using pMET: MET ratios as assay endpoints, MET inhibitor pharmacodynamics were characterized in MET-amplified and-compensated (VEGFR blockade) models. Results: By limiting cold ischemia time to less than two minutes, the pharmacodynamic effects of the MET inhibitors PHA665752 and PF02341066 (crizotinib) were quantifiable using core needle biopsies of human gastric carcinoma xenografts (GTL-16 and SNU5). One dose decreased pY1234/1235 MET: MET, pY1235-MET: MET, and pY1356-MET: MET ratios by 60% to 80% within 4 hours, but this effect was not fully sustained despite continued daily dosing. VEGFR blockade by pazopanib increased pY1235-MET: MET and pY1356-MET: MET ratios, which was reversed by tivantinib. Full-length MET was quantifiable in 5 of 5 core needle samples obtained from a resected hereditary papillary renal carcinoma, but the levels of pMET species were near the assay lower limit of quantitation. Conclusions: These validated immunoassays for pharmacodynamic biomarkers of MET signaling are suitable for studying MET responses in amplified cancers as well as compensatory responses to VEGFR blockade. Incorporating pharmacodynamic biomarker studies into clinical trials of MET inhibitors could provide critical proof of mechanism and proof of concept for the field. (C) 2016 AACR. C1 [Srivastava, Apurva K.; Weiner, Jennifer; Navas, Tony; Evrard, Yvonne A.; Khin, Sonny A.; Pfister, Thomas D.; Kinders, Robert J.; Parchment, Ralph E.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Appl Dev Res Directorate, Lab Human Toxicol & Pharmacol, Frederick, MD USA. [Hollingshead, Melinda G.] Frederick Natl Lab Canc Res, Biol Testing Branch, Dev Therapeut Program, Frederick, MD USA. [Ji, Jiuping Jay; Zhang, Yiping] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Natl Clin Target Validat Lab, Appl Dev Res Directorate, Frederick, MD USA. [Borgel, Suzanne] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Appl Dev Res Directorate, In Vivo Evaluat Grp, Frederick, MD USA. [Bottaro, Donald P.; Linehan, W. Marston] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Tomaszewski, Joseph E.; Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Parchment, RE (reprint author), Frederick Natl Lab Canc Res, 1050 Boyles St, Frederick, MD 21702 USA. EM parchmentr@mail.nih.gov FU NCI, NIH [HHSN261200800001E] FX Grant Support This project has been funded in whole or in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E. NR 53 TC 3 Z9 3 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2016 VL 22 IS 14 BP 3683 EP 3694 DI 10.1158/1078-0432.CCR-15-2323 PG 12 WC Oncology SC Oncology GA DS9ON UT WOS:000381113000027 PM 27001313 ER PT J AU Mishra, PK Ciftci-Yilmaz, S Reynolds, D Au, WC Boeckmann, L Dittman, LE Jowhar, Z Pachpor, T Yeh, E Baker, RE Hoyt, MA D'Amours, D Bloom, K Basrai, MA AF Mishra, Prashant K. Ciftci-Yilmaz, Sultan Reynolds, David Au, Wei-Chun Boeckmann, Lars Dittman, Lauren E. Jowhar, Ziad Pachpor, Tejaswini Yeh, Elaine Baker, Richard E. Hoyt, M. Andrew D'Amours, Damien Bloom, Kerry Basrai, Munira A. TI Polo kinase Cdc5 associates with centromeres to facilitate the removal of centromeric cohesin during mitosis SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID SISTER-CHROMATID COHESION; CHROMOSOME TRANSMISSION FIDELITY; H3 VARIANT CSE4; SACCHAROMYCES-CEREVISIAE; BUDDING YEAST; PROTEIN-KINASE; MITOTIC EXIT; REC8 PHOSPHORYLATION; ANAPHASE INITIATION; SOMATIC MUTATIONS AB Sister chromatid cohesion is essential for tension-sensing mechanisms that monitor bipolar attachment of replicated chromatids in metaphase. Cohesion is mediated by the association of cohesins along the length of sister chromatid arms. In contrast, centromeric cohesin generates intrastrand cohesion and sister centromeres, while highly cohesin enriched, are separated by >800 nm at metaphase in yeast. Removal of cohesin is necessary for sister chromatid separation during anaphase, and this is regulated by evolutionarily conserved polo-like kinase (Cdc5 in yeast, Plk1 in humans). Here we address how high levels of cohesins at centromeric chromatin are removed. Cdc5 associates with centromeric chromatin and cohesin-associated regions. Maximum enrichment of Cdc5 in centromeric chromatin occurs during the metaphase-to-anaphase transition and coincides with the removal of chromosome- associated cohesin. Cdc5 interacts with cohesin in vivo, and cohesin is required for association of Cdc5 at centromeric chromatin. Cohesin removal from centromeric chromatin requires Cdc5 but removal at distal chromosomal arm sites does not. Our results define a novel role for Cdc5 in regulating removal of centromeric cohesins and faithful chromosome segregation. C1 [Mishra, Prashant K.; Ciftci-Yilmaz, Sultan; Au, Wei-Chun; Boeckmann, Lars; Dittman, Lauren E.; Jowhar, Ziad; Pachpor, Tejaswini; Basrai, Munira A.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Reynolds, David; Hoyt, M. Andrew] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Yeh, Elaine; Bloom, Kerry] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Baker, Richard E.] Univ Massachusetts, Sch Med, Dept Microbiol & Physiol Syst, Worcester, MA 01655 USA. [D'Amours, Damien] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada. [D'Amours, Damien] Univ Montreal, Dept Pathol & Biol Cellulaire, Montreal, PQ H3C 3J7, Canada. [Ciftci-Yilmaz, Sultan] Turgut Ozal Univ, Fac Med, Dept Med Genet, TR-06010 Ankara, Turkey. RP Basrai, MA (reprint author), NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. EM basraim@nih.gov RI Ciftci-Yilmaz, Sultan/D-7971-2017 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health; National Science Foundation; National Institutes of Health [R37 GM32238]; Cancer Research Society; Canadian Institutes of Health Research [MOP 82912] FX We are highly thankful to Vincent Guacci and Robert Skibbens for strains, plasmids, and helpful suggestions. We thank Sue Biggins for plasmids and Jennifer Gerton for strains, Kathy McKinnon of the National Cancer Institute Vaccine Branch FACS Core for assistance with FACS and the Basrai laboratory for discussions. P.K.M., S.C.Y., W.C.A., L.B., L.E.D., Z.J., T.P., and M.A.B. were supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health; M.A.H. and D.R. by the National Science Foundation; E.Y. and K.B. by the National Institutes of Health (R37 GM32238); and D.D. by the Cancer Research Society and the Canadian Institutes of Health Research (MOP 82912). NR 94 TC 0 Z9 0 U1 0 U2 0 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 JUL 15 PY 2016 VL 27 IS 14 BP 2286 EP 2300 DI 10.1091/mbc.E16-01-0004 PG 15 WC Cell Biology SC Cell Biology GA DS5LL UT WOS:000380823500012 PM 27226485 ER PT J AU Rubinstein, BY Mattingly, HH Berezhkovskii, AM Shvartsman, SY AF Rubinstein, Boris Y. Mattingly, Henry H. Berezhkovskii, Alexander M. Shvartsman, Stanislav Y. TI Long-term dynamics of multisite phosphorylation SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; DUAL-SPECIFICITY PHOSPHATASE; MAP KINASE PHOSPHATASE; SUBSTRATE-DEPENDENT CONTROL; SIGNAL-REGULATED KINASE-2; OF-FUNCTION MUTATION; ORDERED PHOSPHORYLATION; IN-VIVO; PROCESSIVE PHOSPHORYLATION; FUNCTIONAL REDUNDANCY AB Multisite phosphorylation cycles are ubiquitous in cell regulation systems and are studied at multiple levels of complexity, from molecules to organisms, with the ultimate goal of establishing predictive understanding of the effects of genetic and pharmacological perturbations of protein phosphorylation in vivo. Achieving this goal is essentially impossible without mathematical models, which provide a systematic framework for exploring dynamic interactions of multiple network components. Most of the models studied to date do not discriminate between the distinct partially phosphorylated forms and focus on two limiting reaction regimes, distributive and processive, which differ in the number of enzyme-substrate binding events needed for complete phosphorylation or dephosphorylation. Here we use a minimal model of extracellular signal-related kinase regulation to explore the dynamics of a reaction network that includes all essential phosphorylation forms and arbitrary levels of reaction processivity. In addition to bistability, which has been studied extensively in distributive mechanisms, this network can generate periodic oscillations. Both bistability and oscillations can be realized at high levels of reaction processivity. Our work provides a general framework for systematic analysis of dynamics in multisite phosphorylation systems. C1 [Rubinstein, Boris Y.] Stowers Inst Med Res, Kansas City, MO 64110 USA. [Mattingly, Henry H.; Shvartsman, Stanislav Y.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Mattingly, Henry H.; Shvartsman, Stanislav Y.] Princeton Univ, Dept Chem & Biol Engn, Princeton, NJ 08544 USA. [Berezhkovskii, Alexander M.] NIH, Ctr Informat Technol, Div Computat Biosci, Math & Stat Comp Lab, Bethesda, MD 20892 USA. RP Shvartsman, SY (reprint author), Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA.; Shvartsman, SY (reprint author), Princeton Univ, Dept Chem & Biol Engn, Princeton, NJ 08544 USA. EM stas@princeton.edu FU National Institutes of Health [R01GM086537]; Intramural Research Program of the National Institutes of Health, Center for Information Technology FX We thank Anne Shiu, Jeremy Gunawardena, Heather Harrington, J. Krishnan, Boris Kholodenko, Rony Seger, Elizabeth Goldsmith, Alexey Veraksa, Irina Gopich, Georghe Craciun, and Alan Futran for helpful discussions and comments on the manuscript. H.H.M. and S.Y.S. were supported by National Institutes of Health Grant R01GM086537, and A.M.B. by the Intramural Research Program of the National Institutes of Health, Center for Information Technology. NR 86 TC 0 Z9 0 U1 4 U2 4 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 JUL 15 PY 2016 VL 27 IS 14 BP 2331 EP 2340 DI 10.1091/mbc.E16-03-0137 PG 10 WC Cell Biology SC Cell Biology GA DS5LL UT WOS:000380823500015 PM 27226482 ER PT J AU Shui, IM Wong, CJ Zhao, SS Kolb, S Ebot, EM Geybels, MS Rubicz, R Wright, JL Lin, DW Klotzle, B Bibikova, M Fan, JB Ostrander, EA Feng, ZD Stanford, JL AF Shui, Irene M. Wong, Chao-Jen Zhao, Shanshan Kolb, Suzanne Ebot, Ericka M. Geybels, Milan S. Rubicz, Rohina Wright, Jonathan L. Lin, Daniel W. Klotzle, Brandy Bibikova, Marina Fan, Jian-Bing Ostrander, Elaine A. Feng, Ziding Stanford, Janet L. TI Prostate tumor DNA methylation is associated with cigarette smoking and adverse prostate cancer outcomes SO CANCER LA English DT Article DE DNA methylation; epigenetics; prostate cancer; prostate cancer outcomes; smoking ID RADICAL PROSTATECTOMY; BIOCHEMICAL RECURRENCE; EXPRESSION DATA; HUMAN GENOME; GALECTIN-3; RISK; MORTALITY; ARRAY; HYPERMETHYLATION; IDENTIFICATION AB BACKGROUNDDNA methylation has been hypothesized as a mechanism for explaining the association between smoking and adverse prostate cancer (PCa) outcomes. This study was aimed at assessing whether smoking is associated with prostate tumor DNA methylation and whether these alterations may explain in part the association of smoking with PCa recurrence and mortality. METHODSA total of 523 men had radical prostatectomy as their primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes, and tumor tissue profiled for DNA methylation. Ninety percent of the men also had matched tumor gene expression data. A methylome-wide analysis was conducted to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, their correlation with the messenger RNA (mRNA) expression of corresponding genes was evaluated. Finally, a smoking-related methylation score based on the top-ranked DMRs was created to assess its association with PCa outcomes. RESULTSForty DMRs were associated with smoking status, and 10 of these were strongly correlated with mRNA expression (aldehyde oxidase 1 [AOX1], claudin 5 [CLDN5], early B-cell factor 1 [EBF1], homeobox A7 [HOXA7], lectin galactoside-binding soluble 3 [LGALS3], microtubule-associated protein [MAPT], protocadherin A [PCDHGA]/protocadherin B [PCDHGB], paraoxonase 3 [PON3], synaptonemal complex protein 2 like [SYCP2L], and zinc finger and SCAN domain containing 12 [ZSCAN12]). Men who were in the highest tertile for the smoking-methylation score derived from these DMRs had a higher risk of recurrence (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.42-3.72) and lethal disease (OR, 4.21; 95% CI, 1.65-11.78) in comparison with men in the lower 2 tertiles. CONCLUSIONSThis integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain at least part of the association between smoking and adverse PCa outcomes. Future studies are warranted to confirm these findings and understand the implications for improving patient outcomes. Cancer 2016;122:2168-77. (c) 2016 American Cancer Society. This unique analysis integrates smoking status, tumor DNA methylation, tumor gene expression, and long-term follow-up for prostate cancer outcomes. The results support the hypothesis that smoking-associated tumor DNA methylation changes may explain at least part of the association between smoking and adverse prostate cancer outcomes. C1 [Shui, Irene M.; Wong, Chao-Jen; Kolb, Suzanne; Geybels, Milan S.; Rubicz, Rohina; Wright, Jonathan L.; Lin, Daniel W.; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave North,POB 19024, Seattle, WA 98109 USA. [Shui, Irene M.; Ebot, Ericka M.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Zhao, Shanshan] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Wright, Jonathan L.; Lin, Daniel W.] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Klotzle, Brandy; Bibikova, Marina] Illumina Inc, San Diego, CA USA. [Fan, Jian-Bing] AnchorDx Corp, Guangzhou, Guangdong, Peoples R China. [Ostrander, Elaine A.] NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. [Feng, Ziding] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Stanford, Janet L.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. RP Shui, IM (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave North,POB 19024, Seattle, WA 98109 USA. EM ishui@hsph.harvard.edu OI Ostrander, Elaine/0000-0001-6075-9738 FU National Cancer Institute [R01 CA056678, R01 CA092579, K05 CA175147, P30 CA015704, P50 CA097186]; Fred Hutchinson Cancer Research Center; Intramural Program of the National Human Genome Research Institute; Prostate Cancer Foundation; National Institutes of Health; Dutch Cancer Society Fellowship [BUIT 2014-6645]; Department of Defense Prostate Cancer Research Program Postdoctoral Training Award [W81XWH-14-1-0250] FX This work was supported by grants from the National Cancer Institute (R01 CA056678, R01 CA092579, K05 CA175147 [to Janet L. Stanford], P30 CA015704, and P50 CA097186), and additional support was provided by the Fred Hutchinson Cancer Research Center, the Intramural Program of the National Human Genome Research Institute, and the Prostate Cancer Foundation. Irene M. Shui reports grants from the National Institutes of Health during the conduct of the study. Milan Geybels is the recipient of a Dutch Cancer Society Fellowship (BUIT 2014-6645). Ericka M. Ebot is supported by a Department of Defense Prostate Cancer Research Program Postdoctoral Training Award (W81XWH-14-1-0250). NR 54 TC 1 Z9 1 U1 4 U2 5 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 JUL 15 PY 2016 VL 122 IS 14 BP 2168 EP 2177 DI 10.1002/cncr.30045 PG 10 WC Oncology SC Oncology GA DR4SY UT WOS:000379894000009 PM 27142338 ER PT J AU Mahabir, S AF Mahabir, Somdat TI Is nonalcoholic fatty liver disease driving the increased incidence of liver cancer? SO CANCER LA English DT Letter ID UNITED-STATES; STEATOHEPATITIS; PREVALENCE C1 [Mahabir, Somdat] NCI, Epidemiol & Genom Res Program, NIH, Bethesda, MD 20892 USA. RP Mahabir, S (reprint author), NCI, Epidemiol & Genom Res Program, NIH, Bethesda, MD 20892 USA. NR 13 TC 0 Z9 0 U1 3 U2 3 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 JUL 15 PY 2016 VL 122 IS 14 BP 2277 EP 2278 DI 10.1002/cncr.30055 PG 2 WC Oncology SC Oncology GA DR4SY UT WOS:000379894000021 PM 27142562 ER PT J AU Grier, BD Belluscio, L Cheetham, CEJ AF Grier, Bryce D. Belluscio, Leonardo Cheetham, Claire E. J. TI Olfactory Sensory Activity Modulates Microglial-Neuronal Interactions during Dopaminergic Cell Loss in the Olfactory Bulb SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE olfactory; dopaminergic neuron; microglia; plasticity; naris occlusion; 2-photon ID IN-VIVO; ADULT NEUROGENESIS; SUBVENTRICULAR ZONE; PARKINSONS-DISEASE; BRAIN; ACTIVATION; DEATH; TURNOVER; REVEALS; PROMOTE AB The mammalian olfactory bulb (OB) displays robust activity-dependent plasticity throughout life. Dopaminergic (DA) neurons in the glomerular layer (GL) of the OB are particularly plastic, with loss of sensory input rapidly reducing tyrosine hydroxylase (TH) expression and dopamine production, followed by a substantial reduction in DA neuron number. Here, we asked whether microglia participate in activity-dependent elimination of DA neurons in the mouse OB. Interestingly, we found a significant reduction in the number of both DA neurons and their synapses in the OB ipsilateral to the occluded naris (occluded OB) within just 7 days of sensory deprivation. Concomitantly, the volume of the occluded OB decreased, resulting in an increase in microglial density. Microglia in the occluded OB also adopted morphologies consistent with activation. Using in vivo 2-photon imaging and histological analysis we then showed that loss of olfactory input markedly altered microglial-neuronal interactions during the time that DA neurons are being eliminated: both microglial process motility and the frequency of wrapping of DA neuron somata by activated microglia increased significantly in the occluded OB. Furthermore, we found microglia in the occluded OB that had completely engulfed components of DA neurons. Together, our data provide evidence that loss of olfactory input modulates microglial-DA neuron interactions in the OB, thereby suggesting an important role for microglia in the activity-dependent elimination of DA neurons and their synapses. C1 [Grier, Bryce D.; Belluscio, Leonardo; Cheetham, Claire E. J.] NINDS, Dev Neural Plast Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Cheetham, Claire E. J.] Carnegie Mellon Univ, Dept Biol Sci, 4400 5th Ave, Pittsburgh, PA 15213 USA. RP Belluscio, L; Cheetham, CEJ (reprint author), NINDS, Dev Neural Plast Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.; Cheetham, CEJ (reprint author), Carnegie Mellon Univ, Dept Biol Sci, 4400 5th Ave, Pittsburgh, PA 15213 USA. EM belluscl@ninds.nih.gov; cheetham@andrew.cmu.edu RI Cheetham, Claire/A-2612-2017; OI Cheetham, Claire/0000-0002-4038-1501; Grier, Bryce/0000-0002-7550-7784 FU NINDS Intramural Program [1-ZIA-NS003002]; Human Frontier Science Program Long-Term Fellowship FX This work was supported by the NINDS Intramural Program (1-ZIA-NS003002) and a Human Frontier Science Program Long-Term Fellowship to CC. NR 36 TC 2 Z9 2 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD JUL 15 PY 2016 VL 10 AR 178 DI 10.3389/fncel.2016.00178 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DR1IN UT WOS:000379659300001 PM 27471450 ER PT J AU Mendes-Sousa, AF Queiroz, DC Vale, VF Ribeiro, JMC Valenzuela, JG Gontijo, NF Andersen, JF AF Mendes-Sousa, Antonio F. Queiroz, Daniel C. Vale, Vladimir F. Ribeiro, Jose M. C. Valenzuela, Jesus G. Gontijo, Nelder F. Andersen, John F. TI An Inhibitor of the Alternative Pathway of Complement in Saliva of New World Anopheline Mosquitoes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; ANTICOMPLEMENT PROTEINS; GLAND TRANSCRIPTOME; IXODES-RICINUS; C3 CONVERTASE; PROPERDIN; SYSTEM; TICK; TRANSMISSION; ACTIVATION AB The complement system present in circulating blood is an effective mechanism of host defense, responsible for the killing of pathogens and the production of potent anaphylatoxins. Inhibitors of the complement system have been described in the saliva of hematophagous arthropods that are involved in the protection of digestive tissues against complement system-mediated damage. In this study, we describe albicin, a novel inhibitor of the alternative pathway of complement from the salivary glands of the malaria vector, Anopheles albimanus. The inhibitor was purified from salivary gland homogenates by reverse-phase HPLC and identified by mass spectrometry as a small (13.4-kDa) protein related to the gSG7 protein of Anopheles gambiae and Anopheles stephensi. Recombinant albicin was produced in Escherichia coli and found to potently inhibit lysis of rabbit erythrocytes in assays of the alternative pathway while having no inhibitory effect on the classical or lectin pathways. Albicin also inhibited the deposition of complement components on agarose-coated plates, although it could not remove previously bound components. Antisera produced against recombinant albicin recognized both the native and recombinant inhibitors and also blocked their activities in in vitro assays. Using surface plasmon resonance and enzymatic assays, we found that albicin binds and stabilizes the C3-convertase complex (C3bBb) formed on a properdin surface and inhibits the convertase activity of a reconstituted C3bBb complex in solution. The data indicate that albicin specifically recognizes the activated form of the complex, allowing more efficient inhibition by an inhibitor whose quantity is limited. C1 [Mendes-Sousa, Antonio F.; Ribeiro, Jose M. C.; Valenzuela, Jesus G.; Andersen, John F.] NIAID, Lab Malaria & Vector Res, NIH, 2E32B Twinbrook 3 Bldg,12735 Twinbrook Pkway, Rockville, MD 20852 USA. [Mendes-Sousa, Antonio F.; Queiroz, Daniel C.; Vale, Vladimir F.; Gontijo, Nelder F.] Univ Minas Gerais, Dept Parasitol, BR-30123970 Belo Horizonte, MG, Brazil. [Vale, Vladimir F.] Fiocruz MS, Inst Oswaldo Cruz, Lab Simuliids & Onchocerciasis, BR-21040900 Rio De Janeiro, Brazil. RP Andersen, JF (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 2E32B Twinbrook 3 Bldg,12735 Twinbrook Pkway, Rockville, MD 20852 USA. EM jandersen@niaid.nih.gov OI Gontijo, Nelder/0000-0003-3357-2497; Ribeiro, Jose/0000-0002-9107-0818 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; Comissao de Aperfeicoamento de Pessoal de Nival Superior [23038.005604/2012-62] FX This work was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. A.F.M.-S. was supported by Comissao de Aperfeicoamento de Pessoal de Nival Superior (Grant 23038.005604/2012-62). NR 35 TC 1 Z9 1 U1 3 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2016 VL 197 IS 2 BP 599 EP 610 DI 10.4049/jimmunol.1600020 PG 12 WC Immunology SC Immunology GA DQ8ZL UT WOS:000379500100018 PM 27307559 ER PT J AU Bocharov, AV Wu, TH Baranova, IN Birukova, AA Sviridov, D Vishnyakova, TG Remaley, AT Eggerman, TL Patterson, AP Birukov, KG AF Bocharov, Alexander V. Wu, Tinghuai Baranova, Irina N. Birukova, Anna A. Sviridov, Denis Vishnyakova, Tatyana G. Remaley, Alan T. Eggerman, Thomas L. Patterson, Amy P. Birukov, Konstantin G. TI Synthetic Amphipathic Helical Peptides Targeting CD36 Attenuate Lipopolysaccharide-Induced Inflammation and Acute Lung Injury SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-A-I; RECEPTOR CLASS-B; SERUM-AMYLOID-A; MIMETIC PEPTIDE; SR-BI; BACTERIAL RECOGNITION; SCAVENGER RECEPTORS; CHOLESTEROL EFFLUX; WESTERN DIET AB Synthetic amphipathic helical peptides (SAHPs) designed as apolipoprotein A-I mimetics are known to bind to class B scavenger receptors (SR-Bs), SR-BI, SR-BII, and CD36, receptors that mediate lipid transport and facilitate pathogen recognition. In this study, we evaluated SAHPs, selected for targeting human CD36, by their ability to attenuate LPS-induced inflammation, endothelial barrier dysfunction, and acute lung injury (ALI). L37pA, which targets CD36 and SR-BI equally, inhibited LPS-induced IL-8 secretion and barrier dysfunction in cultured endothelial cells while reducing lung neutrophil infiltration by 40% in a mouse model of LPS-induced ALI. A panel of 20 SAHPs was tested in HEK293 cell lines stably transfected with various SR-Bs to identify SAHPs with preferential selectivity toward CD36. Among several SAHPs targeting both SR-BI/BII and CD36 receptors, ELK-B acted predominantly through CD36. Compared with L37pA, 5A, and ELK SAHPs, ELK-B was most effective in reducing the pulmonary barrier dysfunction, neutrophil migration into the lung, and lung inflammation induced by LPS. We conclude that SAHPs with relative selectivity toward CD36 are more potent at inhibiting acute pulmonary inflammation and dysfunction. These data indicate that therapeutic strategies using SAHPs targeting CD36, but not necessarily mimicking all apolipoprotein A-I functions, may be considered a possible new treatment approach for inflammation-induced ALI and pulmonary edema. C1 [Bocharov, Alexander V.; Baranova, Irina N.; Vishnyakova, Tatyana G.; Eggerman, Thomas L.; Patterson, Amy P.] NIH, Dept Lab Med, Ctr Clin, Bldg 9,Room 1N128,8800 Rockville Pike, Bethesda, MD 20892 USA. [Bocharov, Alexander V.; Remaley, Alan T.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Wu, Tinghuai; Birukova, Anna A.; Birukov, Konstantin G.] Univ Chicago, Lung Injury Ctr, Chicago, IL 60637 USA. [Sviridov, Denis; Eggerman, Thomas L.] NIDDK, Bethesda, MD 20892 USA. [Patterson, Amy P.] NIH, Off Sci Policy, Off Director, Bldg 10, Bethesda, MD 20892 USA. RP Bocharov, AV (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 9,Room 1N128,8800 Rockville Pike, Bethesda, MD 20892 USA. EM abocharov@mail.cc.nih.gov FU National Institutes of Health Intramural Research Programs at the Clinical Center; National Institute of Diabetes, Digestive, and Kidney Diseases; National Institutes of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; National Institutes of Health FX This work was supported by the National Institutes of Health Intramural Research Programs at the Clinical Center, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Allergy and Infectious Diseases, and National Heart, Lung, and Blood Institute, as well as by National Institutes of Health grants to the Lung Injury Center, The University of Chicago. NR 60 TC 1 Z9 1 U1 4 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2016 VL 197 IS 2 BP 611 EP 619 DI 10.4049/jimmunol.1401028 PG 9 WC Immunology SC Immunology GA DQ8ZL UT WOS:000379500100019 PM 27316682 ER PT J AU Moogk, D Zhong, S Yu, ZY Liadi, I Rittase, W Fang, V Dougherty, J Perez-Garcia, A Osman, I Zhu, C Varadarajan, N Restifo, NP Frey, AB Krogsgaard, M AF Moogk, Duane Zhong, Shi Yu, Zhiya Liadi, Ivan Rittase, William Fang, Victoria Dougherty, Janna Perez-Garcia, Arianne Osman, Iman Zhu, Cheng Varadarajan, Navin Restifo, Nicholas P. Frey, Alan B. Krogsgaard, Michelle TI Constitutive Lck Activity Drives Sensitivity Differences between CD8(+) Memory T Cell Subsets SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; TYROSINE PROTEIN-KINASE; IN-VIVO; ADOPTIVE IMMUNOTHERAPY; IMMUNOLOGICAL SYNAPSE; EFFECTOR FUNCTION; ANTIGEN RECEPTOR; LINEAGE RELATIONSHIP; METASTATIC MELANOMA; SIGNAL-TRANSDUCTION AB CD8(+) T cells develop increased sensitivity following Ag experience, and differences in sensitivity exist between T cell memory subsets. How differential TCR signaling between memory subsets contributes to sensitivity differences is unclear. We show in mouse effector memory T cells (T-EM) that >50% of lymphocyte-specific protein tyrosine kinase (Lck) exists in a constitutively active conformation, compared with < 20% in central memory T cells (T-CM). Immediately proximal to Lck signaling, we observed enhanced Zap-70 phosphorylation in T-EM following TCR ligation compared with T-CM. Furthermore, we observed superior cytotoxic effector function in T-EM compared with T-CM, and we provide evidence that this results from a lower probability of T-CM reaching threshold signaling owing to the decreased magnitude of TCR-proximal signaling. We provide evidence that the differences in Lck constitutive activity between CD8(+) T-CM and T-EM are due to differential regulation by SH2 domain-containing phosphatase-1 (Shp-1) and C-terminal Src kinase, and we use modeling of early TCR signaling to reveal the significance of these differences. We show that inhibition of Shp-1 results in increased constitutive Lck activity in T-CM to levels similar to T-EM, as well as increased cytotoxic effector function in T-CM. Collectively, this work demonstrates a role for constitutive Lck activity in controlling Ag sensitivity, and it suggests that differential activities of TCR-proximal signaling components may contribute to establishing the divergent effector properties of T-CM and T-EM. This work also identifies Shp-1 as a potential target to improve the cytotoxic effector functions of T-CM for adoptive cell therapy applications. C1 [Moogk, Duane; Zhong, Shi; Fang, Victoria; Dougherty, Janna; Perez-Garcia, Arianne; Osman, Iman; Krogsgaard, Michelle] NYU, Sch Med, Laura & Isaac Perlmutter Canc Ctr, New York, NY 10016 USA. [Yu, Zhiya; Liadi, Ivan; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Varadarajan, Navin] Univ Houston, Dept Chem & Biomol Engn, Houston, TX 77004 USA. [Rittase, William; Zhu, Cheng] Georgia Inst Technol, George W Woodruff Sch Mech Engn, Atlanta, GA 30332 USA. [Fang, Victoria] NYU, Med Scientist Training Program, New York, NY 10016 USA. [Osman, Iman] NYU, Sch Med, Ronald Perelman Dept Dermatol, New York, NY 10016 USA. [Frey, Alan B.] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. [Krogsgaard, Michelle] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Zhong, Shi] Xiangxue Pharmaceut Co Ltd, Life Sci Ctr, Guangzhou, Guangdong, Peoples R China. [Perez-Garcia, Arianne] Kite Pharma, Santa Monica, CA USA. RP Krogsgaard, M (reprint author), NYU, Sch Med, 522 First Ave,Smilow 1311, New York, NY 10016 USA. EM Michelle.Krogsgaard@nyumc.org OI frey, alan/0000-0003-4151-561X; Fang, Victoria/0000-0001-9376-1279 FU NCI NIH HHS [R01 CA108573, P30 CA016087, R01 CA174385, U01 CA137070]; NIGMS NIH HHS [R01 GM085586]; NIH HHS [R24 OD018339] NR 71 TC 0 Z9 0 U1 5 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2016 VL 197 IS 2 BP 644 EP 654 DI 10.4049/jimmunol.1600178 PG 11 WC Immunology SC Immunology GA DQ8ZL UT WOS:000379500100022 PM 27271569 ER PT J AU Thomas, M Lemaitre, M Wilson, ML Viboud, C Yordanov, Y Wackernagel, H Carrat, F AF Thomas, Maud Lemaitre, Magali Wilson, Mark L. Viboud, Cecile Yordanov, Youri Wackernagel, Hans Carrat, Fabrice TI Applications of Extreme Value Theory in Public Health SO PLOS ONE LA English DT Article AB Objectives We present how Extreme Value Theory (EVT) can be used in public health to predict future extreme events. Methods We applied EVT to weekly rates of Pneumonia and Influenza (P&I) deaths over 1979-2011. We further explored the daily number of emergency department visits in a network of 37 hospitals over 2004-2014. Maxima of grouped consecutive observations were fitted to a generalized extreme value distribution. The distribution was used to estimate the probability of extreme values in specified time periods. Results An annual P&I death rate of 12 per 100,000 (the highest maximum observed) should be exceeded once over the next 30 years and each year, there should be a 3% risk that the P&I death rate will exceed this value. Over the past 10 years, the observed maximum increase in the daily number of visits from the same weekday between two consecutive weeks was 1133. We estimated at 0.37% the probability of exceeding a daily increase of 1000 on each month. Conclusion The EVT method can be applied to various topics in epidemiology thus contributing to public health planning for extreme events. C1 [Thomas, Maud] Chalmers Univ Technol Goteborg, Dept Math Stat, Gothenburg, Sweden. [Lemaitre, Magali; Carrat, Fabrice] Univ Paris 06, Sorbonne Univ, INSERM, Inst Pierre Louis Epidemiol & Sante Publ,UMR S 11, F-75012 Paris, France. [Lemaitre, Magali; Viboud, Cecile] NIH, Fogarty Int Ctr, Washington, DC USA. [Wilson, Mark L.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Yordanov, Youri] Hop St Antoine, AP HP, Serv Urgences, Paris, France. [Wackernagel, Hans] PSL Res Univ, MINES ParisTech, Geostat Grp, Ctr Geosci, Fontainebleau, France. [Carrat, Fabrice] St Antoine Hosp, AP HP, Publ Hlth Unit, F-75012 Paris, France. RP Carrat, F (reprint author), Univ Paris 06, Sorbonne Univ, INSERM, Inst Pierre Louis Epidemiol & Sante Publ,UMR S 11, F-75012 Paris, France.; Carrat, F (reprint author), St Antoine Hosp, AP HP, Publ Hlth Unit, F-75012 Paris, France. EM fabrice.carrat@iplesp.upmc.fr OI CARRAT, fabrice/0000-0002-8672-7918 NR 10 TC 1 Z9 1 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 15 PY 2016 VL 11 IS 7 AR e0159312 DI 10.1371/journal.pone.0159312 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR1JR UT WOS:000379662300011 PM 27419853 ER PT J AU Meier, TB Savitz, J Singh, R Teague, TK Bellgowan, PSF AF Meier, Timothy B. Savitz, Jonathan Singh, Rashmi Teague, T. Kent Bellgowan, Patrick S. F. TI Smaller Dentate Gyrus and CA2 and CA3 Volumes Are Associated with Kynurenine Metabolites in Collegiate Football Athletes SO JOURNAL OF NEUROTRAUMA LA English DT Article DE concussion; football; hippocampus; kynurenine pathway; mTBI ID TRAUMATIC BRAIN-INJURY; POSTTRAUMATIC-STRESS-DISORDER; MAJOR DEPRESSIVE DISORDER; QUINOLINIC ACID; HIPPOCAMPAL SUBFIELDS; OXIDATIVE STRESS; IN-VIVO; PATHWAY; RAT; 3-HYDROXYKYNURENINE AB An imbalance in kynurenine pathway metabolism is hypothesized to be associated with dysregulated glutamatergic neurotransmission, which has been proposed as a mechanism underlying the hippocampal volume loss observed in a variety of neurological disorders. Pre-clinical models suggest that the CA2-3 and dentate gyrus hippocampal subfields are particularly susceptible to excitotoxicity after experimental traumatic brain injury. We tested the hypothesis that smaller hippocampal volumes in collegiate football athletes with (n = 25) and without (n = 24) a concussion history would be most evident in the dentate gyrus and CA2-3 subfields relative to nonfootball healthy controls (n = 27). Further, we investigated whether the concentration of peripheral levels of kynurenine metabolites are altered in football athletes. Football athletes with and without a self-reported concussion history had smaller dentate gyrus (p < 0.05, p < 0.10) and CA2-3 volumes (p's < 0.05) relative to healthy controls. Football athletes with and without a concussion history had a trend toward lower (p < 0.10) and significantly lower (p < 0.05) kynurenine levels compared with healthy controls, while athletes with a concussion history had greater levels of quinolinic acid compared with athletes without a concussion history (p < 0.05). Finally, plasma levels of 3-hydroxykynurenine inversely correlated with bilateral hippocampal volumes in football athletes with a concussion history (p < 0.01), and left hippocampal volume was correlated with the ratio of kynurenic acid to quinolinic acid in football athletes without a concussion history (p < 0.05). Our results raise the possibility that abnormalities of the kynurenine metabolic pathway constitute a mechanism for hippocampal volume differences in the context of sports-related brain injury. C1 [Meier, Timothy B.] Med Coll Wisconsin, Dept Neurosurg, Milwaukee, WI 53226 USA. [Meier, Timothy B.; Savitz, Jonathan; Singh, Rashmi] Laureate Inst Brain Res, Tulsa, OK USA. [Savitz, Jonathan] Univ Tulsa, Fac Community Med, Tulsa, OK 74104 USA. [Teague, T. Kent] Univ Oklahoma, Coll Med, Dept Surg, Tulsa, OK USA. [Teague, T. Kent] Univ Oklahoma, Coll Med, Dept Psychiat, Tulsa, OK USA. [Teague, T. Kent] Univ Oklahoma, Coll Pharm, Dept Pharmaceut Sci, Tulsa, OK USA. [Teague, T. Kent] Oklahoma State Univ, Ctr Hlth Sci, Dept Biochem & Microbiol, Tulsa, OK USA. [Bellgowan, Patrick S. F.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Meier, TB (reprint author), Med Coll Wisconsin, Neurosci Res Ctr, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM tmeier@mcw.edu RI Teague, Kent/A-2527-2008 OI Teague, Kent/0000-0002-4680-5440 NR 51 TC 2 Z9 2 U1 1 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL 15 PY 2016 VL 33 IS 14 BP 1349 EP 1357 DI 10.1089/neu.2015.4118 PG 9 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DQ5CX UT WOS:000379223100006 PM 26493952 ER PT J AU Krystal, JH Abi-Dargham, A Akbarian, S Arnsten, AFT Barch, DM Bearden, CE Braff, DL Brown, ES Bullmore, ET Carlezon, WA Carter, CS Cook, EH Daskalakis, ZJ DiLeone, RJ Duman, RS Grace, AA Hariri, AR Harrison, PJ Hiroi, N Kenny, PJ Kleinman, JE Krystal, AD Lewis, DA Lipska, BK Marder, SR Mason, GF Mathalon, DH McClung, CA McDougle, CJ McIntosh, AM McMahon, FJ Mirnics, K Monteggia, LM Narendran, R Nestler, EJ Neumeister, A O'Donovan, MC Ongur, D Pariante, CM Paulus, MP Pearlson, G Phillips, ML Pine, DS Pizzagalli, DA Pletnikov, MV Ragland, JD Rapoport, JL Ressler, KJ Russo, SJ Sanacora, G Sawa, A Schatzberg, AF Shaham, Y Shamay-Tsoory, SG Sklar, P State, MW Stein, MB Strakowski, SM Taylor, SF Turecki, G Turetsky, BI Weissman, MM Zachariou, V Zarate, CA Zubieta, JK AF Krystal, John H. Abi-Dargham, Anissa Akbarian, Schahram Arnsten, Amy F. T. Barch, Deanna M. Bearden, Carrie E. Braff, David L. Brown, E. Sherwood Bullmore, Edward T. Carlezon, William A., Jr. Carter, Cameron S. Cook, Edwin H., Jr. Daskalakis, Zafiris Jeff DiLeone, Ralph J. Duman, Ronald S. Grace, Anthony A. Hariri, Ahmad R. Harrison, Paul J. Hiroi, Noboru Kenny, Paul J. Kleinman, Joel E. Krystal, Andrew D. Lewis, David A. Lipska, Barbara K. Marder, Stephen R. Mason, Graeme F. Mathalon, Daniel H. McClung, Colleen A. McDougle, Christopher J. McIntosh, Andrew M. McMahon, Francis J. Mirnics, Karoly Monteggia, Lisa M. Narendran, Rajesh Nestler, Eric J. Neumeister, Alexander O'Donovan, Michael C. Ongur, Dost Pariante, Carmine M. Paulus, Martin P. Pearlson, Godfrey Phillips, Mary L. Pine, Daniel S. Pizzagalli, Diego A. Pletnikov, Mikhail V. Ragland, J. Daniel Rapoport, Judith L. Ressler, Kerry J. Russo, Scott J. Sanacora, Gerard Sawa, Akira Schatzberg, Alan F. Shaham, Yavin Shamay-Tsoory, Simone G. Sklar, Pamela State, Matthew W. Stein, Murray B. Strakowski, Stephen M. Taylor, Stephan F. Turecki, Gustavo Turetsky, Bruce I. Weissman, Myrna M. Zachariou, Venetia Zarate, Carlos A., Jr. Zubieta, Jon-Kar TI Constance E. Lieber, Theodore R. Stanley, and the Enduring Impact of Philanthropy on Psychiatry Research SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 [Krystal, John H.; Arnsten, Amy F. T.; Duman, Ronald S.] Yale Univ, Sch Med, Dept Psychiat & Neurosci, New Haven, CT 06511 USA. [Krystal, John H.] Yale New Haven Med Ctr, Behav Hlth Serv, 20 York St, New Haven, CT 06504 USA. [Krystal, John H.] VA Connecticut Healthcare Syst, Clin Neurosci Div, West Haven, CT USA. [Abi-Dargham, Anissa] Columbia Univ, Dept Psychiat, New York, NY USA. [Abi-Dargham, Anissa] Columbia Univ, Dept Radiol, New York, NY USA. [Abi-Dargham, Anissa] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Akbarian, Schahram] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Arnsten, Amy F. T.] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06511 USA. [Barch, Deanna M.] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Psychiat, Los Angeles, CA 90024 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Psychol, Los Angeles, CA 90024 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Brain Res Inst, Los Angeles, CA 90024 USA. [Braff, David L.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Brown, E. Sherwood] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Bullmore, Edward T.] Univ Cambridge, Dept Psychiat & Behav, Cambridge, England. [Bullmore, Edward T.] Univ Cambridge, Neurosci Inst, Cambridge, England. [Bullmore, Edward T.] GlaxoSmithKline, ImmunoPsychiat, Cambridge, England. [Carlezon, William A., Jr.] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat & Neurosci, Belmont, MA 02178 USA. [Carter, Cameron S.] Univ Calif Davis, Dept Psychiat & Behav Sci, Imaging Res Ctr, Davis, CA 95616 USA. [Carter, Cameron S.] Univ Calif Davis, Ctr Neurosci, Davis, CA 95616 USA. [Cook, Edwin H., Jr.] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA. [Daskalakis, Zafiris Jeff] Ctr Addict & Mental Hlth, Mood & Anxiety Div, Temerty Ctr Therapeut Brain Intervent, Toronto, ON, Canada. [Daskalakis, Zafiris Jeff] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [DiLeone, Ralph J.] Yale Univ, Dept Psychiat, New Haven, CT 06511 USA. [Grace, Anthony A.] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA USA. [Grace, Anthony A.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Grace, Anthony A.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Hariri, Ahmad R.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Harrison, Paul J.] Univ Oxford, Dept Psychiat, Oxford, England. [Hiroi, Noboru] Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY 10467 USA. [Hiroi, Noboru] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10467 USA. [Hiroi, Noboru] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA. [Kenny, Paul J.] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Kleinman, Joel E.] Johns Hopkins Univ, Sch Med, Lieber Inst Brain Dev, Genet Neuropathol Sect, Baltimore, MD USA. [Kleinman, Joel E.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Krystal, Andrew D.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. [Lewis, David A.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Lipska, Barbara K.] NIMH, Human Brain Collect Core, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Marder, Stephen R.] Univ Calif Los Angeles, Semel Inst Neurosci, Los Angeles, CA USA. [Marder, Stephen R.] VA Desert Pacific Mental Illness Res Educ & Clin, Los Angeles, CA USA. [Mason, Graeme F.] Yale Univ, Sch Med, Dept Radiol & Biomed Imaging, New Haven, CT 06511 USA. [Mason, Graeme F.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06511 USA. [Mathalon, Daniel H.; State, Matthew W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Mathalon, Daniel H.] San Francisco VA Med Ctr, Psychiat Serv, San Francisco, CA USA. [McClung, Colleen A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [McDougle, Christopher J.] Massachusetts Gen Hosp, Lexington, MA USA. [McDougle, Christopher J.] MassGen Hosp Children, Lurie Ctr Autism, Lexington, MA USA. [McDougle, Christopher J.; Pizzagalli, Diego A.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [McIntosh, Andrew M.] Univ Edinburgh, Div Psychiat, Edinburgh, Midlothian, Scotland. [McMahon, Francis J.] NIMH, Human Genet Branch, Intramural Res Program, Bethesda, MD 20892 USA. [McMahon, Francis J.] NIMH, Intramural Res Program, Genet Basis Mood & Anxiety Disorders Sect, Bethesda, MD 20892 USA. [Mirnics, Karoly] Vanderbilt Univ, Dept Psychiat, 221 Kirkland Hall, Nashville, TN 37235 USA. [Monteggia, Lisa M.] Univ Texas SW Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA. [Narendran, Rajesh] Univ Pittsburgh, Sch Med, Dept Radiol, Pittsburgh, PA USA. [Narendran, Rajesh] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Nestler, Eric J.; Russo, Scott J.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Nestler, Eric J.; Russo, Scott J.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Neumeister, Alexander] Mitsubishi Tanabe Pharma Dev Amer Inc, Jersey City, NJ USA. [O'Donovan, Michael C.] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Ongur, Dost; Ressler, Kerry J.] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA USA. [Pariante, Carmine M.] Kings Coll London, Inst Psychiat, Dept Psychol, London, England. [Pariante, Carmine M.] Kings Coll London, Inst Psychiat, Dept Neurosci, London, England. [Pariante, Carmine M.] Maurice Wohl Clin Neurosci Inst, Psychiat & Immunol Lab & Perinatal Psychiat, London, England. [Paulus, Martin P.] Laureate Inst Brain Res, Tulsa, OK USA. [Pearlson, Godfrey] Yale Univ, Dept Psychiat, Hartford, CT USA. [Pearlson, Godfrey] Yale Univ, Dept Neurobiol, Hartford, CT USA. [Pearlson, Godfrey] Olin Neuropsychiat Res Ctr, Hartford, CT USA. [Phillips, Mary L.] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA USA. [Pine, Daniel S.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Pizzagalli, Diego A.] McLean Hosp, McLean Imaging Ctr, 115 Mill St, Belmont, MA 02178 USA. [Pletnikov, Mikhail V.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Pletnikov, Mikhail V.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21205 USA. [Ragland, J. Daniel] Univ Calif Davis, Imaging Res Ctr, Dept Psychiat & Behav Sci, Sacramento, CA 95817 USA. [Rapoport, Judith L.] NIMH, Child Psychiat Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Sanacora, Gerard] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Sawa, Akira] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Schatzberg, Alan F.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA USA. [Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD USA. [Shamay-Tsoory, Simone G.] Univ Haifa, Dept Psychol, IL-31999 Haifa, Israel. [Sklar, Pamela] Icahn Sch Med Mt Sinai, Div Psychiat Genom, Dept Psychiat, New York, NY 10029 USA. [Stein, Murray B.] Univ Calif San Diego, Sch Med, Dept Psychiat, 9500 Gillman Dr, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Sch Med, Dept Family Med & Publ Hlth, La Jolla, CA USA. [Strakowski, Stephen M.] Univ Texas Austin, Dept Psychiat, Dell Med Sch, Austin, TX USA. [Taylor, Stephan F.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Turecki, Gustavo] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. [Turetsky, Bruce I.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weissman, Myrna M.] Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, New York, NY USA. [Weissman, Myrna M.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Zachariou, Venetia] Mt Sinai Sch Med, Fishberg Dept Neurosci, New York, NY USA. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Zubieta, Jon-Kar] Univ Utah, Hlth Sci Ctr, Dept Psychiat, Univ Neuropsychiat Inst, Salt Lake City, UT USA. RP Krystal, JH (reprint author), Yale Univ, Sch Med, Dept Psychiat, 300 George St,Suite 901, New Haven, CT 06511 USA. EM john.krystal@yale.edu RI Lipska, Barbara/E-4569-2017; OI McIntosh, Andrew/0000-0002-0198-4588 FU Medical Research Council [G1000183, MR/K026992/1] NR 2 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 2016 VL 80 IS 2 BP 84 EP 86 DI 10.1016/j.biopsych.2016.05.004 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DP5IT UT WOS:000378530200002 PM 27346079 ER PT J AU Zhou, YD Oskolkov, N Shcherbina, L Ratti, J Kock, KH Su, J Martin, B Oskolkova, MZ Goransson, O Bacon, J Li, WM Bucciarelli, S Cilio, C Brazma, A Thatcher, B Rung, J Wierup, N Renstrom, E Groop, L Hansson, O AF Zhou, Yuedan Oskolkov, Nikolay Shcherbina, Liliya Ratti, Joyce Kock, Kian-Hong Su, Jing Martin, Brian Oskolkova, Malin Zackrisson Goransson, Olga Bacon, Julie Li, Weimin Bucciarelli, Saskia Cilio, Corrado Brazma, Alvis Thatcher, Bradley Rung, Johan Wierup, Nils Renstrom, Erik Groop, Leif Hansson, Ola TI HMGB1 binds to the rs7903146 locus in TCF7L2 in human pancreatic islets SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE TCF7L2; Type 2 diabetes; HMGB1; Chromatin binding ID NONDIABETIC INDIVIDUALS; GLUCOSE-METABOLISM; OPEN CHROMATIN; DIABETES RISK; GENE; DNA; PROTEIN; VISUALIZATION; VARIANTS; SURVIVAL AB The intronic SNP rs7903146 in the T-cell factor 7-like 2 gene (TCF7L2) is the common genetic variant most highly associated with Type 2 diabetes known to date. The risk T-allele is located in an open chromatin region specific to human pancreatic islets of Langerhans, thereby accessible for binding of regulatory proteins. The risk T-allele locus exhibits stronger enhancer activity compared to the non-risk C-allele. The aim of this study was to identify transcriptional regulators that bind the open chromatin region in the rs7903146 locus and thereby potentially regulate TCF7L2 expression and activity. Using affinity chromatography followed by Edman sequencing, we identified one candidate regulatory protein, i.e. high-mobility group protein B1 (HMGB1). The binding of HMGB1 to the rs7903146 locus was confirmed in pancreatic islets from human deceased donors, in HCT116 and in HEK293 cell lines using: (i) protein purification on affinity columns followed by Western blot, (ii) chromatin immunoprecipitation followed by qPCR and (iii) electrophoretic mobility shift assay. The results also suggested that HMGB1 might have higher binding affinity to the C-allele of rs7903146 compared to the T-allele, which was supported in vitro using Dynamic Light Scattering, possibly in a tissue-specific manner. The functional consequence of HMGB1 depletion in HCT116 and INS1 cells was reduced insulin and TCF7L2 mRNA expression, TCF7L2 transcriptional activity and glucose stimulated insulin secretion. These findings suggest that the rs7903146 locus might exert its enhancer function by interacting with HMGB1 in an allele dependent manner. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Zhou, Yuedan; Oskolkov, Nikolay; Shcherbina, Liliya; Goransson, Olga; Bacon, Julie; Cilio, Corrado; Thatcher, Bradley; Wierup, Nils; Renstrom, Erik; Groop, Leif; Hansson, Ola] Lund Univ, CRC, Dept Clin Sci, S-20502 Malmo, Sweden. [Ratti, Joyce; Kock, Kian-Hong] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England. [Su, Jing; Brazma, Alvis; Rung, Johan] European Bioinformat Inst, Funct Genom, Cambridge CB10 1SD, England. [Martin, Brian] NIMH, NIH, Bethesda, MD 20892 USA. [Oskolkova, Malin Zackrisson; Li, Weimin; Bucciarelli, Saskia] Lund Univ, Dept Phys Chem, S-22100 Lund, Sweden. RP Hansson, O (reprint author), Lund Univ, Skane Univ Sjukhus, Dept Clin Sci Endocrinol & Diabet, Ing 72,91 12 18, S-22100 Lund, Sweden. EM Ola.Hansson@med.lu.se RI Hansson, Ola/F-1793-2011; OI Hansson, Ola/0000-0002-7394-7639; Zackrisson Oskolkova, Malin/0000-0002-3777-1269; Brazma, Alvis/0000-0001-5988-7409 FU Swedish Research Council; Linnaeus grant [349-2006-237]; Exo-Diab grant [2009-1039]; Swedish Research Council [521-2010-3490]; European Research Council [269045]; Lund University Medical Faculty; IRP, NIMH [MH002344-24]; [521-2008-2974]; [2011-3315] FX All authors would like to acknowledge our dear colleague Dr Bradley Thatcher who sadly passed away during the preparation of this manuscript. We would also like to thank Drs Stollenwerk (Malmo Hogskola) and Fadista (Lund University) for constructive suggestions. This work has been funded by the Swedish Research Council, the Linnaeus grant (number 349-2006-237) and the Exo-Diab grant (number 2009-1039); Swedish Research Council project grant (number 521-2010-3490), collaborative grants (number 521-2008-2974 and 2011-3315), European Research Council Advanced Researcher grant to Leif Groop (GENETARGET T2D number 269045) and funding from Lund University Medical Faculty, as well as the IRP, NIMH under MH002344-24 to Dr. Brian Martin. NR 36 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUL 15 PY 2016 VL 430 IS C BP 138 EP 145 DI 10.1016/j.mce.2016.01.027 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DP4HO UT WOS:000378457200014 PM 26845344 ER PT J AU Mordukhovich, I Beyea, J Herring, AH Hatch, M Stellman, SD Teitelbaum, SL Richardson, DB Millikan, RC Engel, LS Shantakumar, S Steck, SE Neugut, AI Rossner, P Santella, RM Gammon, MD AF Mordukhovich, Irina Beyea, Jan Herring, Amy H. Hatch, Maureen Stellman, Steven D. Teitelbaum, Susan L. Richardson, David B. Millikan, Robert C. Engel, Lawrence S. Shantakumar, Sumitra Steck, Susan E. Neugut, Alfred I. Rossner, Pavel, Jr. Santella, Regina M. Gammon, Marilie D. TI Polymorphisms in DNA repair genes, traffic-related polycyclic aromatic hydrocarbon exposure and breast cancer incidence SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE traffic; DNA repair; polycyclic aromatic hydrocarbons; breast cancer ID SINGLE NUCLEOTIDE POLYMORPHISMS; EXCISION-REPAIR; LONG-ISLAND; CIGARETTE-SMOKING; MAMMALIAN-CELLS; RISK; ADDUCTS; ASSOCIATION; WORKERS; XRCC1 AB Vehicular traffic polycyclic aromatic hydrocarbons (PAHs) have been associated with breast cancer incidence in epidemiologic studies, including our own. Because PAHs damage DNA by forming adducts and oxidative lesions, genetic polymorphisms that alter DNA repair capacity may modify associations between PAH-related exposures and breast cancer risk. Our goal was to examine the association between vehicular traffic exposure and breast cancer incidence within strata of a panel of nine biologically plausible nucleotide excision repair (NER) and base excision repair (BER) genotypes. Residential histories of 1,508 cases and 1,556 controls were assessed in the Long Island Breast Cancer Study Project between 1996 and 1997 and used to reconstruct residential traffic exposures to benzo[a]pyrene, as a proxy for traffic-related PAHs. Likelihood ratio tests from adjusted unconditional logistic regression models were used to assess multiplicative interactions. A gene-traffic interaction was evident (p = 0.04) for ERCC2 (Lys751); when comparing the upper and lower tertiles of 1995 traffic exposure estimates, the odds ratio (95% confidence interval) was 2.09 (1.13, 3.90) among women with homozygous variant alleles. Corresponding odds ratios for 1960-1990 traffic were also elevated nearly 2-3-fold for XRCC/(Arg194Trp), XRCC1(Arg399Gln) and OGG1(-Ser326Cys), but formal multiplicative interaction was not evident. When DNA repair variants for ERCC2, XRCC1 and OGG1 were combined, among women with 4-6 variants, the odds ratios were 2.32 (1.22, 4.49) for 1995 traffic and 2.96 (1.06, 8.21) for 1960-1990 traffic. Our study is first to report positive associations between traffic-related PAH exposure and breast cancer incidence among women with select biologically plausible DNA repair genotypes. C1 [Mordukhovich, Irina; Richardson, David B.; Millikan, Robert C.; Engel, Lawrence S.; Gammon, Marilie D.] Dept Epidemiol, Lambertville, NJ USA. [Beyea, Jan] Consulting Publ Interest, Lambertville, NJ USA. [Herring, Amy H.] Univ N Carolina, Biostat, Chapel Hill, NC USA. [Herring, Amy H.] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Hatch, Maureen] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Stellman, Steven D.; Neugut, Alfred I.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Teitelbaum, Susan L.] Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA. [Shantakumar, Sumitra] Glaxo Smith Kline Inc, Singapore, Singapore. [Steck, Susan E.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Neugut, Alfred I.] Columbia Univ, Dept Med, New York, NY USA. [Rossner, Pavel, Jr.; Santella, Regina M.] Columbia Univ, Environm Hlth Sci, New York, NY USA. [Rossner, Pavel, Jr.] Acad Sci Czech Republic, Inst Expt Med, Lab Genet Ecotoxicol, Prague, Czech Republic. RP Mordukhovich, I (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Landmark Ctr, Epidemiol & Risk,Program Dept Environm Hlth, 401 Pk Dr, Boston, MA 02215 USA. EM imordukh@hsph.harvard.edu RI Rossner, Pavel/H-2569-2014; OI Beyea, Jan/0000-0002-0547-880X; Engel, Lawrence/0000-0001-9268-4830 FU U.S. Department of Defense [BC100414, BC972772]; National Cancer Institute; National Institute of Environmental Health Sciences [CA/ES66572, P30ES009089, P30ES10126, T32CA09330, T32ES007018]; Breast Cancer Research Foundation, Columbia University Women at Risk Program FX Grant sponsor: U.S. Department of Defense; Grant number: BC100414, BC972772; Grant sponsor: National Cancer Institute and the National Institute of Environmental Health Sciences; Grant number: CA/ES66572, P30ES009089, P30ES10126, T32CA09330 and T32ES007018; Grant sponsor: Breast Cancer Research Foundation, Columbia University Women at Risk Program NR 50 TC 0 Z9 0 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUL 15 PY 2016 VL 139 IS 2 BP 310 EP 321 DI 10.1002/ijc.30079 PG 12 WC Oncology SC Oncology GA DP3TE UT WOS:000378417500007 PM 26946191 ER PT J AU Yang, Y Gao, J Li, HL Zheng, W Yang, G Zhang, W Ma, X Tan, YT Rothman, N Gao, YT Chow, WH Shu, XO Xiang, YB AF Yang, Yang Gao, Jing Li, Hong-Lan Zheng, Wei Yang, Gong Zhang, Wei Ma, Xiao Tan, Yu-Ting Rothman, Nathaniel Gao, Yu-Tang Chow, Wong-Ho Shu, Xiao-Ou Xiang, Yong-Bing TI Dose-response association between hepatitis B surface antigen levels and liver cancer risk in Chinese men and women SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Hepatitis B surface antigen; liver cancer; dose-response relationship; gender disparity; prospective study ID ENHANCER-BINDING FACTOR-1; HEPATOCELLULAR-CARCINOMA; NATURAL-HISTORY; TRANSGENIC MICE; VIRUS INFECTION; EPIDEMIOLOGY; SHANGHAI; QUANTIFICATION; PERSPECTIVE; EXPRESSION AB We aimed at evaluating the risk of liver cancer in different levels of HBsAg among Chinese men and women. We carried out a nested case-control study including 363 cases and 3,511 controls in two population-based cohorts in Shanghai. Plasma samples collected at enrollment were quantified for HBsAg levels using the Architect QT assay. Conditional logistic regression was performed to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for liver cancer, with adjustment for potential confounders. HBsAg was detected in 6.29% of control subjects overall (7.02% in men and 4.98% in women). HBsAg levels were positively associated with liver cancer risk in a dose-response manner (p(trend) < 0.001). Such association showed a significant gender disparity. With increasing levels of HBsAg, liver cancer risks rose more steeply in men than in women. In men, the adjusted ORs increased from 7.27 (95% CI: 3.49-15.15) at the lowest detectable level of HBsAg (5-9 IU/ml) to 7.16 (95% CI: 3.21-15.96), 34.30 (95% CI: 16.94-69.44), and 47.33 (95% CI: 23.50-95.34) at the highest level of HBsAg (=1,000 IU/ml) compared to those negative for HBsAg. The corresponding ORs were much lower for women, from 1.37 (95% CI: 0.25-7.47), 3.81 (95% CI: 1.09-13.28), 7.36 (95% CI: 2.41-22.46) and 16.86 (95% CI: 7.24-39.27), respectively. HBsAg quantification has potential to distinguish individuals at different risks of liver cancer. Men with the lowest detectable level of HBsAg should still pay attention to their liver cancer risks, but those with a higher level may be given a higher priority in future liver cancer surveillance program. C1 [Yang, Yang] Fudan Univ, Sch Publ Hlth, Shanghai 200433, Peoples R China. [Yang, Yang; Gao, Jing; Li, Hong-Lan; Zhang, Wei; Ma, Xiao; Tan, Yu-Ting; Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, SKLORG,Shanghai Canc Inst, 25,Lane 2200,Xie Tu Rd, Shanghai 200030, Peoples R China. [Zheng, Wei; Yang, Gong; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. RP Xiang, YB (reprint author), Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, SKLORG,Shanghai Canc Inst, 25,Lane 2200,Xie Tu Rd, Shanghai 200030, Peoples R China.; Xiang, YB (reprint author), Shanghai Jiao Tong Univ, Renji Hosp, Shanghai Canc Inst, Dept Epidemiol, 25,Lane 2200,Xie Tu Rd, Shanghai 200032, Peoples R China. EM ybxiang@shsci.org RI Zheng, Wei/O-3351-2013 OI Zheng, Wei/0000-0003-1226-070X FU State Key Project Specialized for Infectious Diseases of China [2008ZX10002-015, 2012ZX10002008-002]; National Key Basic Research Program "973 project" [2015CB554000]; Innovative Research Groups of the National Natural Science Foundation of China [81421001]; US National Institutes of Health [R37 CA070867, UM1 CA182910, R01 CA082729, UM1 CA173640] FX Grant sponsor: State Key Project Specialized for Infectious Diseases of China; Grant numbers: 2008ZX10002-015, 2012ZX10002008-002; Grant sponsor: National Key Basic Research Program "973 project;" Grant number: 2015CB554000; Grant sponsor: Innovative Research Groups of the National Natural Science Foundation of China; Grant number: 81421001; Grant sponsor: US National Institutes of Health; Grant numbers: R37 CA070867 and UM1 CA182910, R01 CA082729 and UM1 CA173640 NR 30 TC 2 Z9 3 U1 3 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUL 15 PY 2016 VL 139 IS 2 BP 355 EP 362 DI 10.1002/ijc.30086 PG 8 WC Oncology SC Oncology GA DP3TE UT WOS:000378417500011 PM 26990915 ER PT J AU Benjamini, D Komlosh, ME Holtzclaw, LA Nevo, U Basser, PJ AF Benjamini, Dan Komlosh, Michal E. Holtzclaw, Lynne A. Nevo, Uri Basser, Peter J. TI White matter microstructure from nonparametric axon diameter distribution mapping SO NEUROIMAGE LA English DT Article DE MRI; Double diffusion encoding; Double pulsed field gradient; Axon diameter distribution; Pore size distribution; Nonparametric; Empirical; Average axon diameter ID PORE-SIZE DISTRIBUTION; MICROSCOPIC DIFFUSION ANISOTROPY; FIELD-GRADIENT; SPINAL-CORD; MULTIPLE-SCLEROSIS; CORPUS-CALLOSUM; RESTRICTED DIFFUSION; CLUSTER-ANALYSIS; NERVE-FIBERS; HUMAN BRAIN AB We report the development of a double diffusion encoding (DDE) MRI method to estimate and map the axon diameter distribution (ADD) within an imaging volume. A variety of biological processes, ranging from development to disease and trauma, may lead to changes in the ADD in the central and peripheral nervous systems. Unlike previously proposed methods, this ADD experimental design and estimation framework employs a more general, nonparametric approach, without a priori assumptions about the underlying form of the ADD, making it suitable to analyze abnormal tissue. In the current study, this framework was used on an ex vivo ferret spinal cord, while emphasizing the way in which the ADD can be weighted by either the number or the volume of the axons. The different weightings, which result in different spatial contrasts, were considered throughout this work. DDE data were analyzed to derive spatially resolved maps of average axon diameter, ADD variance, and extra-axonal volume fraction, along with a novel sub-micron restricted structures map. The morphological information contained in these maps was then used to segment white matter into distinct domains by using a proposed k-means clustering algorithm with spatial contiguity and left-right symmetry constraints, resulting in identifiable white matter tracks. The method was validated by comparing histological measures to the estimated ADDs using a quantitative similarity metric, resulting in good agreement. With further acquisition acceleration and experimental parameters adjustments, this ADD estimation framework could be first used preclinically, and eventually clinically, enabling a wide range of neuroimaging applications for improved understanding of neurodegenerative pathologies and assessing microstructural changes resulting from trauma. Published by Elsevier Inc. C1 [Benjamini, Dan; Komlosh, Michal E.; Basser, Peter J.] NICHD, Quantitat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Benjamini, Dan; Nevo, Uri] Tel Aviv Univ, Iby & Aladar Fleischman Fac Engn, Dept Biomed Engn, IL-69978 Tel Aviv, Israel. [Komlosh, Michal E.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Holtzclaw, Lynne A.] NICHD, Microscopy & Imaging Core, NIH, Bethesda, MD 20892 USA. RP Benjamini, D (reprint author), NICHD, Quantitat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. EM dan.benjamini@nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [ZIA-HD000266]; Center for Neuroregenerative Medicine (CNRM) under the Henry Jackson Foundation [306135-2.01-60855] FX This work was supported by funds provided by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number ZIA-HD000266), and the Center for Neuroregenerative Medicine (CNRM) under the auspices of the Henry Jackson Foundation (grant number 306135-2.01-60855). The authors thank Dr. Alexandru Avram for fruitful discussions, Dr. Kryslaine Radomski and Dr. Elizabeth B. Hutchinson for dissecting and preparing the spinal cord, Dr. Carlo Pierpaoli and Dr. Sharon Juliano for providing the spinal cord, and Ms. Liz Salak for editing the manuscript. NR 93 TC 1 Z9 1 U1 4 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2016 VL 135 BP 333 EP 344 DI 10.1016/j.neuroimage.2016.04.052 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DO8QF UT WOS:000378047600030 PM 27126002 ER PT J AU Nguyen, KP O'Neal, TJ Bolonduro, OA White, E Kravitz, AV AF Nguyen, Katrina P. O'Neal, Timothy J. Bolonduro, Olurotimi A. White, Elecia Kravitz, Alexxai V. TI Feeding Experimentation Device (FED): A flexible open-source device for measuring feeding behavior SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Arduino; Feeding behavior; Food intake; Open-source AB Background: Measuring food intake in rodents is a conceptually simple yet labor-intensive and temporally-imprecise task. Most commonly, food is weighed manually, with an interval of hours or days between measurements. Commercial feeding monitors are excellent, but are costly and require specialized caging and equipment. New method: We have developed the Feeding Experimentation Device (FED): a low-cost, open-source, home cage-compatible feeding system. FED utilizes an Arduino microcontroller and open-source software and hardware. FED dispenses a single food pellet into a food well where it is monitored by an infrared beam. When the mouse removes the pellet, FED logs the timestamp to a secure digital (SD) card and dispenses a new pellet into the well. Post-hoc analyses of pellet retrieval timestamps reveal high-resolution details about feeding behavior. Results: FED is capable of accurately measuring food intake, identifying discrete trends during light and dark-cycle feeding. Additionally, we show the utility of FED for measuring increases in feeding resulting from optogenetic stimulation of agouti-related peptide neurons in the arcuate nucleus of the hypothalamus. Comparison to existing methods: With a cost of similar to$350 per device, FED is >10x cheaper than commercially available feeding systems. FED is also self-contained, battery powered, and designed to be placed in standard colony rack cages, allowing for monitoring of true home cage feeding behavior. Moreover, FED is highly adaptable and can be synchronized with emerging techniques in neuroscience, such as optogenetics, as we demonstrate here. Conclusions: FED allows for accurate, precise monitoring of feeding behavior in a home cage setting. Published by Elsevier B.V. C1 [Nguyen, Katrina P.; O'Neal, Timothy J.; Bolonduro, Olurotimi A.; Kravitz, Alexxai V.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bldg 10 CRC,Room 5-5932, Bethesda, MD 20892 USA. [White, Elecia] Log Elegance, San Jose, CA 95130 USA. RP Kravitz, AV (reprint author), NIDDK, NIH, NIDA, Bldg 10 CRC,Room 5-5932,10 Ctr Dr, Bethesda, MD 20814 USA. EM katrina.nguyen@nih.gov; timothy.oneal@nih.gov; obolonduro@gmail.com; elecia@logicalelegance.com; alexxai.kravitz@nih.gov FU National Institutes of Health Intramural Research Program FX Research was funded by the National Institutes of Health Intramural Research Program. We would like to thank the NIH Section on Instrumentation and the NIH Library for their generous assistance with 3D printing, Dr. Michael Krashes and Dr. Chia Li for their donation of AgRP-IRES-Cre mice, and Dr. Miriam Bocarsly for food intake measurements via Sable's Promethion System. NR 6 TC 2 Z9 2 U1 9 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD JUL 15 PY 2016 VL 267 BP 108 EP 114 DI 10.1016/j.jneumeth.2016.04.003 PG 7 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DO6WB UT WOS:000377923100010 PM 27060385 ER PT J AU Krajczyk, A Zeidler, J Januszczyk, P Dawadi, S Boshoff, HI Barry, CE Ostrowski, T Aldrich, CC AF Krajczyk, Anna Zeidler, Joanna Januszczyk, Piotr Dawadi, Surendra Boshoff, Helena I. Barry, Clifton E., III Ostrowski, Tomasz Aldrich, Courtney C. TI 2-Aryl-8-aza-3-deazaadenosine analogues of 5 '-O-[N-(salicyl)sulfamoyl]adenosine: Nucleoside antibiotics that block siderophore biosynthesis in Mycobacterium tuberculosis SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE 8-Aza-3-deazaadenosine; Modified nucleoside; Tuberculosis; Siderophore biosynthesis; Adenylation inhibitor ID ANTITUMOR-ACTIVITY; RING-CLOSURE; 3-DEAZAPURINE NUCLEOSIDES; NUCLEOTIDES; INHIBITION; 5-ETHYNYL-1-BETA-D-RIBOFURANOSYLIMIDAZOLE-4-CARBOXAMIDE; DERIVATIVES; DOMAIN AB A series of 5'-O-[N-(salicyl) sulfamoyl]-2-aryl-8-aza-3-deazaadenosines were designed to block mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) through inhibition of the essential adenylating enzyme MbtA. The synthesis of the 2-aryl-8-aza-3-deazaadenosine nucleosides featured sequential copper-free palladium-catalyzed Sonogashira coupling of a precursor 4-cyano-5-iodo-1,2,3-triazolonucleoside with terminal alkynes and a Minakawa-Matsuda annulation reaction. These modified nucleosides were shown to inhibit MbtA with apparent K-i values ranging from 6.1 to 25 nM and to inhibit Mtb growth under iron-deficient conditions with minimum inhibitory concentrations ranging from 12.5 to >50 mu M. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Krajczyk, Anna; Zeidler, Joanna; Januszczyk, Piotr; Ostrowski, Tomasz] Polish Acad Sci, Inst Bioorgan Chem, Noskowskiego 12-14, PL-61704 Poznan, Poland. [Dawadi, Surendra; Aldrich, Courtney C.] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA. [Boshoff, Helena I.; Barry, Clifton E., III] NIAID, TB Res Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Ostrowski, T (reprint author), Polish Acad Sci, Inst Bioorgan Chem, Noskowskiego 12-14, PL-61704 Poznan, Poland.; Aldrich, CC (reprint author), Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA. EM tostr@ibch.poznan.pl; aldri015@umn.edu FU Polish Ministry of Science and Higher Education [N N405 2516 33]; KNOW program; NIH [AI070219]; Intramural Research Program of the NIAID, NIH FX This work was supported by the Polish Ministry of Science and Higher Education grant no. N N405 2516 33 (J.Z.), under statutory financing, and under the KNOW program. It was also supported by a grant from the NIH (AI070219 to C.C.A.) and the Intramural Research Program of the NIAID, NIH (C.E.B.). We wish to thank Dr. Lukasz Marczak and Dr. Barbara Swarcewicz for MS spectra measurements. NR 35 TC 0 Z9 0 U1 7 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUL 15 PY 2016 VL 24 IS 14 BP 3133 EP 3143 DI 10.1016/j.bmc.2016.05.037 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DO0LG UT WOS:000377469800006 PM 27265685 ER PT J AU Kossmann, BR Abdelmalak, M Lopez, S Tender, G Yan, CL Pommier, Y Marchand, C Ivanov, I AF Kossmann, Bradley R. Abdelmalak, Monica Lopez, Sophia Tender, Gabrielle Yan, Chunli Pommier, Yves Marchand, Christophe Ivanov, Ivaylo TI Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Tyrosyl-DNA phosphodiesterase 2; TDP2; Inhibitor; Virtual screening; Rational drug design ID MOLECULAR-DYNAMICS; VERTEBRATE CELLS; TDP1; TOPOISOMERASES; COMPLEXES; DATABASE; ADDUCTS; REPAIR; DAMAGE AB Tyrosyl-DNA phosphodiesterase 2 (TDP2) processes protein/DNA adducts resulting from abortive DNA topoisomerase II (Top2) activity. TDP2 inhibition could provide synergism with the Top2 poison class of chemotherapeutics. By virtual screening of the NCI diversity small molecule database, we identified selective TDP2 inhibitors and experimentally verified their selective inhibitory activity. Three inhibitors exhibited low-micromolar IC50 values. Molecular dynamics simulations revealed a common binding mode for these inhibitors, involving association to the TDP2 DNA-binding cleft. MM-PBSA per-residue energy decomposition identified important interactions of the compounds with specific TDP2 residues. These interactions could provide new avenues for synthetic optimization of these scaffolds. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Kossmann, Bradley R.; Yan, Chunli; Ivanov, Ivaylo] Georgia State Univ, Dept Chem, Ctr Diagnost & Therapeut, Atlanta, GA 30302 USA. [Abdelmalak, Monica; Lopez, Sophia; Tender, Gabrielle; Pommier, Yves; Marchand, Christophe] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ivanov, I (reprint author), Georgia State Univ, Dept Chem, Ctr Diagnost & Therapeut, Atlanta, GA 30302 USA.; Marchand, C (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM marchanc@mail.nih.gov; iivanov@gsu.edu RI Kossmann, Bradley/O-5016-2016; OI Kossmann, Bradley/0000-0001-5368-0976; Ivanov, Ivaylo/0000-0002-5306-1005 FU National Science Foundation CAREER award [MCB-1149521]; National Institutes of Health (NIH) [R01GM110387]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research [Z01 BC 006161]; U.S. Department of Energy Office of Science [DE-AC02-05CH11231] FX This work was supported by a National Science Foundation CAREER award MCB-1149521 and a National Institutes of Health (NIH) grant R01GM110387. This work was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (Z01 BC 006161). Computational resources were provided in part by a National Science Foundation XSEDE allocation CHE110042 and through an allocation at NERSC supported by the U.S. Department of Energy Office of Science contract DE-AC02-05CH11231. The authors wish to thank Drs. Gary Pauly and Joel Schneider from the Chemical Biology Laboratory, CCR, NCI for their support in purity analysis. The authors also thank Dr. Nouri Neamati from the University of Michigan College of Pharmacy who provided us with the APE1 inhibitor compound 21. NR 25 TC 1 Z9 1 U1 4 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUL 15 PY 2016 VL 26 IS 14 BP 3232 EP 3236 DI 10.1016/j.bmcl.2016.05.065 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA DO0LW UT WOS:000377471400006 PM 27262595 ER PT J AU Cheng, HM Chuang, SY Wang, JJ Shih, YT Wang, HN Huang, CJ Huang, JT Sung, SH Lakatta, EG Yin, FCP Chou, P Yeh, CJ Bai, CH Pan, WH Chen, CH AF Cheng, Hao-Min Chuang, Shao-Yuan Wang, Jiun-Jr Shih, Yuan-Ta Wang, Hsin-Ning Huang, Chi-Jung Huang, Jui-Tzu Sung, Shih-Hsien Lakatta, Edward G. Yin, Frank C. P. Chou, Pesus Yeh, Chih-Jung Bai, Chyi-Huey Pan, Wen-Harn Chen, Chen-Huan TI Prognostic significance of mechanical biomarkers derived from pulse wave analysis for predicting long-term cardiovascular mortality in two population-based cohorts SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Wave reflection; Pulse wave analysis; Vascular aging; Mortality; Epidemiology; Reservoir pressure ID PRESERVED EJECTION FRACTION; ASCENDING AORTIC PRESSURE; CAROTID-ARTERY TONOMETRY; LEFT-VENTRICULAR MASS; RESERVOIR-WAVE; ISCHEMIC-STROKE; BLOOD-PRESSURE; HEART-FAILURE; INTEGRATED DISCRIMINATION; ALL-CAUSE AB Background: Numerous mechanical biomarkers derived from pulse wave analysis (PWA) have been proposed to predict cardiovascular outcomes. However, whether these biomarkers carry independent prognostic value and clinical utility beyond traditional cardiovascular risk factors hasn't been systematically evaluated. We aimed to investigate the additive utility of PWA-derived biomarkers in two independent population-based cohorts. Methods: PWA on central arterial pressure waveforms obtained from subjects without a prior history of cardiovascular diseases of two studies was conducted based on the wave transmission and reservoir-wave theory: firstly in the Kinmen study (1272 individuals, a median follow-up of 19.8 years); and then in the Cardiovascular Disease Risk Factors Two-Township Study (2221 individuals, median follow-up of 10 years). The incremental value of the biomarkers was evaluated by net reclassification index (NRI). Results: In multivariate Cox analyses accounting for age, gender, body mass index, systolic blood pressure, fasting glucose, high-density-and low-density-lipoprotein cholesterol, and smoking, only systolic (SC) and diastolic rate constant (DC) of reservoir pressure could independently and consistently predict cardiovascular mortality in both cohorts and the combined cohort (SC: hazard ratio 1.18 [95% confidence interval 1.08-1.28, p < 0.001; DC: 1.18 [1.09-1.28], p < 0.001]. Risk prediction estimates in traditional risk prediction models were significantly more accurate when incorporating peak of reservoir pressure (NRI = 0.049, p = 0.0361), SC (NRI = 0.043, p = 0.0236) and DC (NRI = 0.054, p = 0.047). Conclusions: Of all PWA-derived biomarkers, SC and DC were consistently identified as valuable parameters for incremental cardiovascular risk prediction in two large prospective cohorts. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Cheng, Hao-Min; Huang, Chi-Jung; Chen, Chen-Huan] Taipei Vet Gen Hosp, Dept Med Educ, Taipei, Taiwan. [Sung, Shih-Hsien] Taipei Vet Gen Hosp, Dept Med, Taipei, Taiwan. [Chuang, Shao-Yuan] Natl Hlth Res Inst, Res Inst Populat Hlth Sci, Div Prevent Med & Hlth Serv, Miaoli, Taiwan. [Wang, Jiun-Jr] Fu Jen Catholic Univ, Sch Med, New Taipei, Taiwan. [Shih, Yuan-Ta] Natl Taiwan Univ, Mol Imaging Ctr, Taipei 10764, Taiwan. [Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Intramural Res Program, Baltimore, MD 21224 USA. [Yin, Frank C. P.] Washington Univ, Dept Biomed Engn, St Louis, MO USA. [Chen, Chen-Huan] Natl Yang Ming Univ, Cardiovasc Res Ctr, Taipei 112, Taiwan. [Wang, Hsin-Ning; Huang, Jui-Tzu; Chen, Chen-Huan] Natl Yang Ming Univ, Fac Med, Taipei 112, Taiwan. [Chou, Pesus; Chen, Chen-Huan] Natl Yang Ming Univ, Dept Publ Hlth, Taipei 112, Taiwan. [Yeh, Chih-Jung] Chung Shan Med Univ, Dept Publ Hlth, Taichung 40201, Taiwan. [Pan, Wen-Harn] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Bai, Chyi-Huey] Taipei Med Univ, Sch Publ Hlth, Taipei, Taiwan. RP Chen, CH (reprint author), Taipei Vet Gen Hosp, Dept Med Educ, Taipei, Taiwan.; Chen, CH (reprint author), Natl Yang Ming Univ, Cardiovasc Res Ctr, Taipei 112, Taiwan.; Chen, CH (reprint author), Natl Yang Ming Univ, Fac Med, Taipei 112, Taiwan.; Chen, CH (reprint author), Natl Yang Ming Univ, Dept Publ Hlth, Taipei 112, Taiwan.; Pan, WH (reprint author), Acad Sinica, Inst Biomed Sci, Taipei, Taiwan.; Chen, CH (reprint author), Taipei Vet Gen Hosp, Div Cardiol, 201,Sec 2,Shih Pai Rd, Taipei, Taiwan. EM chench@vghtpe.gov.tw FU Ministry of Science and Technology [MOST 103-2314-B-010-012 -]; Taipei Veterans General Hospital [V104C-140]; Intramural Research Program of the National Institute on Aging, National Institutes of Health [NO1-AG-1-2118] FX This work was supported in part by a grant from the Ministry of Science and Technology (MOST 103-2314-B-010-012 -), an intramural grant from the Taipei Veterans General Hospital (Grant No. V104C-140), and the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NO1-AG-1-2118). NR 46 TC 1 Z9 1 U1 2 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 15 PY 2016 VL 215 BP 388 EP 395 DI 10.1016/j.ijcard.2016.04.070 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM4DX UT WOS:000376297100085 PM 27128568 ER PT J AU Roschewski, M AF Roschewski, Mark TI Precision monitoring takes the stage SO BLOOD LA English DT Editorial Material ID CIRCULATING TUMOR DNA; B-CELL LYMPHOMA AB In this issue of Blood, Assouline et al report the clinical activity of the oral histone deacetylase inhibitor, panobinostat, in 40 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not preselected on the basis of molecular subtype as well as transformed lymphomas. 1 The authors found a modest overall response rate (ORR) of 28% in the entire cohort with no benefit from the addition of rituximab. Importantly, a subset of responders achieved relatively durable remissions, including 6 responders (55%) who had yet to progress. C1 [Roschewski, Mark] NCI, Bethesda, MD 20892 USA. RP Roschewski, M (reprint author), NCI, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 14 PY 2016 VL 128 IS 2 BP 149 EP 150 DI 10.1182/blood-2016-05-717520 PG 2 WC Hematology SC Hematology GA DW7KQ UT WOS:000383830000001 PM 27418622 ER EF