FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Morissette, R Chen, WY Perritt, AF Dreiling, JL Arai, AE Sachdev, V Hannoush, H Mallappa, A Xu, Z McDonnell, NB Quezado, M Merke, DP AF Morissette, Rachel Chen, Wuyan Perritt, Ashley F. Dreiling, Jennifer L. Arai, Andrew E. Sachdev, Vandana Hannoush, Hwaida Mallappa, Ashwini Xu, Zhi McDonnell, Nazli B. Quezado, Martha Merke, Deborah P. TI Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TENASCIN-X DEFICIENCY; GROWTH-FACTOR-BETA; 21-HYDROXYLASE DEFICIENCY; HYPERMOBILITY TYPE; AORTIC-ANEURYSM; TGF-BETA; PREDICTION SERVER; MUTATIONS; ABNORMALITIES; TNXB AB Context: The contiguous gene deletion syndrome (CAH-X) was described in a subset (7%) of congenital adrenal hyperplasia (CAH) patients with a TNXA/TNXB chimera, resulting in deletions of CYP21A2, encoding 21-hydroxylase necessary for cortisol biosynthesis, and TNXB, encoding the extracellular matrix glycoprotein tenascin-X (TNX). This TNXA/TNXB chimera is characterized by a 120-bp deletion in exon 35 and results in TNXB haploinsufficiency, disrupted TGF-beta signaling, and an Ehlers Danlos syndrome phenotype. Objective: The objective of the study was to determine the genetic status of TNXB and resulting protein defects in CAH patients with a CAH-X phenotype but not the previously described TNXA/TNXB chimera. Design, Settings, Participants, and Intervention: A total of 246 unrelated CAH patients were screened for TNXB defects. Genetic defects were investigated by Southern blotting, multiplex ligation-dependent probe amplification, Sanger, and next-generation sequencing. Dermal fibroblasts and tissue were used for immunoblotting, immunohistochemical, and coimmunoprecipitation experiments. Main Outcome Measures: The genetic and protein status of tenascin-X in phenotypic CAH-X patients was measured. Results: Seven families harbor a novelTNXBmissense variant c. 12174C>G(p.C4058W) and a clinical phenotype consistent with hypermobility-type Ehlers Danlos syndrome. Fourteen CAH probands carry previously described TNXA/TNXB chimeras, and seven unrelated patients carry the novel TNXB variant, resulting in a CAH-X prevalence of 8.5%. This highly conserved pseudogene-derived variant in the TNX fibrinogen-like domain is predicted to be deleterious and disulfide bonded, results in reduced dermal elastin and fibrillin-1 staining and altered TGF-beta 1 binding, and represents a novel TNXA/TNXB chimera. Tenascin-X protein expression was normal in dermal fibroblasts, suggesting a dominant-negative effect. Conclusions: CAH-Xsyndrome is commonly foundin CAH due to 21-hydroxylase deficiency and may result from various etiological mechanisms. C1 [Morissette, Rachel; Perritt, Ashley F.; Mallappa, Ashwini; Merke, Deborah P.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Chen, Wuyan] PreventionGenetics, Marshfield, WI 54449 USA. [Dreiling, Jennifer L.; Quezado, Martha] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Arai, Andrew E.; Sachdev, Vandana; Hannoush, Hwaida] NHLBI, Bethesda, MD 20892 USA. [Xu, Zhi; McDonnell, Nazli B.] NIA, NIH, Baltimore, MD 21224 USA. RP Morissette, R (reprint author), NIH, Ctr Clin, Bldg 10,Room 1-2610,10 Ctr Dr, Bethesda, MD 20892 USA. EM morissetter@mail.nih.gov FU Intramural Research Programs of the National Institutes of Health Clinical Center; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute; National Institute on Aging FX This work was supported by the Intramural Research Programs of the National Institutes of Health Clinical Center, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, and the National Institute on Aging. D.P.M. is a commissioned officer in the US Public Health Service. NR 37 TC 2 Z9 2 U1 0 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 2015 VL 100 IS 8 BP E1143 EP E1152 DI 10.1210/jc.2015-2232 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CW2XH UT WOS:000364855900016 PM 26075496 ER PT J AU Yeoh, AJ Pedley, A Rosenquist, KJ Hoffmann, U Fox, CS AF Yeoh, Aaron J. Pedley, Alison Rosenquist, Klara J. Hoffmann, Udo Fox, Caroline S. TI The Association Between Subcutaneous Fat Density and the Propensity to Store Fat Viscerally SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CARDIOMETABOLIC RISK PROFILE; ADIPOSE-TISSUE FIBROSIS; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; HUMAN OBESITY; FRAMINGHAM; HEART; DYSFUNCTION; ACCUMULATION; INFLAMMATION AB Background: Alterations in the cellular characteristics of subcutaneous adipose tissue (SAT) may reduce its ability to expand in times of caloric excess, increasing the propensity to store excess calories viscerally (visceral adipose tissue [VAT]). We hypothesized (1) that increased SAT density, an indirect marker of fat quality, would be associated with an increased VAT/SAT ratio and increased cardiovascular disease (CVD) risk and (2) that these associations would be independent of the absolute volume of SAT. Methods: We investigated the association of SAT density with the VAT/SAT ratio and CVD risk in 3212 participants (48% women, mean age, 50.7 years) from the Framingham Heart Study. Adipose tissue depot density and volume were quantified by computed tomography; traditional CVD risk factors were quantified. Results: Higher SAT density was correlated with a higher VAT/SAT ratio in men (r = 0.17; P < .0001) but not in women (r = 0.04; P >= .05). More adverse levels of CVD risk factors were observed in the high SAT density/high VAT/SAT ratio group than in the referent group (low density/low ratio). For example, women had an increased risk of diabetes (odds ratio [OR], 6.7; 95% confidence interval [CI], 2.6-17.6; P = .0001) and hypertension (OR, 1.6; 95% CI, 1.1-2.4; P = .009). Additional adjustment for SAT volume generally strengthened these associations (diabetes OR, 10.8; 95% CI, 4.1-29.0; hypertension OR, 2.5; 95% CI, 1.7-3.7; all P = .0001). These trends were similar but generally weaker in men. Conclusion: High fat density, an indirect marker of fat quality, is associated with the propensity to store fat viscerally vs subcutaneously and is jointly characterized by an increased burden of CVD risk factors. C1 [Yeoh, Aaron J.; Pedley, Alison; Rosenquist, Klara J.; Fox, Caroline S.] Natl Heart & Lung Blood Inst Framingham Heart Stu, Framingham, MA 01702 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Fox, CS (reprint author), Natl Heart & Lung Blood Inst Framingham Heart Stu, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxa@nhlbi.nih.gov FU National Heart, Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine [N01-HC-25195] FX This work was supported by in part using resources and data from the Framingham Heart Study of the National Heart, Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine (Grant N01-HC-25195). NR 43 TC 6 Z9 6 U1 1 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2015 VL 100 IS 8 BP E1056 EP E1064 DI 10.1210/jc.2014-4032 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CW2XH UT WOS:000364855900006 PM 26062015 ER PT J AU Mascio, HM Joya, CA Plasse, RA Baker, TP Flessner, MF Nee, R AF Mascio, Heather M. Joya, Christie A. Plasse, Richard A. Baker, Thomas P. Flessner, Michael F. Nee, Robert TI An unusual cause of acute kidney injury due to oxalate nephropathy in systemic scleroderma SO CLINICAL NEPHROLOGY LA English DT Article DE oxalate nephropathy; acute kidney injury; scleroderma ID RENAL-FAILURE; OXALOBACTER-FORMIGENES; STONE DISEASE; SCLEROSIS; HYPEROXALURIA; MANAGEMENT; CRISIS AB Oxalate nephropathy is an uncommon cause of acute kidney injury. Far rarer is its association with scleroderma, with only one other published case report in the literature. We report a case of a 75-year-old African-American female with a history of systemic scleroderma manifested by chronic pseudo-obstruction and small intestinal bacterial overgrowth (SIBO) treated with rifaximin, who presented with acute kidney injury with normal blood pressure. A renal biopsy demonstrated extensive acute tubular injury with numerous intratubular birefringent crystals, consistent with oxalate nephropathy. We hypothesize that her recent treatment with rifaximin for SIBO and decreased intestinal transit time in pseudo-obstruction may have significantly increased intestinal oxalate absorption, leading to acute kidney injury. Oxalate nephropathy should be considered in the differential diagnosis of acute kidney injury in scleroderma with normotension, and subsequent evaluation should be focused on bowel function to include alterations in gut flora due to antibiotic administration. C1 [Mascio, Heather M.; Nee, Robert] Walter Reed Natl Mil Med Ctr, Serv Nephrol, Bethesda, MD 20889 USA. [Joya, Christie A.; Plasse, Richard A.] Walter Reed Natl Mil Med Ctr, Dept Med, Bethesda, MD 20889 USA. [Baker, Thomas P.] Def Hlth Agcy, Joint Pathol Ctr, Silver Spring, MD USA. [Flessner, Michael F.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Nee, R (reprint author), Walter Reed Natl Mil Med Ctr, Serv Nephrol, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM robert.nee.civ@mail.mil NR 27 TC 0 Z9 0 U1 1 U2 2 PU DUSTRI-VERLAG DR KARL FEISTLE PI DEISENHOFEN-MUENCHEN PA BAHNHOFSTRASSE 9 POSTFACH 49, D-82032 DEISENHOFEN-MUENCHEN, GERMANY SN 0301-0430 J9 CLIN NEPHROL JI Clin. Nephrol. PD AUG PY 2015 VL 84 IS 2 BP 111 EP 115 DI 10.5414/CN108406 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA CV8JV UT WOS:000364531400008 PM 25500295 ER PT J AU Gordon, D Cooper-Arnold, K Lauer, M AF Gordon, David Cooper-Arnold, Katharine Lauer, Michael TI Publication Speed, Reporting Metrics, and Citation Impact of Cardiovascular Trials Supported by the National Heart, Lung, and Blood Institute SO Journal of the American Heart Association LA English DT Article DE bibliometrics; citation; public policy; randomized, controlled trial; research funding ID RANDOMIZED CONTROLLED-TRIAL; LEFT-VENTRICULAR FUNCTION; MARROW MONONUCLEAR-CELLS; POSTMENOPAUSAL WOMEN; ATRIAL-FIBRILLATION; CLINICAL-TRIALS; MORTALITY; DELIVERY; FAILURE AB Background-We previously demonstrated that cardiovascular (CV) trials funded by the National Heart, Lung, and Blood Institute (NHLBI) were more likely to be published in a timely manner and receive high raw citation counts if they focused on clinical endpoints. We did not examine the metrics of trial reports, and our citation measures were limited by failure to account for topic-related citation behaviors. Methods and Results-Of 244 CV trials completed between 2000 and 2011, we identified 184 whose main results were published by August 20, 2014. One investigator who was blinded to rapidity of publication and citation data read each publication and characterized it according to modified Delphi criteria. There were 46 trials (25%) that had Delphi scores of 8 or 9 (of a possible 9); these trials published faster (median time from trial completion to publication, 12.6 [interquartile range {IQR}, 6.7 to 23.3] vs. 21.8 [IQR, 12.1 to 34.9] months; P<0.01). They also had better normalized citation impact (median citation percentile for topic and date of publication, with 0 best and 100 worst, 1.92 [IQR, 0.64 to 7.83] vs. 8.41 [IQR, 1.80 to 24.75]; P=0.002). By random forest regression, we found that the 3 most important predictors of normalized citation percentile values were total costs, intentionto- treat analyses (as a modified Delphi quality measure), and focus on clinical (not surrogate) endpoints. Conclusions-NHLBI CV trials were more likely to publish results quickly and yield higher topic-normalized citation impact if they reported results according to well-defined metrics, along with focus on clinical endpoints. C1 [Gordon, David; Cooper-Arnold, Katharine; Lauer, Michael] NHLBI, Div Cardiovasc Sci DCVS, Bethesda, MD 20892 USA. RP Lauer, M (reprint author), 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI) FX This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) through the efforts of the 3 authors, who are full-time NHLBI employees and conducted the work as part of their official federal duties. NR 25 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD AUG PY 2015 VL 4 IS 8 AR e002292 DI 10.1161/JAHA.115.002292 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CV3HW UT WOS:000364150900032 PM 26231845 ER PT J AU Fritz, R Kohan-Ghadr, HR Bolnick, JM Bolnick, AD Kilburn, BA Diamond, MP Drewlo, S Armant, DR AF Fritz, Rani Kohan-Ghadr, Hamid-Reza Bolnick, Jay M. Bolnick, Alan D. Kilburn, Brian A. Diamond, Michael P. Drewlo, Sascha Armant, D. Randall TI Noninvasive detection of trophoblast protein signatures linked to early pregnancy loss using trophoblast retrieval and isolation from the cervix (TRIC) SO FERTILITY AND STERILITY LA English DT Article DE Early pregnancy loss; prenatal testing; trophoblast; uteroplacental insufficiency ID INTRAUTERINE GROWTH RESTRICTION; PLACENTAL OXIDATIVE STRESS; SERUM ALPHA-FETOPROTEIN; GENE-EXPRESSION; WEEKS GESTATION; 13 PP13; PREECLAMPSIA; MISCARRIAGE; CYTOKINE; ENDOGLIN AB Objective: To examine the expression pattern of biomarker proteins in extravillous trophoblast (EVT) cells obtained noninvasively by trophoblast retrieval and isolation from the cervix (TRIC) in patients with early pregnancy loss compared with control patients with uncomplicated term delivery. Design: Case-control study. Setting: Academic medical center. Patient(s): Women with either early pregnancy loss (EPL, n = 10) or an uncomplicated term delivery (N = 10). Intervention(s): Endocervical specimens obtained from ongoing pregnancies at gestational ages of 5-10 weeks to generate an archive of EVT cells isolated by TRIC, with medical records examined to select specimens matched for gestational age at the time of endocervical sampling. Main Outcome Measure(s): Known serum biomarkers for adverse pregnancy outcome that are expressed by EVT cells were evaluated by semiquantitative immunocytochemistry, using antibodies against endoglin (ENG), FMS-like tyrosine kinase-1 (FLT-1), alpha-fetoprotein (AFP), pregnancy-associated plasma protein-A (PAPP-A), galectin-13 (LGALS13), galectin-14 (LGALS14), and placental growth factor (PGF). Result(s): The EVT purity was over 95% in all specimens, based on chorionic gonadotropin expression; however, the number of EVT cells obtained was significantly lower in women with EPL than the control group. There was a statistically significant elevation of AFP, ENG, and FLT-1, and statistically significant reduction of PAPP-A, LGALS14, and PGF in the EPL group compared with controls. Conclusion(s): In this pilot study, EVT cells isolated by TRIC early in gestation exhibited altered protein expression patterns before an EPL compared with uncomplicated term pregnancies. (C) 2015 by American Society for Reproductive Medicine. C1 [Fritz, Rani; Kohan-Ghadr, Hamid-Reza; Bolnick, Jay M.; Bolnick, Alan D.; Kilburn, Brian A.; Drewlo, Sascha; Armant, D. Randall] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Armant, D. Randall] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Armant, D. Randall] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Armant, DR (reprint author), Wayne State Univ, Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, 275 East Hancock St, Detroit, MI 48201 USA. EM d.armant@wayne.edu OI Diamond, Michael/0000-0001-6353-4489; Armant, D. Randall/0000-0001-5904-9325 FU March of Dimes; Perkin Elmer; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HD071408]; W.K. Kellogg Foundation FX R.F. has nothing to disclose. H.-R.K.-G. has nothing to disclose. J.M.B. has nothing to disclose. A.D.B. has nothing to disclose. B.A.K. has nothing to disclose. M.P.D. has a pending patent and receives payment for intellectual property that has been licensed on his behalf by Wayne State University to Perkin Elmer, Inc. S.D. has received grants from the March of Dimes and Perkin Elmer, and receives payment for intellectual property that has been licensed on his behalf by Wayne State University to Perkin Elmer, Inc. D.R.A. has received a grant from Perkin Elmer, has a pending patent, and receives payment for intellectual property that has been licensed on his behalf by Wayne State University to Perkin Elmer, Inc.; Supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health Grant HD071408, and the W.K. Kellogg Foundation. NR 50 TC 1 Z9 1 U1 4 U2 11 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 2015 VL 104 IS 2 BP 339 EP + DI 10.1016/j.fertnstert.2015.05.010 PG 12 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CV0PX UT WOS:000363954000016 PM 26051097 ER PT J AU Barboza, T Gomes, T Mizurini, DM Monteiro, RQ Konig, S Francischetti, IMB Signoretti, PVP Ramos, IP Gutfilen, B Souza, SAL AF Barboza, Thiago Gomes, Taina Mizurini, Daniella M. Monteiro, Robson Q. Koenig, Sandra Francischetti, Ivo M. B. Signoretti, Paula V. P. Ramos, Isalira P. Gutfilen, Bianca Souza, Sergio A. L. TI Tc-99m-ixolaris targets glioblastoma-associated tissue factor: In vitro and pre-clinical applications SO THROMBOSIS RESEARCH LA English DT Article DE Ixolaris; Glioblastoma; Technetium-99 m; Tissue factor ID FACTOR SIGNALING PATHWAY; PRIMARY TUMOR-GROWTH; FACTOR EXPRESSION; GLIOMA-CELLS; BLOOD-COAGULATION; FACTOR-VIIA; FACTOR-XA; IXOLARIS; CANCER; THROMBOSIS AB Background: The clotting initiator protein tissue factor (TF) has recently been described as a potential target that can be exploited to image aggressive tumors. Ixolaris is a specific TF inhibitor that blocks tumor cell procoagulant activity and tumor growth. Objective: Herein we evaluated the ability of Tc-99m-ixolaris to target tumor-derived TF using an orthotopic glioblastoma (GBM) model in mice. Methods: The right forebrains of Swiss mice were stereotactically inoculated with U87-MG human GBM cells. Histological and immunohistochemical analyses were performed on the resulting tumors after 35-45 days. The biodistribution of Tc-99m-ixolaris was evaluated by semi-quantitative whole-body scintigraphy and a quantitative analysis of radioactivity in isolated organs. Results: No Tc-99m-ixolaris uptake was observed in brain of tumor-free mice, independently of the integrity of brain-blood barrier. In contrast, the presence of TF-expressing brain tumor masses determined a significant Tc-99m-ixolaris uptake. Conclusion: Tc-99m-ixolaris recognized TF-expressing GBM cells in vivo. Given the proposed role of TF in tumor progression, Tc-99m-ixolaris is a promising radiopharmaceutical agent for quantifying cancer-associated TF in aggressive tumors, including GBM. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Barboza, Thiago; Gutfilen, Bianca; Souza, Sergio A. L.] Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Dept Radiol, Lab Marcacao Celulas & Mol, Rio De Janeiro, Brazil. [Gomes, Taina; Koenig, Sandra] Univ Fed Rio de Janeiro, Inst Ciencias Biomed, Rio De Janeiro, Brazil. [Gomes, Taina; Mizurini, Daniella M.; Monteiro, Robson Q.] Univ Fed Rio de Janeiro, Inst Bioquim Med Leopoldo Meis, Rio De Janeiro, Brazil. [Francischetti, Ivo M. B.] NIH, Vector Biol Sect, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Signoretti, Paula V. P.] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Fis Quim Biol Aida Hasson Voloch, BR-21941 Rio De Janeiro, Brazil. [Signoretti, Paula V. P.] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Intermediario Biomembranas, BR-21941 Rio De Janeiro, Brazil. [Ramos, Isalira P.] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Cardiol Celular & Mol, BR-21941 Rio De Janeiro, Brazil. RP Souza, SAL (reprint author), Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Dept Radiol, Lab Marcacao Celulas & Mol, Rio De Janeiro, Brazil. EM sergioalsouza@gmail.com RI Monteiro, Robson/B-8007-2014 FU Brazilian National Council for Scientific and Technological Development (CNPq); State of Rio de Janeiro Research Foundation (FAPERJ); Brazilian Cancer Foundation; Intramural Research Program of the NIH, NIAID FX We thank Vitor Hugo L.R. Almeida for technical assistance. This research was supported by the Brazilian National Council for Scientific and Technological Development (CNPq), the State of Rio de Janeiro Research Foundation (FAPERJ), the Brazilian Cancer Foundation and by the Intramural Research Program of the NIH, NIAID. Because IMBF, is a government employee and this is a government work, the work is in the public domain of the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. NR 47 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD AUG PY 2015 VL 136 IS 2 BP 432 EP 439 DI 10.1016/j.thromres.2015.05.032 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CV0PN UT WOS:000363953000041 PM 26070446 ER PT J AU Bakulski, KM Lee, H Feinberg, JI Wells, EM Brown, S Herbstman, JB Witter, FR Halden, RU Caldwell, K Mortensen, ME Jaffe, AE Moye, J Caulfield, LE Pan, Y Goldman, LR Feinberg, AP Fallin, MD AF Bakulski, Kelly M. Lee, HwaJin Feinberg, Jason I. Wells, Ellen M. Brown, Shannon Herbstman, Julie B. Witter, Frank R. Halden, Rolf U. Caldwell, Kathleen Mortensen, Mary Ellen Jaffe, Andrew E. Moye, John, Jr. Caulfield, Laura E. Pan, Yi Goldman, Lynn R. Feinberg, Andrew P. Fallin, M. Daniele TI Prenatal mercury concentration is associated with changes in DNA methylation at TCEANC2 in newborns SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE DNA methylation; mercury exposure; epigenetics; cord blood; methylmercury ID CORD BLOOD; EPIGENETIC EPIDEMIOLOGY; WIDE ASSOCIATION; MATERNAL BLOOD; WHOLE-BLOOD; METHYLMERCURY; EXPOSURE; HETEROGENEITY; EXPRESSION; BALTIMORE AB Background: Human exposure to the widespread environmental contaminant mercury is a known risk factor for common diseases such as cancer, cardiovascular disease and neurological disorders through poorly characterized mechanisms. Evidence suggests mercury exposure may alter DNA methylation levels, but to date, the effects in early life on a genome-wide scale have not been investigated. Methods: A study sample of 141 newborns was recruited in Baltimore, MD, USA and total mercury and methylmercury were measured in cord blood samples. We quantified genome-wide DNA methylation data using CHARM 2.0, an array-based method, and used region-finding analyses to identify concentration-associated differentially methylated regions (DMRs). To test for replication of these identified DMRs in the pilot, or Vanguard, phase of the National Children's Study (NCS), we compared bisulfite-pyrosequenced DNA at candidate regions from 85 whole cord blood samples with matched first trimester maternal mercury concentration measures. Results: Total mercury concentration was associated with methylation at DMRs inside ANGPT2 and near PRPF18 genes [false discovery rate (FDR) < 0.05], as well as DMRs near FOXD2 and within TCEANC2 (FDR<0.1) genes. Methylmercury concentration was associated with an overlapping DMR within TCEANC2 (FDR<0.05). In NCS replication analyses, methylation levels at three of four cytosine-guanine DNA dinucleotides (CpG sites) within the TCEANC2 DMR were associated with total mercury concentration (P<0.05), and this association was diminished after adjusting for estimated cell proportions. Conclusions: Evidence for an association between mercury and DNA methylation at the TCEANC2 region was found, which may represent a mercury-associated shift in cord blood cell composition or a change in methylation within blood cell types. Further confirmatory studies are needed. C1 [Bakulski, Kelly M.; Feinberg, Jason I.; Brown, Shannon; Herbstman, Julie B.; Caulfield, Laura E.; Goldman, Lynn R.; Feinberg, Andrew P.; Fallin, M. Daniele] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Lee, HwaJin; Feinberg, Jason I.; Witter, Frank R.; Halden, Rolf U.; Jaffe, Andrew E.; Feinberg, Andrew P.; Fallin, M. Daniele] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Wells, Ellen M.] Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA. [Herbstman, Julie B.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Halden, Rolf U.] Arizona State Univ, Fulton Sch Engn, Tempe, AZ USA. [Caldwell, Kathleen; Mortensen, Mary Ellen; Pan, Yi] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. [Jaffe, Andrew E.] Lieber Inst Brain Dev, Baltimore, MD USA. [Moye, John, Jr.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Goldman, Lynn R.] George Washington Univ, Sch Publ Hlth, Washington, DC USA. RP Fallin, MD (reprint author), 624 N Broadway,Hampton House 850, Baltimore, MD 21205 USA. EM dfallin@jhu.edu RI Halden, Rolf/F-9562-2010; Jaffe, Andrew/L-3089-2016; OI Halden, Rolf/0000-0001-5232-7361; Jaffe, Andrew/0000-0001-6886-1454; moye, john/0000-0001-9976-8586; Wells, Ellen/0000-0002-7293-1395 FU National Institute for Environmental Health Sciences at the National Institutes for Health [ES017646]; Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health [HHSN27520080033C, HHSN275200503414C, HHSN275200503411C, HHSN275200603416C, HHSN275200503415C, HHSN275200503413C, HHSN275200503410C, HHSN275200503396C, HHSN275201000121U, HHSN275200900010C]; National Center for Environmental Health, Centers for Disease Control and Prevention FX This work was supported by the National Institute for Environmental Health Sciences at the National Institutes for Health (ES017646). The National Children's Study (NCS) Initial Vanguard Centers from which the samples were collected, the NCS biospecimen team and the NCS repository were supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health contracts numbers: HHSN27520080033C, HHSN275200503414C, HHSN275200503411C, HHSN275200603416C, HHSN275200503415C, HHSN275200503413C, HHSN275200503410C, HHSN275200503396C, HHSN275201000121U and HHSN275200900010C. Funding for the blood mercury analyses was provided by the National Center for Environmental Health, Centers for Disease Control and Prevention. NR 45 TC 8 Z9 8 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 2015 VL 44 IS 4 BP 1249 EP 1262 DI 10.1093/ije/dyv032 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CT8JK UT WOS:000363061500023 PM 25906783 ER PT J AU Sung, H Yang, HH Zhang, H Yang, Q Hu, N Tang, ZZ Su, H Wang, LM Wang, CY Ding, T Fan, JH Qiao, YL Wheeler, W Giffen, C Burdett, L Wang, ZM Lee, MP Chanock, SJ Dawsey, SM Freedman, ND Abnet, CC Goldstein, AM Yu, K Taylor, PR Hyland, PL AF Sung, Hyuna Yang, Howard H. Zhang, Han Yang, Qi Hu, Nan Tang, Ze-Zhong Su, Hua Wang, Lemin Wang, Chaoyu Ding, Ti Fan, Jin-Hu Qiao, You-Lin Wheeler, William Giffen, Carol Burdett, Laurie Wang, Zhaoming Lee, Maxwell P. Chanock, Stephen J. Dawsey, Sanford M. Freedman, Neal D. Abnet, Christian C. Goldstein, Alisa M. Yu, Kai Taylor, Philip R. Hyland, Paula L. TI Common genetic variants in epigenetic machinery genes and risk of upper gastrointestinal cancers SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Epigenetics; chromatin remodelling; DNA methylation; microRNA; oesophageal squamous cell carcinoma; gastric cancer; gastric cardia; gastric non-cardia; SNP; gene-based; pathway-based ID SQUAMOUS-CELL CARCINOMA; GENOME-WIDE ASSOCIATION; MICRORNA-RELATED GENES; SUSCEPTIBILITY LOCI; GASTRIC-CANCER; CHINESE POPULATIONS; ESOPHAGEAL CANCER; ADENOCARCINOMA; POLYMORPHISM; EXPRESSION AB Background: Populations in north central China are at high risk for oesophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), and genetic variation in epigenetic machinery genes and pathways may contribute to this risk. Methods: We used the adaptive multilocus joint test to analyse 192 epigenetic genes involved in chromatin remodelling, DNA methylation and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with Chinese ancestry. We examined potential function of risk alleles using in silico and expression quantitative trait loci (eQTLs) analyses. Results: Suggestive pathway-based associations were observed for the overall epigenetic (P-value(PATH) = 0.034) and chromatin remodelling (P-value(PATH) = 0.039) pathways with risk of GCA, but not GC, GNCA or ESCC. Overall, 37 different epigenetic machinery genes were associated with risk of one or more upper gastrointestinal (UGI) cancer sites (P-value(GENE) < 0.05), including 14 chromatin remodelling genes whose products are involved in the regulation of HOX genes. We identified a gastric eQTL (rs12724079; rho = 0.37; P = 0.0006) which regulates mRNA expression of ASH1L. Several suggestive eQTLs were also found in oesophageal (rs10898459 in EED), gastric cardia (rs7157322 in DICER1; rs8179271 in ASH1L), and gastric non-cardia (rs1790733 in PPP1CA) tissues. Conclusions: Results of our analyses provide limited but suggestive evidence for a role of epigenetic gene variation in the aetiology of UGI cancer. C1 [Sung, Hyuna; Zhang, Han; Yang, Qi; Hu, Nan; Su, Hua; Wang, Lemin; Wang, Chaoyu; Wang, Zhaoming; Chanock, Stephen J.; Dawsey, Sanford M.; Freedman, Neal D.; Abnet, Christian C.; Goldstein, Alisa M.; Yu, Kai; Taylor, Philip R.; Hyland, Paula L.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Yang, Howard H.; Lee, Maxwell P.] NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. [Tang, Ze-Zhong; Ding, Ti] Shanxi Canc Hosp, Taiyuan, Peoples R China. [Fan, Jin-Hu; Qiao, You-Lin] Chinese Acad Med Sci, Canc Inst Hosp, Dept Epidemiol, Beijing 100730, Peoples R China. [Wheeler, William; Giffen, Carol] Informat Management Serv Inc, Silver Spring, MD USA. [Burdett, Laurie; Wang, Zhaoming] SAIC Frederick Inc, NCI Frederick, Canc Genom Res Lab, Frederick, MD USA. RP Hyland, PL (reprint author), NIH, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD 20852 USA. EM hylandpl@mail.nih.gov RI Abnet, Christian/C-4111-2015; Zhang, Han/K-2118-2016; OI Abnet, Christian/0000-0002-3008-7843; Zhang, Han/0000-0001-7977-9616; Qiao, You-Lin/0000-0001-6380-0871 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This research was funded by Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 61 TC 1 Z9 1 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 2015 VL 44 IS 4 BP 1341 EP 1352 DI 10.1093/ije/dyv050 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CT8JK UT WOS:000363061500030 PM 25921222 ER PT J AU Billings, L AF Billings, Linda TI Words matter: A call for responsible communication about asteroid impact hazards and plans for planetary defense SO SPACE POLICY LA English DT Editorial Material DE Near-Earth objects; Asteroids; Planetary defense; Communication; Strategic planning AB The global community of scientists involved in finding and tracking near-Earth asteroids (NEOs), identifying potentially hazardous NEOs, and characterizing the possible effects of asteroid impacts with Earth is developing an awareness of the need to improve and expand efforts to communicate with policy and decision makers about the work they do. This paper addresses the criticality of clear, concise, correct communications about asteroid impact risks and hazards, as well as proper distinctions among risks, hazards, and actual threats. It reviews recent progress in communication about NEO hazards and impact risks, including new recommendations from expert groups, guidelines for responsible communication about hazards and risks, communication issues raised in collaborations with disaster planners, and other relevant developments. The next significant asteroid impact with Earth could be 500 years from now, or next week. The need to be prepared for such an event is clear. Policy and decision makers will depend on the community of experts involved in NEO observations and planning for planetary defense for information on the risks and hazards of asteroid impacts with Earth. (C) 2015 Elsevier Ltd. All rights reserved. C1 NIA, Arlington, VA 20009 USA. RP Billings, L (reprint author), NIA, Arlington, VA 20009 USA. EM Billingslinda1@gmail.com NR 7 TC 0 Z9 0 U1 2 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0265-9646 EI 1879-338X J9 SPACE POLICY JI Space Policy PD AUG PY 2015 VL 33 BP 8 EP 12 DI 10.1016/j.spacepol.2015.07.001 PN 1 PG 5 WC International Relations; Social Sciences, Interdisciplinary SC International Relations; Social Sciences - Other Topics GA CU3OH UT WOS:000363434200003 ER PT J AU Wallace, ME Mendola, P Liu, DP Grantz, KL AF Wallace, Maeve E. Mendola, Pauline Liu, Danping Grantz, Katherine L. TI Joint Effects of Structural Racism and Income Inequality on Small-for-Gestational-Age Birth SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID PRETERM BIRTH; AFRICAN-AMERICAN; UNITED-STATES; NEIGHBORHOOD DEPRIVATION; RESIDENTIAL SEGREGATION; WHITE WOMEN; METROPOLITAN-AREAS; HEALTH OUTCOMES; INFANT HEALTH; MATERNAL AGE AB Objectives. We examined potential synergistic effects of racial and socioeconomic inequality associated with small-for-gestational-age (SGA) birth. Methods. Electronic medical records from singleton births to White and Black women in 10 US states and the District of Columbia (n = 121 758) were linked to state-level indicators of structural racism, including the ratios of Blacks to Whites who were employed, were incarcerated, and had a bachelor's or higher degree. We used state-level Gini coefficients to assess income inequality. Generalized estimating equations models were used to quantify the adjusted odds of SGA birth associated with each indicator and the joint effects of structural racism and income inequality. Results. Structural racism indicators were associated with higher odds of SGA birth, and similar effects were observed for both races. The joint effects of racial and income inequality were significantly associated with SGA birth only when levels of both were high; in areas with high inequality levels, adjusted odds ratios ranged from 1.81 to 2.11 for the 3 structural racism indicators. Conclusions. High levels of racial inequality and socioeconomic inequality appear to increase the risk of SGA birth, particularly when they co-occur. C1 [Wallace, Maeve E.; Mendola, Pauline; Liu, Danping; Grantz, Katherine L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd, Rockville, MD 20852 USA. EM pauline.mendola@nih.gov OI Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN267200603425C] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract HHSN267200603425C). NR 46 TC 3 Z9 3 U1 3 U2 6 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2015 VL 105 IS 8 BP 1681 EP 1688 DI 10.2105/AJPH.2015.302613 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CT6VL UT WOS:000362950400057 PM 26066964 ER PT J AU Christofferson, DE Hamlett-Berry, K Augustson, E AF Christofferson, Dana E. Hamlett-Berry, Kim Augustson, Erik TI Suicide Prevention Referrals in a Mobile Health Smoking Cessation Intervention SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID RISK; SERVICES; ADULTS AB Automated mobile health (mHealth) programs deliver effective smoking cessation interventions through text message platforms. Smoking is an independent risk factor for suicide, so the Department of Veterans Affairs incorporated information about the Veterans Crisis Line into its SmokefreeVET smoking cessation text messaging program. Almost 7% of all SmokefreeVET enrollees have accessed this information. Because of the reach and automated nature of this and similar programs, we recommend including a referral to a suicide prevention hotline for all smoking cessation mHealth interventions. C1 [Christofferson, Dana E.; Hamlett-Berry, Kim] Vet Hlth Adm, Off Publ Hlth, Dept Vet Affairs, Washington, DC USA. [Augustson, Erik] NCI, Tobacco Control Res Branch, NIH, Bethesda, MD 20892 USA. RP Christofferson, DE (reprint author), Dept Vet Affairs, 810 Vermont Ave NW 10P3B, Washington, DC 20420 USA. EM dana.christofferson@va.gov NR 10 TC 2 Z9 2 U1 1 U2 2 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2015 VL 105 IS 8 BP E7 EP E9 DI 10.2105/AJPH.2015.302690 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CT6VL UT WOS:000362950400005 PM 26066949 ER PT J AU Fee, E AF Fee, Elizabeth TI John H. Landis (1860-1918): Devoted Health Officer of Cincinnati SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Fee, E (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM feee@mail.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2015 VL 105 IS 8 BP E48 EP E48 DI 10.2105/AJPH.2015.302658 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CT6VL UT WOS:000362950400012 PM 26066952 ER PT J AU Mattapallil, MJ Silver, PB Cortes, LM St Leger, AJ Jittayasothorn, Y Kielczewski, JL Moon, JJ Chan, CC Caspi, RR AF Mattapallil, Mary J. Silver, Phyllis B. Cortes, Lizette M. St Leger, Anthony J. Jittayasothorn, Yingyos Kielczewski, Jennifer L. Moon, James J. Chan, Chi-Chao Caspi, Rachel R. TI Characterization of a New Epitope of IRBP That Induces Moderate to Severe Uveoretinitis in Mice With H-2(b) Haplotype SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE autoimmune; EAU; IRBP; H-2(b) mice ID RETINOID-BINDING PROTEIN; AUTOREACTIVE T-CELLS; AUTOIMMUNE UVEORETINITIS; UVEITIS; IDENTIFICATION; FREQUENCY; PEPTIDES; DISEASE; CD4(+); MODEL AB PURPOSE. Experimental autoimmune uveitis (EAU) induced in mice using the retinal antigen interphotoreceptor retinoid binding protein (IRBP) is an animal model for posterior uveitis in humans. However, EAU induced by native IRBP protein or its widely used epitope amino acid residues 1 to 20 of human IRBP (hIRBP1-20) is inconsistent, often showing low scores and incidence. We found an urgent need to identify a better pathogenic epitope for the C57BL/6 strain. METHODS. Mice were immunized with uveitogenic peptides or with native bovine IRBP. Clinical and histological disease and associated immunological responses were evaluated. Truncated and substituted peptides, as well as bioinformatic analyses, were used to identify critical major histocompatibility complex (MHC)/T cell receptor (TCR) contact residues and the minimal core epitope. RESULTS. The new uveitogenic epitope of IRBP, amino acid residues 651 to 670 of human IRBP (LAQGAYRTAVDLESLASQLT [hIRBP651-670]) is uveitogenic for mice of the H-2(b) haplotype and elicits EAU with a higher severity and incidence in C57BL/6 mice than the previously characterized hIRBP1-20 epitope. Using truncated and substituted peptides, as well as bioinformatic analysis, we identified the critical contact residues with MHC/TCR and defined the minimal core epitope. This made it possible to design MHC tetramers and use them to detect epitope-specific T cells in the uveitic eye and in lymphoid organs of hIRBP651-670-immunized mice. CONCLUSIONS. Data suggest that hIRBP651-670 is an epitope naturally processed from a conserved region of native IRBP, potentially explaining its relatively high uveitogenicity. This epitope should be useful for basic and preclinical studies of uveitis in the C57BL/6 model and gives access to genetically engineered mice available on this background. C1 [Mattapallil, Mary J.; Silver, Phyllis B.; Cortes, Lizette M.; St Leger, Anthony J.; Jittayasothorn, Yingyos; Kielczewski, Jennifer L.; Chan, Chi-Chao; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Moon, James J.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Moon, James J.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Moon, James J.] Harvard Univ, Sch Med, Boston, MA USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, 10 Ctr Dr,10-10N222, Bethesda, MD 20892 USA. EM rcaspi@helix.nih.gov OI Caspi, Rachel/0000-0002-7140-7671 FU Intramural NIH HHS; NEI NIH HHS [ZIA EY000184]; NIAID NIH HHS [AI107020, R01 AI107020, U19 AI095261] NR 25 TC 6 Z9 6 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2015 VL 56 IS 9 BP 5439 EP 5449 DI 10.1167/iovs.15-17280 PG 11 WC Ophthalmology SC Ophthalmology GA CT5WW UT WOS:000362882800053 PM 26284549 ER PT J AU Castro, NP Salomon, DS AF Castro, Nadia P. Salomon, David S. TI Cripto-1 in TNBC SO AGING-US LA English DT Editorial Material ID NEGATIVE BREAST-CANCER; POPULATION; AGE C1 [Castro, Nadia P.] NCI, Mouse Canc Genet Program, Tumor Growth Factor Sect, Frederick, MD 21701 USA. RP Castro, NP (reprint author), NCI, Mouse Canc Genet Program, Tumor Growth Factor Sect, Frederick, MD 21701 USA. EM castron2@mail.nih.gov NR 5 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 1945-4589 J9 AGING-US JI Aging-US PD AUG PY 2015 VL 7 IS 8 BP 515 EP 516 PG 2 WC Cell Biology SC Cell Biology GA CS7JU UT WOS:000362260700002 PM 26298547 ER PT J AU Yang, CZ Hong, CS Zhuang, ZP AF Yang, Chunzhang Hong, Christopher S. Zhuang, Zhengping TI Hypoxia and glioblastoma therapy SO AGING-US LA English DT Editorial Material ID STEM-CELLS C1 [Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Zhuang, ZP (reprint author), NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM zhuangp@ninds.nih.gov NR 7 TC 1 Z9 1 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD AUG PY 2015 VL 7 IS 8 BP 523 EP 524 PG 2 WC Cell Biology SC Cell Biology GA CS7JU UT WOS:000362260700006 PM 26298282 ER PT J AU Hallwirth, CV Smith, RH Hetherington, NA Ziegler, ML Westerman, M Kotin, RM Alexander, IE AF Hallwirth, Claus V. Smith, Richard H. Hetherington, Nicola A. Ziegler, Mona-Larissa Westerman, Michael Kotin, Robert M. Alexander, Ian E. TI DISCOVERY OF ANCIENT AND CONTEMPORARY ADENO-ASSOCIATED VIRUSES FROM AUSTRALIAN MARSUPIALS SO JOURNAL OF GENE MEDICINE LA English DT Meeting Abstract CT 9th Biennial Meeting of the Australasian-Gene-and-Cell-Therapy-Society (AGCTS) CY APR 29-MAY 01, 2015 CL Univ Melbourne, Univ Coll, Parkville, AUSTRALIA SP Australasian Gene & Cell Therapy Soc, Benitec Biopharma, Bioline, Bio Rad, BlueBird Bio, Calimmune, Childrens Med Res Inst, Journal Gene Med, Life Technologies, Lonza, Miltenyi Biotec, Murdoch Childrens Res Inst, Murdoch Univ, Promega, Sigma Aldrich, Stem Cell Technologies, Thalassaemia Australia, Sydney Childrens Hosp Network, Thermo Fisher Sci, Western Australian Neuroscience Res Inst HO Univ Melbourne, Univ Coll C1 [Hallwirth, Claus V.; Hetherington, Nicola A.; Ziegler, Mona-Larissa; Alexander, Ian E.] Childrens Med Res Inst, Gene Therapy Res Unit, Westmead, NSW, Australia. [Hallwirth, Claus V.; Hetherington, Nicola A.; Ziegler, Mona-Larissa; Alexander, Ian E.] Childrens Hosp Westmead, Westmead, NSW, Australia. [Smith, Richard H.; Kotin, Robert M.] NHLBI, Lab Mol Virol & Gene Therapy, Bethesda, MD 20892 USA. [Westerman, Michael] La Trobe Univ, Dept Biochem & Genet, Bundoora, Vic, Australia. [Alexander, Ian E.] Univ Sydney, Discipline Paediat & Child Hlth, Westmead, NSW 2145, Australia. 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 1099-498X EI 1521-2254 J9 J GENE MED JI J. Gene. Med. PD AUG-SEP PY 2015 VL 17 IS 8-9 MA O1 BP 183 EP 183 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CT1WH UT WOS:000362592700017 ER PT J AU Himes, SK Tassiopoulos, K Yogev, R Huestis, MA AF Himes, Sarah K. Tassiopoulos, Katherine Yogev, Ram Huestis, Marilyn A. CA PHACS TI Antiretroviral Drugs in Meconium: Detection for Different Gestational Periods of Exposure SO JOURNAL OF PEDIATRICS LA English DT Article ID ACID ETHYL-ESTERS; PRENATAL CANNABIS EXPOSURE; IN-UTERO; NEONATAL GROWTH; SIMULTANEOUS QUANTIFICATION; CLINICAL-IMPLICATIONS; UNINFECTED CHILDREN; PLACENTAL-TRANSFER; TOBACCO EXPOSURE; METABOLITES AB Objectives To determine whether antiretroviral (ARV) medications can be detected in meconium from second or third trimester, labor and delivery (L&D), or postnatal exposures. Study design Twenty ARV medications were quantified by liquid chromatography-tandemmass spectrometry in 598 meconium samples from uninfected infants born to pregnant women with HIV enrolled in the Pediatric HIV/AIDS Cohort Study. Results ARV detection in meconium following third trimester exposure was 85.7%-94.4% for all ARVs except stavudine (0%, n = 2), likely because of low doses and a high limit for quantification. Of 107 samples with some second trimester only ARV exposures, meconium was positive for only lopinavir, tenofovir, or efavirenz in 11.8%-14.3% of exposed neonates; administration of these ARVs occurred between gestational weeks 25-28 in the positive samples. Days without lopinavir or tenofovir before delivery significantly correlated with decreasing concentrations of lopinavir and tenofovir in meconium. Tenofovir and lamivudine concentrations significantly correlated with increasing gestational age among infants with continuous second and third trimester exposure. Zidovudine given during L&D or for neonatal prophylaxis was detected in 95.1% and 94.6% of meconium samples, respectively. Conclusions Changes in ARV treatments during pregnancy offered a unique opportunity to investigate ARV detection in meconium. ARVs in meconium primarily reflect third trimester ARV exposures, although 6 of 107 second trimester only exposures were detected. Zidovudine administration during L&D was detected in meconium indicating potential urine contamination or rapid incorporation into meconium. These data will improve interpretation of meconium drug test results. C1 [Himes, Sarah K.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Tassiopoulos, Katherine] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Yogev, Ram] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200,Rm 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; Harvard T.H. Chan University School of Public Health [HD052102]; Tulane University School of Medicine [HD052104] FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism through cooperative agreements with the Harvard T.H. Chan University School of Public Health [HD052102] and Tulane University School of Medicine [HD052104]. Data management services were provided by Frontier Science and Technology Research Foundation, Boston, MA (Principal Investigator: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc, Rockville, MD (Principal Investigator: Julie Davidson). The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or US Department of Health and Human Services. The authors declare no conflicts of interest. NR 32 TC 0 Z9 0 U1 1 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD AUG PY 2015 VL 167 IS 2 BP 305 EP + DI 10.1016/j.jpeds.2015.04.062 PG 10 WC Pediatrics SC Pediatrics GA CT0AF UT WOS:000362455300019 PM 26001315 ER PT J AU Kamath, BM Chen, Z Romero, R Fredericks, EM Alonso, EM Arnon, R Heubi, J Hertel, PM Karpen, SJ Loomes, KM Murray, KF Rosenthal, P Schwarz, KB Subbarao, G Teckman, JH Turmelle, YP Wang, KS Sherker, AH Sokol, RJ Magee, JC AF Kamath, Binita M. Chen, Zhen Romero, Rene Fredericks, Emily M. Alonso, Estella M. Arnon, Ronen Heubi, James Hertel, Paula M. Karpen, Saul J. Loomes, Kathleen M. Murray, Karen F. Rosenthal, Philip Schwarz, Kathleen B. Subbarao, Girish Teckman, Jeffrey H. Turmelle, Yumirle P. Wang, Kasper S. Sherker, Averell H. Sokol, Ronald J. Magee, John C. CA ChiLDReN TI Quality of Life and Its Determinants in a Multicenter Cohort of Children with Alagille Syndrome SO JOURNAL OF PEDIATRICS LA English DT Article ID PEDIATRIC LIVER-TRANSPLANTATION; OUTCOMES; PEDSQL(TM)-4.0; RELIABILITY; ADOLESCENTS; RECIPIENTS; VALIDITY AB Objectives To assess health-related quality of life (HRQOL) in children with Alagille syndrome (ALGS) in comparison with healthy and other liver disease cohorts, and to identify determinants of HRQOL in patients with ALGS. Study design Within the Childhood Liver Disease Research Network prospective study of cholestasis, Pediatric Quality of Life Inventory (PedsQL) questionnaires were administered to 70 children with ALGS, 95 children with alpha-1-antitrypsin deficiency (A1ATD), and 49 children with other causes of chronic intrahepatic cholestasis (IHC) aged 5-18 years. Parent proxy PedsQL scores were recorded for children aged 2-18 years (98 ALGS, 123 A1ATD, and 68 IHC). Results Mean ages and total bilirubin (mg/dL) were ALGS 9.4 years; 4.4, A1ATD 9.5 years; 0.7, and IHC 10.3 years; 2.9. ALGS child PedsQL scores were lower than in healthy children and children with A1ATD (mean 73 vs 83; P = .001). Children with ALGS and IHC were similar, except in physical scores (73 vs 79; P = .05). Parents of children with ALGS perceived their children to have worse HRQOL than A1ATD (P <= .001) and marginally lower compared with IHC. Univariate analysis revealed ALGS child-reported scores were positively associated with better growth and inversely with total bilirubin. Growth failure, elevated international normalized ratio, and an intracardiac defect were predictive of poor parental scores (P <= .05). In multivariate analysis, only weight z-score remained significant for child-and parent-reported scores. Conclusions HRQOL is impaired in children with ALGS compared with healthy and children with A1ATD, similar to children with IHC and is associated with growth failure, which is a potentially treatable cause of impaired HRQOL. C1 [Kamath, Binita M.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Kamath, Binita M.] Univ Toronto, Toronto, ON, Canada. [Chen, Zhen; Fredericks, Emily M.; Magee, John C.] Univ Michigan, Ann Arbor, MI 48109 USA. [Romero, Rene; Karpen, Saul J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Romero, Rene; Karpen, Saul J.] Emory Univ, Sch Med, Atlanta, GA USA. [Alonso, Estella M.] Ann & Robert H Lurie Childrens Hosp, Chicago, IL USA. [Alonso, Estella M.] Northwestern Univ, Chicago, IL 60611 USA. [Arnon, Ronen] Mt Sinai Med Ctr, New York, NY 10029 USA. [Heubi, James] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Hertel, Paula M.] Baylor Coll Med, Houston, TX 77030 USA. [Hertel, Paula M.] Texas Childrens Hosp, Houston, TX 77030 USA. [Loomes, Kathleen M.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Loomes, Kathleen M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Murray, Karen F.] Seattle Childrens Hosp, Seattle, WA USA. [Murray, Karen F.] Univ Washington, Sch Med, Seattle, WA USA. [Rosenthal, Philip] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Loomes, Kathleen M.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Subbarao, Girish] Indiana Univ, Riley Hosp Children, Indianapolis, IN 46204 USA. [Teckman, Jeffrey H.] St Louis Univ, Sch Med, St Louis, MO USA. [Turmelle, Yumirle P.] Washington Univ, St Louis, MO USA. [Wang, Kasper S.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Sherker, Averell H.] NIDDKD, NIH, Bethesda, MD USA. [Sokol, Ronald J.] Univ Colorado, Sch Med, Aurora, CO USA. [Sokol, Ronald J.] Childrens Hosp Colorado, Aurora, CO USA. RP Kamath, BM (reprint author), Univ Toronto, Div Gastroenterol Hepatol & Nutr, Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM binita.kamath@sickkids.ca FU NCATS NIH HHS [UL1 TR001082, UL1 TR0000775, UL1 TR000005, UL 1TR000130, UL 1TR000424, UL 1TR000448, UL1 TR000004, UL1 TR000067, UL1 TR000154, UL1 TR000448, UL 1TR000150, UL1 TR000003, UL1 TR001425]; NIDDK NIH HHS [DK 62452, DK 62470, DK 62497, DK 62500, DK 62503, DK 84538, U01 DK062456, U01 DK084575, U01 DK084536, U01 DK084538, U01 DK103135, U01 DK062500, U01 DK062497, P30 DK078392, DK 62481, DK 62466, DK 62445, DK 62453, DK 62456, DK 84536, DK 84575, P30 DK026743, U01 DK062436, U01 DK062481, U54DK078377] NR 20 TC 2 Z9 2 U1 2 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD AUG PY 2015 VL 167 IS 2 BP 390 EP + DI 10.1016/j.jpeds.2015.04.077 PG 10 WC Pediatrics SC Pediatrics GA CT0AF UT WOS:000362455300036 PM 26059338 ER PT J AU Yarnell, CMP Addissie, YA Hadley, DW Sacoto, MJG Agochukwu, NB Hart, RA Wiggs, EA Platte, P Paelecke, Y Collmann, H Schweitzer, T Kruszka, P Muenke, M AF Yarnell, Colin M. P. Addissie, Yonit A. Hadley, Donald W. Sacoto, Maria J. Guillen Agochukwu, Nneamaka B. Hart, Rachel A. Wiggs, Edythe A. Platte, Petra Paelecke, Yvonne Collmann, Hartmut Schweitzer, Tilmann Kruszka, Paul Muenke, Maximilian TI Executive Function and Adaptive Behavior in Muenke Syndrome SO JOURNAL OF PEDIATRICS LA English DT Article ID CRANIOSYNOSTOSIS; CHILDREN; POINT; GENE AB Objective To investigate executive function and adaptive behavior in individuals with Muenke syndrome using validated instruments with a normative population and unaffected siblings as controls. Study design Participants in this cross-sectional study included individuals with Muenke syndrome (P250R mutation in FGFR3) and their mutation-negative siblings. Participants completed validated assessments of executive functioning (Behavior Rating Inventory of Executive Function [BRIEF]) and adaptive behavior skills (Adaptive Behavior Assessment System, Second Edition [ABAS-II]). Results Forty-four with a positive FGFR3 mutation, median age 9 years, range 7 months to 52 years were enrolled. In addition, 10 unaffected siblings served as controls (5 males, 5 females; median age, 13 years; range, 3-18 years). For the General Executive Composite scale of the BRIEF, 32.1% of the cohort had scores greater than +1.5 SD, signifying potential clinical significance. For the General Adaptive Composite of the ABAS-II, 28.2% of affected individuals scored in the 3rd-8th percentile of the normative population, and 56.4% were below the average category (<25th percentile). Multiple regression analysis did not identify craniosynostosis as a predictor of BRIEF (P = .70) or ABAS-II scores (P = .70). In the sibling pair analysis, affected siblings performed significantly poorer on the BRIEF General Executive Composite and the ABAS-II General Adaptive Composite. Conclusion Individuals with Muenke syndrome are at an increased risk for developing adaptive and executive function behavioral changes compared with a normative population and unaffected siblings. C1 [Yarnell, Colin M. P.; Addissie, Yonit A.; Hadley, Donald W.; Sacoto, Maria J. Guillen; Agochukwu, Nneamaka B.; Hart, Rachel A.; Wiggs, Edythe A.; Kruszka, Paul; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Platte, Petra; Paelecke, Yvonne] Univ Wurzburg, Dept Psychol 1, Inst Psychol, D-97070 Wurzburg, Germany. [Collmann, Hartmut] Univ Hosp Wurzburg, Dept Neurosurg, Sect Pediat Neurosurg, Wurzburg, Germany. [Schweitzer, Tilmann] Univ Hosp Wurzburg, Dept Orthodont, Wurzburg, Germany. RP Yarnell, CMP (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. FU Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services FX Funded by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services. The authors declare no conflicts of interest. NR 24 TC 1 Z9 1 U1 1 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD AUG PY 2015 VL 167 IS 2 BP 428 EP 434 DI 10.1016/j.jpeds.2015.04.080 PG 7 WC Pediatrics SC Pediatrics GA CT0AF UT WOS:000362455300042 PM 26028288 ER PT J AU Bonner, C Caldwell, HD Carlson, JH Graham, MR Kari, L Sturdevant, GL Tyler, S Zetner, A McClarty, G AF Bonner, Christine Caldwell, Harlan D. Carlson, John H. Graham, Morag R. Kari, Laszlo Sturdevant, Gail L. Tyler, Shaun Zetner, Adrian McClarty, Grant TI Chlamydia trachomatis virulence factor CT135 is stable in vivo but highly polymorphic in vitro SO PATHOGENS AND DISEASE LA English DT Article DE chlamydia trachomatis; CT135; genomics; single nucleotide polymorphism; virulence factor; deep sequencing ID GENOME SEQUENCE; GENITAL-TRACT; PATHOGENICITY; MURIDARUM; GENES AB Chlamydia trachomatis is an important human pathogen causing both ocular and sexually transmitted disease. Recently, we identified CT135 as an important virulence determinant in a mouse infection model. Results from CEL 1 digestion assays and sequencing analyses indicated that CT135 was much more polymorphic in high in vitro passage reference serovars than it was in clinical strains that had undergone limited passaging. Herein, we used targeted next-generation sequencing of the CT134-135 locus, from reference strains and clinical isolates, enabling accurate discovery of single nucleotide polymorphisms and other population genetic variations. Our results indicate that CT134 is stable in all C. trachomatis serovars examined. In contrast, CT135 is highly polymorphic in high-passaged reference ocular and non-LGV genital serovars, with the majority of the mutations resulting in gene disruption. In low-passaged ocular clinical isolates, CT135 was frequently disrupted, whereas in genital clinical isolates CT135 was intact in almost all instances. When a serovar K isolate, with an intact CT134 and CT135, was subjected to serial passage in vitro CT134 remained invariable, while numerous gene interrupting mutations rapidly accumulated in CT135. Collectively, our data indicate that, for genital serovars, CT135 is under strong positive selection in vivo, and negative selection in vitro. C1 [Bonner, Christine; Graham, Morag R.; Tyler, Shaun; Zetner, Adrian; McClarty, Grant] Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB R3E 3R2, Canada. [Caldwell, Harlan D.; Carlson, John H.; Kari, Laszlo; Sturdevant, Gail L.] NIH, Intracellular Parasites Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. [McClarty, Grant] Dept Med Microbiol, Winnipeg, MB R3E 0W9, Canada. RP McClarty, G (reprint author), Publ Hlth Agcy Canada, Natl Microbiol Lab, 1015 Arlington St, Winnipeg, MB R3E 3R2, Canada. EM Grant.McClarty@umanitoba.ca FU Public Health Agency of Canada; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Public Health Agency of Canada and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 20 TC 4 Z9 4 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD AUG PY 2015 VL 73 IS 6 AR UNSP ftv043 DI 10.1093/femspd/ftv043 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CT1QE UT WOS:000362574300012 PM 26109550 ER PT J AU Bush, RA Wei, LL Sieving, PA AF Bush, Ronald A. Wei, Lisa L. Sieving, Paul A. TI Convergence of Human Genetics and Animal Studies: Gene Therapy for X-Linked Retinoschisis SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID ADENOASSOCIATED VIRUS TYPE-2; LEBERS CONGENITAL AMAUROSIS; JUVENILE RETINOSCHISIS; RETINAL DEGENERATION; MOUSE RETINA; XLRS1 GENE; VECTORS; PROTEIN; EXPRESSION; MUTATIONS AB Retinoschisis is an X-linked recessive genetic disease that leads to vision loss in males. X-linked retinoschisis (XLRS) typically affects young males; however, progressive vision loss continues throughout life. Although discovered in 1898 by Haas in two brothers, the underlying biology leading to blindness has become apparent only in the last 15 years with the advancement of human genetic analyses, generation of XLRS animal models, and the development of ocular monitoring methods such as the electroretinogram and optical coherence tomography. It is now recognized that retinoschisis results from cyst formations within the retinal layers that interrupt normal visual neurosignaling and compromise structural integrity. Mutations in the human retinoschisin gene have been correlated with disease severity of the human XLRS phenotype. Introduction of a normal human retinoschisin cDNA into retinoschisin knockout mice restores retinal structure and improves neural function, providing proof-of-concept that gene replacement therapy is a plausible treatment for XLRS. C1 [Bush, Ronald A.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD 20892 USA. [Wei, Lisa L.; Sieving, Paul A.] NEI, Bethesda, MD 20892 USA. RP Bush, RA (reprint author), Natl Inst Deafness & Other Commun Disorders, Bethesda, MD 20892 USA. EM bushr@nidcd.nih.gov FU National Institutes of Health (NIH) Intramural Research Program through the National Institute on Deafness and Other Communication Disorders; National Eye Institute FX The authors are grateful to Dr. Catherine Cukras for the fundus photo and OCT scan from an XLRS patient and Cindy Best, Matthew McMahon, and Santa Tumminia for their assistance in the preparation of this review. Supported by the National Institutes of Health (NIH) Intramural Research Program through the National Institute on Deafness and Other Communication Disorders and the National Eye Institute. NR 62 TC 0 Z9 0 U1 0 U2 0 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 2015 VL 5 IS 8 AR a017368 DI 10.1101/cshperspect.a017368 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CS4FU UT WOS:000362031800002 PM 26101206 ER PT J AU Stefansdottir, H Sigurdsson, S Aspelund, T Launer, LJ Gudnason, V Arnar, DO AF Stefansdottir, H. Sigurdsson, S. Aspelund, T. Launer, L. J. Gudnason, V. Arnar, D. O. TI Atrial fibrillation accelerates aging of the brain in the general elderly population SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 29-SEP 02, 2015 CL London, ENGLAND SP European Soc Cardiol C1 [Stefansdottir, H.] Univ Hosp Regensburg, Regensburg, Germany. [Sigurdsson, S.; Aspelund, T.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Launer, L. J.] NIH, Bethesda, MD 20892 USA. [Arnar, D. O.] Landspitali Univ Hosp, Reykjavik, Iceland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG 1 PY 2015 VL 36 SU 1 MA 299 BP 26 EP 27 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR3BL UT WOS:000361205101089 ER PT J AU Cheezum, M Redon, C Burrell, A Kaviratne, A Bindeman, J Maeda, D Wisniewski, P Delacruz, P Bonner, W Villines, T AF Cheezum, M. Redon, C. Burrell, A. Kaviratne, A. Bindeman, J. Maeda, D. Wisniewski, P. Delacruz, P. Bonner, W. Villines, T. TI Effects of heart imaging radiation on dna double-strand break levels in blood lymphocytes: the Heart-Break study SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 29-SEP 02, 2015 CL London, ENGLAND SP European Soc Cardiol C1 [Cheezum, M.; Kaviratne, A.; Bindeman, J.; Villines, T.] Walter Reed Natl Mil Med Ctr, Dept Med, Serv Cardiol, Bethesda, MD USA. [Redon, C.; Burrell, A.; Maeda, D.; Bonner, W.] NCI, NIH, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Wisniewski, P.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [Delacruz, P.] San Antonio Mil Med Ctr, Dept Internal Med, Cardiol Serv, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG 1 PY 2015 VL 36 SU 1 MA 2108 BP 349 EP 349 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR3BL UT WOS:000361205103041 ER PT J AU Desai, AS Liu, J Claggett, B Bristow, M Fleg, J Lewis, EF McKinlay, S Pitt, B Solomon, SD Pfeffer, MA AF Desai, A. S. Liu, J. Claggett, B. Bristow, M. Fleg, J. Lewis, E. F. McKinlay, S. Pitt, B. Solomon, S. D. Pfeffer, M. A. CA TOPCAT Investigators TI Incidence and predictors of doubling of serum creatinine during treatment of heart failure and preserved ejection fraction with spironolactone SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 29-SEP 02, 2015 CL London, ENGLAND SP European Soc Cardiol C1 [Desai, A. S.; Liu, J.; Claggett, B.; Lewis, E. F.; Solomon, S. D.; Pfeffer, M. A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bristow, M.] Univ Colorado Hlth, Denver, CO USA. [Fleg, J.] NHLBI, NIH, Bethesda, MD 20892 USA. [McKinlay, S.] New England Res Inst, Watertown, MA 02172 USA. [Pitt, B.] Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG 1 PY 2015 VL 36 SU 1 MA P3756 BP 662 EP 663 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR3BL UT WOS:000361205104569 ER PT J AU Cheng, HM Chuang, SY Sung, SH Spurgeon, HA Ting, CT Najjar, SS Lakatta, EG Yin, FCP Chou, P Chen, CH AF Cheng, H. M. Chuang, S. Y. Sung, S. H. Spurgeon, H. A. Ting, C. T. Najjar, S. S. Lakatta, E. G. Yin, F. C. P. Chou, P. Chen, C. H. TI Central aortic reservoir-wave analysis predicted 20-year all-cause and cardiovascular mortalities independently of wave reflection and arterial stiffness: a community-based study SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 29-SEP 02, 2015 CL London, ENGLAND SP European Soc Cardiol C1 [Cheng, H. M.; Chen, C. H.] Taipei Vet Gen Hosp, Dept Med Educ, Taipei, Taiwan. [Chuang, S. Y.] Natl Hlth Res Inst, Res Inst Populat Hlth Sci, Div Prevent Med & Hlth Serv, Miaoli, Miaoli County, Taiwan. [Sung, S. H.] Taipei Vet Gen Hosp, Dept Med, Taipei, Taiwan. [Spurgeon, H. A.; Najjar, S. S.; Lakatta, E. G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Ting, C. T.] Taichung Vet Gen Hosp, Ctr Cardiovasc, Taichung, Taiwan. [Yin, F. C. P.] Washington Univ, Sch Med, Dept Biomed Engn, St Louis, MO USA. [Chou, P.] Natl Yang Ming Univ, Dept Publ Hlth, Taipei 112, Taiwan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG 1 PY 2015 VL 36 SU 1 MA P5570 BP 979 EP 979 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR3BL UT WOS:000361205106483 ER PT J AU Ryazankina, N Vagida, M Grivel, JC Arakelyan, A Manchurov, V Ivanova, O Lebedeva, A Shpektor, A Margolis, L Vasilieva, E AF Ryazankina, N. Vagida, M. Grivel, J. -C. Arakelyan, A. Manchurov, V. Ivanova, O. Lebedeva, A. Shpektor, A. Margolis, L. Vasilieva, E. TI Effect of remote ischemic preconditioning on extracellular vesicles in patients with acute ST-elevation myocardial infarction SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 29-SEP 02, 2015 CL London, ENGLAND SP European Soc Cardiol C1 [Ryazankina, N.; Vagida, M.; Manchurov, V.; Ivanova, O.; Lebedeva, A.; Shpektor, A.; Vasilieva, E.] Moscow State Univ Med & Dent, Atherothrombosis Dept, Moscow, Russia. [Grivel, J. -C.; Arakelyan, A.; Margolis, L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RI Vasilieva, Elena/B-2137-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG 1 PY 2015 VL 36 SU 1 MA P6332 BP 1116 EP 1116 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR3BL UT WOS:000361205107348 ER PT J AU Brennan, B Weber, F Kormelink, R Schnettler, E Bouloy, M Failloux, AB Weaver, SC Fazakerley, JK Fragkoudis, R Harris, M Barr, JN Palese, P Garcia-Sastre, A Dalzie, RG Dutia, BM Lowen, AC Steel, J Randall, RE Duprex, WP Rice, CM Tesh, RB Murphy, FA Ebihara, H Vasconcelos, PFC Nunes, MR Fooks, AR Smith, GL Goodfellow, I Pappu, HR Lamb, RA Paterson, RG Higgs, S Vanlandingham, DL Dietzgen, RG Lodmell, JS Nichol, ST Daly, J Ullman, DE Plyusnin, A Plyusnina, A Efstathiou, S Hewson, R Tordo, N Cherry, S Boutell, C Hosie, MJ Murcia, PR Neil, JC Palmarini, M Patel, AH Willett, BJ Kohl, A McLauchlan, J AF Brennan, Benjamin Weber, Friedemann Kormelink, Richard Schnettler, Esther Bouloy, Michele Failloux, Anna-Bella Weaver, Scott C. Fazakerley, John K. Fragkoudis, Rennos Harris, Mark Barr, John N. Palese, Peter Garcia-Sastre, Adolfo Dalzie, Robert G. Dutia, Bernadette M. Lowen, Anice C. Steel, John Randall, Richard E. Duprex, W. Paul Rice, Charles M. Tesh, Robert B. Murphy, Frederick A. Ebihara, Hideki Vasconcelos, Pedro F. C. Nunes, Marcio R. Fooks, Anthony R. Smith, Geoffrey L. Goodfellow, Ian Pappu, Hanu R. Lamb, Robert A. Paterson, Reay G. Higgs, Stephen Vanlandingham, Dana L. Dietzgen, Ralf G. Lodmell, J. Stephen Nichol, Stuart T. Daly, Janet Ullman, Diane E. Plyusnin, Alexander Plyusnina, Angelina Efstathiou, Stacey Hewson, Roger Tordo, Noel Cherry, Sara Boutell, Chris Hosie, Margaret J. Murcia, Pablo R. Neil, James C. Palmarini, Massimo Patel, Arvind H. Willett, Brian J. Kohl, Alain McLauchlan, John TI In memoriam - Richard M. Elliott (1954-2015) SO JOURNAL OF GENERAL VIROLOGY LA English DT Biographical-Item C1 [Brennan, Benjamin; Schnettler, Esther; Boutell, Chris; Hosie, Margaret J.; Murcia, Pablo R.; Neil, James C.; Palmarini, Massimo; Patel, Arvind H.; Willett, Brian J.; Kohl, Alain; McLauchlan, John] Univ Glasgow, MRC, Ctr Virus Res, Glasgow G61 1QH, Lanark, Scotland. [Weber, Friedemann] Univ Giessen, Inst Virol, Vet Med FB10, D-35392 Giessen, Germany. [Kormelink, Richard] Wageningen Univ, Dept Plant Sci, Virol Lab, NL-6708 PB Wageningen, Netherlands. [Bouloy, Michele; Failloux, Anna-Bella] Inst Pasteur, F-75724 Paris 15, France. [Weaver, Scott C.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Fazakerley, John K.; Fragkoudis, Rennos] Pirbright Inst, Woking GU24 0NF, Surrey, England. [Harris, Mark; Barr, John N.] Univ Leeds, Fac Biol Sci, Leeds LS2 9JT, W Yorkshire, England. [Palese, Peter; Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Dalzie, Robert G.; Dutia, Bernadette M.] Univ Edinburgh, Roslin Inst, Easter Bush EH25 9RG, Midlothian, Scotland. [Lowen, Anice C.; Steel, John] Emory Univ, Sch Med, Rollins Res Ctr, Atlanta, GA 30322 USA. [Randall, Richard E.] Univ St Andrews, Biomol Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland. [Duprex, W. Paul] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Duprex, W. Paul] Boston Univ, Natl Emerging Infect Dis Labs, Boston, MA 02118 USA. [Rice, Charles M.] Rockefeller Univ, Lab Virol & Infect Dis, New York, NY 10065 USA. [Tesh, Robert B.; Murphy, Frederick A.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Ebihara, Hideki] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. [Vasconcelos, Pedro F. C.; Nunes, Marcio R.] Minist Saude, Inst Evandro Chagas, Secao Arbovirol & Febres Haemorrag, BR-67030000 Ananindeua, Para, Brazil. [Fooks, Anthony R.] APHA Weybridge, Addlestone KT15 3NB, Surrey, England. [Smith, Geoffrey L.; Goodfellow, Ian] Univ Cambridge, Addenbrookes Hosp, Dept Pathol, Div Virol, Cambridge CB2 2QQ, England. [Pappu, Hanu R.] Washington State Univ, Dept Plant Pathol, Pullman, WA 99164 USA. [Lamb, Robert A.; Paterson, Reay G.] Northwestern Univ, Dept Mol Biosci, Evanston, IL 60208 USA. [Higgs, Stephen] Kansas State Univ, Biosecur Res Inst, Manhattan, KS 66506 USA. [Vanlandingham, Dana L.] Kansas State Univ, Coll Vet Med, Dept Diagnost Med Pathobiol, Manhattan, KS 66506 USA. [Dietzgen, Ralf G.] Univ Queensland, St Lucia, Qld 4072, Australia. [Lodmell, J. Stephen] Univ Montana, Div Biol Sci, Missoula, MT 59812 USA. [Nichol, Stuart T.] Ctr Dis Control & Prevent, Viral Special Pathogens Branch, Div High Consequence Pathogens & Pathol, Atlanta, GA 30329 USA. [Daly, Janet] Univ Nottingham, Sch Vet Med & Sci, Loughborough LE12 5RD, Leics, England. [Ullman, Diane E.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Plyusnin, Alexander; Plyusnina, Angelina] Univ Helsinki, Dept Virol, FIN-00014 Helsinki, Finland. [Efstathiou, Stacey] Natl Inst Biol Stand & Controls, Blanche Lane, Potters Bar EN6 3QG, Herts, England. [Hewson, Roger] Publ Hlth England Microbiol Serv, Salisbury SP4 0JG, Wilts, England. [Tordo, Noel] WHO Collaborat Ctr Arboviruses & Viral Haemorrhag, OIE Reference Lab RVFV, F-75724 Paris 15, France. [Tordo, Noel] Inst Pasteur, CCHFV, F-75724 Paris 15, France. [Cherry, Sara] Univ Penn, Philadelphia, PA 19104 USA. RP Brennan, B (reprint author), Univ Glasgow, MRC, Ctr Virus Res, Glasgow G61 1QH, Lanark, Scotland. RI Fooks, Anthony/F-5418-2010; Weaver, Scott/D-6490-2011; OI Palese, Peter/0000-0002-0337-5823; Fazakerley, John/0000-0001-7071-105X; Boutell, Chris/0000-0002-2970-7785; Garcia-Sastre, Adolfo/0000-0002-6551-1827; Daly, Janet/0000-0002-1912-4500; Goodfellow, Ian/0000-0002-9483-510X; Brennan, Benjamin/0000-0003-4707-726X FU Wellcome Trust [097997] NR 1 TC 1 Z9 1 U1 0 U2 8 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD AUG PY 2015 VL 96 BP 1975 EP 1978 DI 10.1099/jgv.0.000241 PN 8 PG 4 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA CS7CZ UT WOS:000362243000001 PM 26315040 ER PT J AU Smyth, JT Schoborg, TA Bergman, ZJ Riggs, B Rusan, NM AF Smyth, Jeremy T. Schoborg, Todd A. Bergman, Zane J. Riggs, Blake Rusan, Nasser M. TI Proper symmetric and asymmetric endoplasmic reticulum partitioning requires astral microtubules SO OPEN BIOLOGY LA English DT Article DE endoplasmic reticulum; centrosome; asymmetric division; Drosophila; mitosis ID CELL-DIVISION; DROSOPHILA PROTEIN; NUCLEAR-ENVELOPE; DYNAMICS; CENTROSOMES; SPINDLE; ER; MITOSIS; ASP; ORGANIZATION AB Mechanisms that regulate partitioning of the endoplasmic reticulum (ER) during cell division are largely unknown. Previous studies have mostly addressed ER partitioning in cultured cells, which may not recapitulate physiological processes that are critical in developing, intact tissues. We have addressed this by analysing ER partitioning in asymmetrically dividing stem cells, in which precise segregation of cellular components is essential for proper development and tissue architecture. We show that in Drosophila neural stem cells, called neuroblasts, the ER asymmetrically partitioned to centrosomes early in mitosis. This correlated closely with the asymmetric nucleation of astral microtubules (MTs) by centrosomes, suggesting that astral MT association may be required for ER partitioning by centrosomes. Consistent with this, the ER also associated with astral MTs in meiotic Drosophila spermatocytes and during syncytial embryonic divisions. Disruption of centrosomes in each of these cell types led to improper ER partitioning, demonstrating the critical role for centrosomes and associated astral MTs in this process. Importantly, we show that the ER also associated with astral MTs in cultured human cells, suggesting that this centrosome/astral MT-based partitioning mechanism is conserved across animal species. C1 [Smyth, Jeremy T.; Schoborg, Todd A.; Rusan, Nasser M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Smyth, Jeremy T.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Bergman, Zane J.; Riggs, Blake] San Francisco State Univ, Dept Biol, San Francisco, CA 94132 USA. RP Rusan, NM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM nasser@nih.gov RI Rusan, Nasser/P-3511-2016 FU National Heart, Lung and Blood Institute (Division of Intramural Research) at the National Institutes of Health [1ZIAHL006126]; National Institutes of Health (NIH) SCORE grant [5SC2 GM098229-02] FX N.M.R. is supported by the National Heart, Lung and Blood Institute (Division of Intramural Research) at the National Institutes of Health (1ZIAHL006126). Z.J.B. and B.R. were supported by a National Institutes of Health (NIH) SCORE grant 5SC2 GM098229-02. NR 33 TC 1 Z9 1 U1 1 U2 3 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 2046-2441 J9 OPEN BIOL JI Open Biol PD AUG PY 2015 VL 5 IS 8 AR 150067 DI 10.1098/rsob.150067 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CS6MP UT WOS:000362193600004 ER PT J AU Horowitz, T AF Horowitz, Todd TI Very large memory sets in hybrid search: Can the log still save us? SO PERCEPTION LA English DT Meeting Abstract C1 [Horowitz, Todd] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0301-0066 EI 1468-4233 J9 PERCEPTION JI Perception PD AUG PY 2015 VL 44 SU 1 MA 3T3B006 BP 285 EP 286 PG 2 WC Ophthalmology; Psychology; Psychology, Experimental SC Ophthalmology; Psychology GA CS7TC UT WOS:000362287800573 ER PT J AU Sutton, RM Case, E Brown, SP Atkins, DL Nadkarni, VM Kaltman, J Callaway, C Idris, A Nichol, G Hutchison, J Drennan, IR Austin, M Daya, M Cheskes, S Nuttall, J Herren, H Christenson, J Andrusiek, D Vaillancourt, C Menegazzi, JJ Rea, TD Berg, RA AF Sutton, Robert M. Case, Erin Brown, Siobhan P. Atkins, Dianne L. Nadkarni, Vinay M. Kaltman, Jonathan Callaway, Clifton Idris, Ahamed Nichol, Graham Hutchison, Jamie Drennan, Ian R. Austin, Michael Daya, Mohamud Cheskes, Sheldon Nuttall, Jack Herren, Heather Christenson, James Andrusiek, Dug Vaillancourt, Christian Menegazzi, James J. Rea, Thomas D. Berg, Robert A. CA ROC Investigators TI A quantitative analysis of out-of-hospital pediatric and adolescent resuscitation quality - A report from the ROC epistry-cardiac arrest SO RESUSCITATION LA English DT Article DE Pediatric; Cardiopulmonary resuscitation; Emergency medical services ID AMERICAN-HEART-ASSOCIATION; CHEST COMPRESSION RATES; CARDIOPULMONARY-RESUSCITATION; TREATMENT RECOMMENDATIONS; INTERNATIONAL CONSENSUS; LIFE-SUPPORT; OUTCOMES; SURVIVAL; CHILDREN; CPR AB Aim: High-quality cardiopulmonary resuscitation (CPR) may improve survival. The quality of CPR performed during pediatric out-of-hospital cardiac arrest (p-OHCA) is largely unknown. The main objective of this study was to describe the quality of CPR performed during p-OHCA resuscitation attempts. Methods: Prospective observational multi-center cohort study of p-OHCA patients >= 1 and <19 years of age registered in the Resuscitation Outcomes Consortium (ROC) Epistry database. The primary outcome was an a priori composite variable of compliance with American Heart Association (AHA) guidelines for both chest compression (CC) rate and CC fraction (CCF). Event compliance was defined as a case with 60% or more of its minute epochs compliant with AHA targets (rate 100-120 min(-1); depth >= 38 mm; and CCF >= 0.80). In a secondary analysis, multivariable logistic regression was used to evaluate the association between guideline compliance and return of spontaneous circulation (ROSC). Results: Between December 2005 and December 2012, 2564 pediatric events were treated by EMS providers, 390 of which were included in the final cohort. Of these events, 22% achieved AHA compliance for both rate and CCF, 36% for rate alone, 53% for CCF alone, and 58% for depth alone. Over time, there was a significant increase in CCF (p < 0.001) and depth (p = 0.03). After controlling for potential confounders, there was no significant association between AHA guideline compliance and ROSC. Conclusions: In this multi-center study, we have established that there are opportunities for professional rescuers to improve prehospital CPR quality. Encouragingly, CCF and depth both increased significantly over time. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Sutton, Robert M.; Nadkarni, Vinay M.; Berg, Robert A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Case, Erin; Brown, Siobhan P.; Herren, Heather] Resuscitat Outcome Consortium, Seattle, WA 98105 USA. [Atkins, Dianne L.] Univ Iowa, Carver Coll Med, Stead Family Dept Pediat, Iowa City, IA 52242 USA. [Kaltman, Jonathan] NHLBI, Bethesda, MD 20817 USA. [Callaway, Clifton] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Idris, Ahamed] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Nichol, Graham] Univ Washington, Resuscitat Outcome Consortium Clin Trial Ctr, Seattle, WA 98104 USA. [Hutchison, Jamie] Hosp Sick Children, Toronto, ON M5G IX8, Canada. [Drennan, Ian R.] Univ Toronto, Li Ka Shing Knowledge Inst, St Michaels Hosp, Toronto, ON M5B IW8, Canada. [Austin, Michael] Univ Ottawa, Ottawa Hosp, Ottawa, ON K1Y 4E9, Canada. [Daya, Mohamud; Nuttall, Jack] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Cheskes, Sheldon] Sunnybrook Ctr Prehosp Med, Toronto, ON M8W 3S2, Canada. [Christenson, James] Univ British Columbia, Fac Med, Dept Emergency Med, Vancouver, BC V5Z 1M9, Canada. [Andrusiek, Dug] Edith Cowan Univ, Sch Med Sci, Fac Hlth Engn & Sci, Western Australia 6023, Australia. [Vaillancourt, Christian] Univ Ottawa, Ottawa Hosp Res Inst, Ottawa Hosp, Ottawa, ON K1Y 4E9, Canada. [Menegazzi, James J.] Univ Pittsburgh, Pittsburgh, PA 15261 USA. [Rea, Thomas D.] Univ Washington, Seattle, WA 98104 USA. RP Sutton, RM (reprint author), Childrens Hosp Philadelphia, 8th Floor Main Bldg,Suite 8566,34th St, Philadelphia, PA 19104 USA. EM suttonr@chop.edu; ecase@uw.edu; spes@uw.edu; dianne-atkins@uiowa.edu; nadkarni@chop.edu; kaltmanj@nhlbi.nih.gov; callawaycw@upmc.edu; ahamed.idris@utsouthwestern.edu; grahamnichol@icloud.com; jamie.hutchison@sickkids.ca; DrennanI@smh.ca; tassiemlm@yahoo.com.au; dayam@ohsu.edu; Sheldon.Cheskes@sunnybrook.ca; nuttallj@ohsu.edu; hherren@uw.edu; jim.christenson@ubc.ca; dug.andrusiek@alumni.ubc.ca; cvaillancourt@ohri.ca; menegazzijj@upmc.edu; rea123@u.washington.edu; bergra@chop.edu RI Drennan, Ian/K-3046-2013; OI Drennan, Ian/0000-0001-8033-4382; Brown, Siobhan/0000-0002-4774-3122 FU University of Washington Data Coordinating Center from the NHLBI [5U01 HL077863]; University of Iowa from the NHLBI [HL077865]; Medical College of Wisconsin from the NHLBI [HL077866]; University of Washington from the NHLBI [HL077867]; University of Pittsburgh from the NHLBI [HL077871]; St. Michael's Hospital from the NHLBI [HL077872]; Oregon Health and Science University from the NHLBI [HL077873]; University of Alabama at Birmingham from the NHLBI [HL077881]; Ottawa Hospital Research Institute from the NHLBI [HL077885]; University of Texas SW Medical Ctr/Dallas from the NHLBI [HL077887]; University of California, San Diego from the NHLBI [HL077908]; National Institute of Neurological Disorders and Stroke (NINDS); U.S. Army Medical Research & Material Command; Canadian Institutes of Health Research (CIHR) - Institute of Circulatory and Respiratory Health; Defense Research and Development Canada; Heart, Stroke Foundation of Canada; AHA FX Financial disclosure: The ROC is supported by a series of cooperative agreements to 10 regional clinical centers and one Data Coordinating Center (5U01 HL077863 - University of Washington Data Coordinating Center, HL077865 - University of Iowa, HL077866 - Medical College of Wisconsin, HL077867 - University of Washington, HL077871 - University of Pittsburgh, HL077872 - St. Michael's Hospital, HL077873 - Oregon Health and Science University, HL077881 - University of Alabama at Birmingham, HL077885 - Ottawa Hospital Research Institute, HL077887 - University of Texas SW Medical Ctr/Dallas, HL077908 - University of California, San Diego) from the NHLBI in partnership with the National Institute of Neurological Disorders and Stroke (NINDS), U.S. Army Medical Research & Material Command, The Canadian Institutes of Health Research (CIHR) - Institute of Circulatory and Respiratory Health, Defense Research and Development Canada, the Heart, Stroke Foundation of Canada and the AHA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI or the NIH. NR 33 TC 17 Z9 18 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-9572 J9 RESUSCITATION JI Resuscitation PD AUG PY 2015 VL 93 BP 150 EP 157 DI 10.1016/j.resuscitation.2015.04.010 PG 8 WC Critical Care Medicine; Emergency Medicine SC General & Internal Medicine; Emergency Medicine GA CS2JQ UT WOS:000361897100043 PM 25917262 ER PT J AU Jacobs, JP Quintessenza, JA Karl, TR Asante-Korang, A Everett, AD Collins, SB Ramirez-Correa, GA Burns, KM Cohen, M Colan, SD Costello, JM Daly, KP Franklin, RCG Fraser, CD Hill, KD Huhta, JC Kaushal, S Law, YM Lipshultz, SE Murphy, AM Pasquali, SK Payne, MR Rossano, J Shirali, G Ware, SM Xu, MG Jacobs, ML AF Jacobs, Jeffrey P. Quintessenza, James A. Karl, Tom R. Asante-Korang, Alfred Everett, Allen D. Collins, Susan B. Ramirez-Correa, Genaro A. Burns, Kristin M. Cohen, Mitchell Colan, Steven D. Costello, John M. Daly, Kevin P. Franklin, Rodney C. G. Fraser, Charles D. Hill, Kevin D. Huhta, James C. Kaushal, Sunjay Law, Yuk M. Lipshultz, Steven E. Murphy, Anne M. Pasquali, Sara K. Payne, Mark R. Rossano, Joseph Shirali, Girish Ware, Stephanie M. Xu, Mingguo Jacobs, Marshall L. TI Summary of the 2015 International Paediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute SO CARDIOLOGY IN THE YOUNG LA English DT Article; Proceedings Paper CT International Pediatric Heart Failure Summit of Johns-Hopkins-All-Children's-Heart-Institute CY FEB 04-05, 2015 CL St. Petersburg, FL DE CHD; heart failure; paediatric heart failure; transplantation; cardiac transplantation; heart transplantation; ventricular assist device ID CARDIOLOGY WORKING GROUP; CARDIAC CRITICAL-CARE; DILATED CARDIOMYOPATHY; EUROPEAN-SOCIETY; INTENSIVE-CARE; HYPERTROPHIC CARDIOMYOPATHY; CHILDHOOD CARDIOMYOPATHY; TRANSPLANT RECIPIENTS; PERICARDIAL DISEASES; POSITION STATEMENT AB In the United States alone, similar to 14,000 children are hospitalised annually with acute heart failure. The science and art of caring for these patients continues to evolve. The International Pediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute was held on February 4 and 5, 2015. The 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute was funded through the Andrews/Daicoff Cardiovascular Program Endowment, a philanthropic collaboration between All Children's Hospital and the Morsani College of Medicine at the University of South Florida (USF). Sponsored by All Children's Hospital Andrews/Daicoff Cardiovascular Program, the International Pediatric Heart Failure Summit assembled leaders in clinical and scientific disciplines related to paediatric heart failure and created a multi-disciplinary "think-tank". The purpose of this manuscript is to summarise the lessons from the 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute, to describe the "state of the art" of the treatment of paediatric cardiac failure, and to discuss future directions for research in the domain of paediatric cardiac failure. C1 [Jacobs, Jeffrey P.; Quintessenza, James A.; Karl, Tom R.; Asante-Korang, Alfred; Everett, Allen D.; Collins, Susan B.; Jacobs, Marshall L.] Johns Hopkins All Childrens Heart Inst, St Petersburg, FL 33701 USA. [Jacobs, Jeffrey P.; Quintessenza, James A.; Karl, Tom R.; Asante-Korang, Alfred; Everett, Allen D.; Collins, Susan B.; Jacobs, Marshall L.] All Childrens Hosp, Tampa, FL USA. [Jacobs, Jeffrey P.; Quintessenza, James A.; Karl, Tom R.; Asante-Korang, Alfred; Everett, Allen D.; Collins, Susan B.; Jacobs, Marshall L.] Florida Hosp Children, Orlando, FL USA. [Jacobs, Jeffrey P.; Quintessenza, James A.; Karl, Tom R.; Asante-Korang, Alfred; Everett, Allen D.; Collins, Susan B.; Ramirez-Correa, Genaro A.; Murphy, Anne M.; Xu, Mingguo; Jacobs, Marshall L.] Johns Hopkins Univ, Sch Med, Dept Surg, Div Cardiac Surg, Baltimore, MD 21205 USA. [Jacobs, Jeffrey P.; Quintessenza, James A.; Karl, Tom R.; Asante-Korang, Alfred; Everett, Allen D.; Collins, Susan B.; Ramirez-Correa, Genaro A.; Murphy, Anne M.; Xu, Mingguo; Jacobs, Marshall L.] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Pediat Cardiol, Baltimore, MD 21205 USA. [Karl, Tom R.] Univ Queensland, Discipline Surg, Sch Med, Brisbane, Qld, Australia. [Burns, Kristin M.] NHLBI, Heart Dev & Struct Dis Branch, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Cohen, Mitchell] Phoenix Childrens Hosp, Phoenix, AZ USA. [Colan, Steven D.; Daly, Kevin P.] Harvard Univ, Sch Med, Dept Cardiol, Boston Childrens Hosp, Boston, MA USA. [Costello, John M.] Northwestern Univ, Ann & Robert H Lurie Childrens Hosp Chicago, Feinberg Sch Med, Chicago, IL 60611 USA. [Franklin, Rodney C. G.] Royal Brompton & Harefield NHS Trust, Paediat Cardiol Directorate, London, England. [Fraser, Charles D.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Hill, Kevin D.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Huhta, James C.] Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA. [Huhta, James C.] Pediatrix Med Grp, Tampa, FL USA. [Kaushal, Sunjay] Univ Maryland, Med Ctr, Dept Surg, Baltimore, MD 21201 USA. [Law, Yuk M.] Univ Washington, Seattle Childrens Hosp, Dept Pediat, Seattle, WA 98195 USA. [Lipshultz, Steven E.] Wayne State Univ, Sch Med, Childrens Hosp Michigan, Detroit, MI USA. [Pasquali, Sara K.] Univ Michigan, Dept Pediat & Communicable Dis, CS Mott Childrens Hosp, Ann Arbor, MI 48109 USA. [Payne, Mark R.] Indiana Univ Sch Med, Riley Heart Res Ctr, Indianapolis, IN 46202 USA. [Rossano, Joseph] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. [Shirali, Girish] Univ Missouri, Childrens Mercy Hosp & Clin, Kansas City, MO 64110 USA. [Ware, Stephanie M.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Ware, Stephanie M.] Indiana Univ Sch Med, Dept Med & Mol, Indianapolis, IN 46202 USA. [Xu, Mingguo] Shen Zhen Childrens Hosp, Dept Cardiol, Shenzhen, Guangdong, Peoples R China. RP Jacobs, JP (reprint author), Johns Hopkins All Childrens Heart Inst, St Petersburg, FL 33701 USA. EM JeffJacobs@msn.com OI Cohen, Mitchell/0000-0002-6090-2394; Daly, Kevin/0000-0003-4327-1532 FU Andrews/Daicoff Cardiovascular Program Endowment FX The 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute was funded through the Andrews/Daicoff Cardiovascular Program Endowment, a philanthropic collaboration between All Children's Hospital and the Morsani College of Medicine at the University of South Florida (USF). The Andrews/Daicoff Endowment was established by Sarianne and Ed Andrews in honor of George Daicoff M.D., their longtime friend. Being an entrepreneur and inventor, Mr. Andrews, along with his wife, bequeathed a significant gift to All Children's in support of Dr. Daicoff, founding Chief of Cardiovascular Surgery at All Children's Hospital (ACH) and heart surgery program director for over 20 years. The generous bequest provided through the Andrews' estate was gifted by ACH to USF for a 1:1 match by the State of Florida eminent scholars program. Each year income from this fund supports the enhancement and growth of cardiovascular research under Dr. Jeff Jacobs, director of the Andrews/Daicoff Cardiovascular Program at All Children's Hospital Johns Hopkins Medicine. NR 55 TC 3 Z9 3 U1 0 U2 5 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 2015 VL 25 SU 2 BP 8 EP 30 DI 10.1017/S1047951115001353 PG 23 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA CR9HZ UT WOS:000361666600002 PM 26377707 ER PT J AU Burns, KM AF Burns, Kristin M. TI Paediatric heart failure research: role of the National Heart, Lung, and Blood Institute SO CARDIOLOGY IN THE YOUNG LA English DT Article; Proceedings Paper CT International Pediatric Heart Failure Summit of Johns-Hopkins-All-Children's-Heart-Institute CY FEB 04-05, 2015 CL St. Petersburg, FL DE Paediatric heart failure; paediatric cardiomyopathy; paediatric heart transplantation; research ID CIRCULATORY SUPPORT PROGRAM; UNITED-STATES; CHILDREN; HOSPITALIZATIONS; CARDIOMYOPATHY; MULTICENTER; MORBIDITY; MORTALITY; DISEASE AB The National Heart, Lung, and Blood Institute, of the National Institutes of Health, is committed to supporting research in paediatric heart failure. The Institute's support of paediatric heart failure research includes both investigator-initiated grants and Institute initiatives. There were 107 funded grants in paediatric heart failure over the past 20 years in basic, translational and clinical research, technology development, and support of registries. Such research includes a broad diversity of scientific topics and approaches. The Institute also supports several initiatives for paediatric heart failure, including the Pediatric Circulatory Support Program, the Pumps for Kids, Infants, and Neonates (PumpKIN) Program, PediMACS, and the Pediatric Heart Network. This review article describes the National Heart, Lung, and Blood Institute's past, present, and future efforts to promote a better understanding of paediatric heart failure, with the ultimate goal of improving outcomes. C1 [Burns, Kristin M.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP Burns, KM (reprint author), NHLBI, Heart Dev & Struct Dis Branch, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Room 8220, Bethesda, MD 20892 USA. EM Kristin.Burns@nih.gov NR 15 TC 1 Z9 1 U1 0 U2 0 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 2015 VL 25 SU 2 BP 167 EP 171 DI 10.1017/S1047951115000979 PG 5 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA CR9HZ UT WOS:000361666600019 PM 26377724 ER PT J AU McCarrey, AC Resnick, SM AF McCarrey, Anna C. Resnick, Susan M. TI Postmenopausal hormone therapy and cognition SO HORMONES AND BEHAVIOR LA English DT Article DE Hormone therapy; Estrogen; Cognition; Aging; Menopause ID ESTROGEN REPLACEMENT THERAPY; HEALTH INITIATIVE MEMORY; CONJUGATED EQUINE ESTROGENS; RANDOMIZED CONTROLLED-TRIAL; OVARIECTOMIZED RHESUS-MONKEYS; SURGICALLY MENOPAUSAL WOMEN; PLUS PROGESTIN; VERBAL MEMORY; OLDER WOMEN; ALZHEIMERS-DISEASE AB Prior to the publication of findings from the Women's Health Initiative (WHI) in 2002, estrogen-containing hormone therapy (HT) was used to prevent age-related disease, especially cardiovascular disease, and to treat menopausal symptoms such as hot flushes and sleep disruptions. Some observational studies of HT in midlife and aging women suggested that HT might also benefit cognitive function, but randomized clinical trials have produced mixed findings in terms of health and cognitive outcomes. This review focuses on hormone effects on cognition and risk for dementia in naturally menopausal women as well as surgically induced menopause, and highlights findings from the large-scale WHI Memory Study (WHIMS) which, contrary to expectation, showed increased dementia risk and poorer cognitive outcomes in older postmenopausal women randomized to HT versus placebo. We consider the 'critical window hypothesis', which suggests that a window of opportunity may exist shortly after menopause during which estrogen treatments are most effective. In addition, we highlight emerging evidence that potential adverse effects of HT on cognition are most pronounced in women who have other health risks, such as lower global cognition or diabetes. Lastly, we point towards implications for future research and clinical treatments. Published by Elsevier Inc. C1 [McCarrey, Anna C.; Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. RP McCarrey, AC (reprint author), NIA, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM anna.mccarrey@nih.gov; resnicks@mail.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 89 TC 7 Z9 7 U1 4 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0018-506X EI 1095-6867 J9 HORM BEHAV JI Horm. Behav. PD AUG PY 2015 VL 74 SI SI BP 167 EP 172 DI 10.1016/j.yhbeh.2015.04.018 PG 6 WC Behavioral Sciences; Endocrinology & Metabolism SC Behavioral Sciences; Endocrinology & Metabolism GA CS0VY UT WOS:000361781500015 PM 25935728 ER PT J AU Goedert, JJ Jones, G Hua, X Xu, X Yu, GQ Flores, R Falk, RT Gail, MH Shi, JX Ravel, J Feigelson, HS AF Goedert, James J. Jones, Gieira Hua, Xing Xu, Xia Yu, Guoqin Flores, Roberto Falk, Roni T. Gail, Mitchell H. Shi, Jianxin Ravel, Jacques Feigelson, Heather Spencer TI Investigation of the Association Between the Fecal Microbiota and Breast Cancer in Postmenopausal Women: a Population-Based Case-Control Pilot Study SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID C-REACTIVE PROTEIN; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; HORMONE-RECEPTOR STATUS; ESTROGEN METABOLITES; GUT MICROBIOME; INTESTINAL BACTERIA; URINARY ESTROGENS; RISK-FACTORS; HEALTH; COHORT AB We investigated whether the gut microbiota differed in 48 postmenopausal breast cancer case patients, pretreatment, vs 48 control patients. Microbiota profiles in fecal DNA were determined by Illumina sequencing and taxonomy of 16S rRNA genes. Estrogens were quantified in urine. Case-control comparisons employed linear and unconditional logistic regression of microbiota alpha-diversity (PD_whole tree) and UniFrac analysis of beta-diversity, with two-sided statistical tests. Total estrogens correlated with alpha-diversity in control patients (Spearman Rho = 0.37, P =.009) but not case patients (Spearman Rho = 0.04, P =.77). Compared with control patients, case patients had statistically significantly altered microbiota composition (beta-diversity, P =.006) and lower alpha-diversity (P =.004). Adjusted for estrogens and other covariates, odds ratio of cancer was 0.50 (95% confidence interval = 0.30 to 0.85) per alpha-diversity tertile. Differences in specific taxa were not statistically significant when adjusted for multiple comparisons. This pilot study shows that postmenopausal women with breast cancer have altered composition and estrogen-independent low diversity of their gut microbiota. Whether these affect breast cancer risk and prognosis is unknown. C1 [Goedert, James J.; Jones, Gieira; Hua, Xing; Yu, Guoqin; Flores, Roberto; Falk, Roni T.; Gail, Mitchell H.; Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Flores, Roberto] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Xu, Xia] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD USA. [Ravel, Jacques] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Feigelson, Heather Spencer] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. RP Goedert, JJ (reprint author), 9609 Med Ctr Dr,Room 6E106 MSC 9767, Bethesda, MD 20892 USA. EM goedertj@mail.nih.gov OI Ravel, Jacques/0000-0002-0851-2233 FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health [Z01CP010214] FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health (Z01CP010214). NR 60 TC 5 Z9 6 U1 2 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2015 VL 107 IS 8 AR djv147 DI 10.1093/jnci/djv147 PG 5 WC Oncology SC Oncology GA CS1OP UT WOS:000361836400012 ER PT J AU Janes, H Pepe, MS McShane, LM Sargent, DJ Heagerty, PJ AF Janes, Holly Pepe, Margaret S. McShane, Lisa M. Sargent, Daniel J. Heagerty, Patrick J. TI The Fundamental Difficulty With Evaluating the Accuracy of Biomarkers for Guiding Treatment SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID INDIVIDUALIZED TREATMENT RULES; CLINICAL-TRIALS; PREDICTIVE BIOMARKERS; TREATMENT-SELECTION; VARIABLE SELECTION; COLORECTAL-CANCER; RAS MUTATIONS; MARKERS; PERFORMANCE; FRAMEWORK AB Developing biomarkers that can predict whether patients are likely to benefit from an intervention is a pressing objective in many areas of medicine. Recent guidance documents have recommended that the accuracy of predictive biomarkers, ie, sensitivity, specificity, and positive and negative predictive values, should be assessed. We clarify the meanings of these entities for predictive markers and demonstrate that generally they cannot be estimated from data without making strong untestable assumptions. Language suggesting that predictive biomarkers can identify patients who benefit from an intervention is also widespread. We show that in general one cannot estimate the chance that a patient will benefit from treatment. We recommend instead that predictive biomarkers be evaluated with respect to their ability to predict clinical outcomes among patients treated and among patients receiving standard of care, and the population impact of treatment rules based on those predictions. Ideally these entities are estimated from a randomized trial comparing the experimental intervention with standard of care. C1 [Janes, Holly; Pepe, Margaret S.] Fred Hutchinson Canc Res Ctr, Div Vaccine & Infect Dis, Seattle, WA 98104 USA. [Janes, Holly; Pepe, Margaret S.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Janes, Holly; Pepe, Margaret S.; Heagerty, Patrick J.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [McShane, Lisa M.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Rockville, MD USA. [Sargent, Daniel J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. RP Janes, H (reprint author), 1100 Fairview Ave North,M2-C200, Seattle, WA 98109 USA. EM hjanes@fhcrc.org FU [R01 CA152089]; [R01 GM54438]; [R01 CA174779]; [R01 HL072966]; [UL1TR000423] FX R01 CA152089 (PI: Janes); R01 GM54438 (PI: Pepe); R01 CA174779 (PI: Sargent); R01 HL072966 (PI: Heagerty); and UL1TR000423 (PI: Disis). NR 32 TC 5 Z9 5 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2015 VL 107 IS 8 AR djv157 DI 10.1093/jnci/djv157 PG 4 WC Oncology SC Oncology GA CS1OP UT WOS:000361836400017 ER PT J AU Simon, R AF Simon, Richard TI Sensitivity, Specificity, PPV, and NPV for Predictive Biomarkers SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article AB Molecularly targeted cancer drugs are often developed with companion diagnostics that attempt to identify which patients will have better outcome on the new drug than the control regimen. Such predictive biomarkers are playing an increasingly important role in precision oncology. For diagnostic tests, sensitivity, specificity, positive predictive value, and negative predictive are usually used as performance measures. This paper discusses these indices for predictive biomarkers, provides methods for their calculation with survival or response endpoints, and describes assumptions involved in their use. C1 NCI, Rockville, MD 20850 USA. RP Simon, R (reprint author), NCI, 9609 Med Ctr Dr,Room 5W110, Rockville, MD 20850 USA. EM rsimon@nih.gov NR 5 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2015 VL 107 IS 8 AR djv153 DI 10.1093/jnci/djv153 PG 3 WC Oncology SC Oncology GA CS1OP UT WOS:000361836400016 ER PT J AU Warren, JL Yabroff, KR AF Warren, Joan L. Yabroff, K. Robin TI Challenges and Opportunities in Measuring Cancer Recurrence in the United States SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID COLORECTAL-CANCER; MEDICARE CLAIMS; BREAST-CANCER; STAGE AB Cancer recurrence and disease-free survival are key outcomes for measuring the burden of illness, assessing the quality of cancer care, and informing decisions about increasingly costly cancer therapies. Yet information about recurrence is not collected in cancer registries or other population-based data sources. To address the lack of population-based recurrence information, researchers are increasingly using algorithms applied to health claims to infer recurrence. However, the validity of these approaches has not been comprehensively evaluated. In this commentary, we review existing studies and discuss options for improving the availability of recurrence data. We found that the validity of claims-based approaches appears promising in small, single institution studies, but larger population-based studies have identified substantial limitations with using claims to identify recurrence. With the increasing availability of health data, there are potential options that can be implemented to enhance information about recurrence. These options include design of software for the electronic medical record that enables rapid and standardized reporting of recurrence, use of electronic pathology reports to facilitate streamlined collection of recurrence by cancer registries, and mandates by insurers to require reporting of recurrence on health claims submitted by physicians. All of these options will require that governmental agencies, health insurers, professional societies, and other groups recognize the importance of population-based recurrence data and determine that this information is a priority for assessing cancer outcomes and costs. C1 [Warren, Joan L.; Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Warren, JL (reprint author), NCI, Healthcare Assessment Res Branch, Healthcare Delivery Res Program, 9609 Med Ctr Dr,Room 3E428, Bethesda, MD 20892 USA. EM joan_warren@n.h.gov OI Yabroff, K. Robin/0000-0003-0644-5572 NR 35 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2015 VL 107 IS 8 AR djv134 DI 10.1093/jnci/djv134 PG 8 WC Oncology SC Oncology GA CS1OP UT WOS:000361836400007 ER PT J AU Milner, JD AF Milner, Joshua D. TI PLAID: a Syndrome of Complex Patterns of Disease and Unique Phenotypes SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Cold urticaria; antibody deficiency; granuloma; PLAIDsyndrome ID PHOSPHOLIPASE C-GAMMA-2; B-CELL; URTICARIA; IMMUNODEFICIENCY; AUTOIMMUNITY; RECEPTORS; MUTATION; PLCG2 AB PLCG2 associated antibody deficiency and immune dysregulation (PLAID) is a complex dominantly inherited disease characterized almost universally by cold urticaria, and variably by recurrent bacterial infection, autoimmunty and skin granuloma formation. Several striking phenotypes can emerge from this disease, and the pathophysiology leads to a complex mix of loss and gain of function in cellular signaling. This review discusses the key phenotypic characteristics and pathophysiologic observations seen in PLAID, and contrasts PLAID to several related disorders in order to best contextualize this fascinating disease. C1 NIAID, Genet & Pathogenesis Allergy Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Milner, JD (reprint author), NIAID, Genet & Pathogenesis Allergy Sect, Lab Allerg Dis, NIH, 10 Ctr Dr,NIH Bldg 10 CRC 5-3950, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov FU Intramural Research Program of the NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. NR 14 TC 3 Z9 3 U1 1 U2 4 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 2015 VL 35 IS 6 BP 527 EP 530 DI 10.1007/s10875-015-0177-x PG 4 WC Immunology SC Immunology GA CR7JD UT WOS:000361524700004 PM 26206677 ER PT J AU Cain, DW Cidlowski, JA AF Cain, Derek W. Cidlowski, John A. TI Specificity and sensitivity of glucocorticoid signaling in health and disease SO BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article DE glucocorticoid; glucocorticoid receptor; glucocorticoid signaling; hypothalamic-pituitary-adrenal axis; isoforms ID RECEPTOR-BETA-ISOFORM; SEXUALLY DIMORPHIC ACTIONS; FACTOR-KAPPA-B; TRANSLATIONAL ISOFORMS; RHEUMATOID-ARTHRITIS; NUCLEAR RECEPTORS; TRANSCRIPTIONAL REGULATION; INFLAMMATORY DISEASES; SELECTIVE REGULATION; ULCERATIVE-COLITIS AB Endogenous glucocorticoids regulate a variety of physiologic processes and are crucial to the systemic stress response. Glucocorticoid receptors are expressed throughout the body, but there is considerable heterogeneity in glucocorticoid sensitivity and induced biological responses across tissues. The immunoregulatory properties of glucocorticoids are exploited in the clinic for the treatment of inflammatory and autoimmune disorders as well as certain hematological malignancies, but adverse side effects hamper prolonged use. Fully understanding the molecular events that shape the physiologic effects of glucocorticoid treatment will provide insight into optimal glucocorticoid therapies, reliable assessment of glucocorticoid sensitivity in patients, and may advance the development of novel GR agonists that exert immunosuppressive effects while avoiding harmful side effects. In this review, we provide an overview of mechanisms that affect glucocorticoid specificity and sensitivity in health and disease, focusing on the distinct isoforms of the glucocorticoid receptor and their unique regulatory and functional properties. Published by Elsevier Ltd. C1 [Cain, Derek W.; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, POB 12233,MD F3-07, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU National Institutes of Health/National Institute of Environmental Health Sciences FX Support provided by the Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Sciences. NR 81 TC 6 Z9 6 U1 2 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-690X EI 1532-1908 J9 BEST PRACT RES CL EN JI Best Pract. Res. Clin. Endoc. Metab. PD AUG PY 2015 VL 29 IS 4 BP 545 EP 556 DI 10.1016/j.beem.2015.04.007 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CR3TF UT WOS:000361255300004 PM 26303082 ER PT J AU Ramsuran, V Kulkarni, S O'huigin, C Yuki, Y Augusto, DG Gao, XJ Carrington, M AF Ramsuran, Veron Kulkarni, Smita O'huigin, Colm Yuki, Yuko Augusto, Danillo G. Gao, Xiaojiang Carrington, Mary TI Epigenetic regulation of differential HLA-A allelic expression levels SO HUMAN MOLECULAR GENETICS LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; CLASS-I MOLECULE; DNA METHYLATION; HIV CONTROL; GENE-EXPRESSION; C EXPRESSION; MHC; CELLS; BINDING; GENOME AB MHC class I expression levels influence the strength of immune responses and represent another variable in determining outcome to disease beyond peptide binding alone. Identification of the HLA loci that vary in allelic expression levels and delineating the mechanism responsible for expression variation may provide the opportunity to modify their expression therapeutically. We have examined the expression levels of allelic lineages at the HLA-A locus in a sample of 216 European Americans using a real-time polymerase chain reaction assay, which amplifies all HLA-A lineages specifically with equal efficiency, and observed a gradient of expression that associates with HLA-A allelic lineage (R = 0.6, P = 5 x 10(-25)). DNA methylation of the HLA-A gene appears to contribute to the variation in HLA-A mRNA expression levels, as a significant inverse correlation was observed between HLA-A mRNA expression levels in untreated cells and the degree to which expression is increased after treatment of the cells with a DNA methyltransferase inhibitor (R = 0.6, P = 2.8 x 10(-6)). Further, deep-sequencing and immunoprecipitation assays revealed allelic lineage-specific methylation patterns within the HLA-A promoter region where increased DNA methylation levels correlated significantly with reduced HLA-A expression levels (R = 0.89, P = 3.7 x 10(-9)). These data demonstrate HLA-A allelic lineage-specific variation in expression levels, and DNA methylation as a likely factor in contributing to this variation. C1 [Ramsuran, Veron; O'huigin, Colm; Yuki, Yuko; Augusto, Danillo G.; Gao, Xiaojiang; Carrington, Mary] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc Inflammat Program, Frederick, MD 21702 USA. [Ramsuran, Veron; Kulkarni, Smita; Augusto, Danillo G.; Carrington, Mary] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Ramsuran, Veron; Kulkarni, Smita; Augusto, Danillo G.; Carrington, Mary] Harvard Univ, Cambridge, MA 02139 USA. RP Carrington, M (reprint author), Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc Inflammat Program, Frederick, MD 21702 USA. EM carringm@mail.nih.gov RI Augusto, Danillo/F-3147-2013 FU National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E, N02-CP-55504, R01-DA04334, R01-DA12568]; NIH, Frederick National Lab, Center for Cancer Research FX This work was supported by federal funds from the National Cancer Institute, National Institutes of Health (NIH), [grant numbers HHSN261200800001E, N02-CP-55504, R01-DA04334 and R01-DA12568]. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. NR 38 TC 6 Z9 6 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 1 PY 2015 VL 24 IS 15 BP 4268 EP 4275 DI 10.1093/hmg/ddv158 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CR4OK UT WOS:000361314100007 PM 25935001 ER PT J AU Grice, SJ Sleigh, JN Motley, WW Liu, JL Burgess, RW Talbot, K Cader, MZ AF Grice, Stuart J. Sleigh, James N. Motley, William W. Liu, Ji-Long Burgess, Robert W. Talbot, Kevin Cader, M. Zameel TI Dominant, toxic gain-of-function mutations in gars lead to non-cell autonomous neuropathology SO HUMAN MOLECULAR GENETICS LA English DT Article ID TRANSFER-RNA SYNTHETASE; SPINAL MUSCULAR-ATROPHY; MARIE-TOOTH-DISEASE; MOTOR-NEURON DISEASE; AXONAL-TRANSPORT; IN-VIVO; PERIPHERAL NEUROPATHY; MOUSE MODEL; GLYCYL; DROSOPHILA AB Charcot-Marie-Tooth (CMT) neuropathies are collectively the most common hereditary neurological condition and a major health burden for society. Dominant mutations in the gene GARS, encoding the ubiquitous enzyme, glycyl-tRNA synthetase (GlyRS), cause peripheral nerve degeneration and lead to CMT disease type 2D. This genetic disorder exemplifies a recurring motif in neurodegeneration, whereby mutations in essential, widely expressed genes have selective deleterious consequences for the nervous system. Here, using novel Drosophila models, we show a potential solution to this phenomenon. Ubiquitous expression of mutant GlyRS leads to motor deficits, progressive neuromuscular junction (NMJ) denervation and pre-synaptic build-up of mutant GlyRS. Intriguingly, neuronal toxicity is, at least in part, non-cell autonomous, as expression of mutant GlyRS in mesoderm or muscle alone results in similar pathology. This mutant GlyRS toxic gain-of-function, which is WHEP domain-dependent, coincides with abnormal NMJ assembly, leading to synaptic degeneration, and, ultimately, reduced viability. Our findings suggest that mutant GlyRS gains access to ectopic sub-compartments of the motor neuron, providing a possible explanation for the selective neuropathology caused by mutations in a widely expressed gene. C1 [Grice, Stuart J.; Liu, Ji-Long] Univ Oxford, Dept Physiol Anat & Genet, MRC Funct Genom Unit, Oxford OX1 3PT, England. [Sleigh, James N.; Talbot, Kevin; Cader, M. Zameel] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England. [Sleigh, James N.; Cader, M. Zameel] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DS, England. [Motley, William W.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Burgess, Robert W.] Jackson Lab, Bar Harbor, ME 04609 USA. RP Cader, MZ (reprint author), Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England. EM zameel.cader@ndcn.ox.ac.uk OI Burgess, Robert/0000-0002-9229-3407; Sleigh, James/0000-0002-3782-9045 FU Medical Research Council; Oxford Biomedical Research Centre; French Muscular Dystrophy Association (AFM-Telethon); Wellcome Trust; National Institutes of Health [NS054154] FX This work was supported by the Medical Research Council (S.J.G., M.Z.C.), the Oxford Biomedical Research Centre (M.Z.C.), the French Muscular Dystrophy Association (AFM-Telethon) (J.N.S., K.T., M.Z.C.), the Wellcome Trust (J.N.S.) and the National Institutes of Health (NS054154 to R.W.B.). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. NR 55 TC 7 Z9 10 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 1 PY 2015 VL 24 IS 15 BP 4397 EP 4406 DI 10.1093/hmg/ddv176 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CR4OK UT WOS:000361314100019 PM 25972375 ER PT J AU Li, Y Yu, S Duncan, T Li, YC Liu, PH Gene, E Cortes-Pena, Y Qian, HH Dong, LJ Redmond, TM AF Li, Yan Yu, Shirley Duncan, Todd Li, Yichao Liu, Pinghu Gene, Erelda Cortes-Pena, Yoel Qian, Haohua Dong, Lijin Redmond, T. Michael TI Mouse model of human RPE65 P25L hypomorph resembles wild type under normal light rearing but is fully resistant to acute light damage SO HUMAN MOLECULAR GENETICS LA English DT Article ID LEBER CONGENITAL AMAUROSIS; INHERITED RETINAL DEGENERATION; DELAYED DARK-ADAPTATION; VISUAL CYCLE; RHODOPSIN REGENERATION; RPE65-DEFICIENT MICE; DEFICIENT MICE; MUTATION; GENE; DYSTROPHY AB Human RPE65 mutations cause a spectrum of blinding retinal dystrophies from severe early-onset disease to milder manifestations. The RPE65 P25L missense mutation, though having <10% of wild-type (WT) activity, causes relatively mild retinal degeneration. To better understand these mild forms of RPE65-related retinal degeneration, and their effect on cone photoreceptor survival, we generated an Rpe65/P25L knock-in (KI/KI) mouse model. We found that, when subject to the low-light regime (similar to 100 lux) of regular mouse housing, homozygous Rpe65/P25L KI/KI mice are morphologically and functionally very similar to WT siblings. While mutant protein expression is decreased by over 80%, KI/KI mice retinae retain comparable 11-cis-retinal levels with WT. Consistently, the scotopic and photopic electroretinographic (ERG) responses to single-flash stimuli also show no difference between KI/KI and WT mice. However, the recovery of a-wave response following moderate visual pigment bleach is delayed in KI/KI mice. Importantly, KI/KI mice show significantly increased resistance to high-intensity (20 000 lux for 30 min) light-induced retinal damage (LIRD) as compared with WT, indicating impaired rhodopsin regeneration in KI/KI. Taken together, the Rpe65/P25L mutant produces sufficient chromophore under normal conditions to keep opsins replete and thus manifests a minimal phenotype. Only when exposed to intensive light is this hypomorphic mutation manifested physiologically, as its reduced expression and catalytic activity protects against the successive cycles of opsin regeneration underlying LIRD. These data also help define minimal requirements of chromophore for photoreceptor survival in vivo and may be useful in assessing a beneficial therapeutic dose for RPE65 gene therapy in humans. C1 [Li, Yan; Yu, Shirley; Duncan, Todd; Gene, Erelda; Cortes-Pena, Yoel; Redmond, T. Michael] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Li, Yichao; Qian, Haohua] NEI, Visual Funct Core, NIH, Bethesda, MD 20892 USA. [Liu, Pinghu; Dong, Lijin] NEI, Genet Engn Core, NIH, Bethesda, MD 20892 USA. RP Redmond, TM (reprint author), NEI LRCMB, NIH, Bldg 6,Rm 117A,6 Ctr Dr,MSC 0608, Bethesda, MD 20892 USA. EM redmondd@helix.nih.gov FU National Eye Institute, National Institutes of Health (US Department of Health and Human Services) FX This research was supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health (US Department of Health and Human Services). NR 51 TC 3 Z9 3 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 1 PY 2015 VL 24 IS 15 BP 4417 EP 4428 DI 10.1093/hmg/ddv178 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CR4OK UT WOS:000361314100021 PM 25972377 ER PT J AU Demerath, EW Guan, WH Grove, ML Aslibekyan, S Mendelson, M Zhou, YH Hedman, AK Sandling, JK Li, LA Irvin, MR Zhi, DG Deloukas, P Liang, LM Liu, CY Bressler, J Spector, TD North, K Li, Y Absher, DM Levy, D Arnett, DK Fornage, M Pankow, JS Boerwinkle, E AF Demerath, Ellen W. Guan, Weihua Grove, Megan L. Aslibekyan, Stella Mendelson, Michael Zhou, Yi-Hui Hedman, Asa K. Sandling, Johanna K. Li, Li-An Irvin, Marguerite R. Zhi, Degui Deloukas, Panos Liang, Liming Liu, Chunyu Bressler, Jan Spector, Tim D. North, Kari Li, Yun Absher, Devin M. Levy, Daniel Arnett, Donna K. Fornage, Myriam Pankow, James S. Boerwinkle, Eric TI Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci SO HUMAN MOLECULAR GENETICS LA English DT Article ID CORONARY-HEART-DISEASE; BODY-MASS INDEX; DEPENDENT DIABETES-MELLITUS; DNA METHYLATION PATTERNS; LIPID-LOWERING DRUGS; FALSE DISCOVERY RATE; ATHEROSCLEROSIS RISK; PROMOTER METHYLATION; WEIGHT-LOSS; INSULIN-RESISTANCE AB Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC (P < 1 x 10(-7); Bonferroni), including probes in the recently reported HIF3A, CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP, KDM2B, PBX1 and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches. C1 [Demerath, Ellen W.; Pankow, James S.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Guan, Weihua] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55454 USA. [Grove, Megan L.; Bressler, Jan; Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Aslibekyan, Stella; Arnett, Donna K.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Zhi, Degui] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [Mendelson, Michael; Liang, Liming] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20824 USA. [Mendelson, Michael; Liang, Liming; Liu, Chunyu] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Mendelson, Michael] Boston Childrens Hosp, Dept Cardiol, Boston, MA 02215 USA. [Zhou, Yi-Hui] N Carolina State Univ, Dept Stat, Raleigh, NC 27695 USA. [Hedman, Asa K.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Hedman, Asa K.; Sandling, Johanna K.] Uppsala Univ, Mol Med & Sci Life Lab, Dept Med Sci, Uppsala, Sweden. [Sandling, Johanna K.; Deloukas, Panos] Wellcome Trust Sanger Inst, Hinxton, England. [Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Liu, Chunyu] Boston Univ, Dept Biostat, Boston, MA 02118 USA. [Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [North, Kari] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Absher, Devin M.] Hudson Alpha Inst Biotechnol, Huntsville, AL 35806 USA. [Fornage, Myriam; Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Li, Yun] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Li, Yun] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Li, Yun] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. RP Demerath, EW (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300 S Second St,Suite 300, Minneapolis, MN 55454 USA. EM ewd@umn.edu RI Sandling, Johanna/B-2973-2016; Deloukas, Panos/B-2922-2013; Mendelson, Michael/I-2874-2014; Lin, LiAn/C-5819-2017; OI Sandling, Johanna/0000-0003-1382-2321; Deloukas, Panos/0000-0001-9251-070X; Mendelson, Michael/0000-0001-7590-3958; Lin, LiAn/0000-0003-2731-1346; Hedman, Asa/0000-0001-5413-204X FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN 268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Institutes of Health (NIH) through American Recovery and Reinvestment Act (ARRA) [5RC2HL102419]; National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) [U01HL072524-04]; National Institutes of Health [N01-HC25195]; Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health; Division of Intramural Research, National Heart, Lung, and Blood Institute; Center for Information Technology, National Institutes of Health, Bethesda, MD; Wellcome Trust; European Community; National Institute for Health Research (NIHR) FX The Atherosclerosis Risk in Communities study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN 268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C). Funding support for 'Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium' was provided by the National Institutes of Health (NIH) through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). The work on the GOLDN study has been funded by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) (grant U01HL072524-04). The FHS is funded by National Institutes of Health contract (N01-HC25195). The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute and the Center for Information Technology, National Institutes of Health, Bethesda, MD. The MuTHER study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. NR 88 TC 42 Z9 43 U1 7 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 1 PY 2015 VL 24 IS 15 BP 4464 EP 4479 DI 10.1093/hmg/ddv161 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CR4OK UT WOS:000361314100025 PM 25935004 ER PT J AU Brubaker, L Litman, HJ Kim, HY Zimmern, P Dyer, K Kusek, JW Richter, HE Stoddard, A AF Brubaker, Linda Litman, Heather J. Kim, Hae-Young Zimmern, Philippe Dyer, Keisha Kusek, John W. Richter, Holly E. Stoddard, Anne CA Urinary Incontinence Treatment Net TI Missing data frequency and correlates in two randomized surgical trials for urinary incontinence in women SO INTERNATIONAL UROGYNECOLOGY JOURNAL LA English DT Article DE Missing data; Urinary incontinence; Clinical outcomes; Surgical trials; Primary outcome measures ID STRESS-INCONTINENCE; CLINICAL-TRIALS; PREVENTION AB Introduction and hypothesis Missing data is frequently observed in clinical trials; high rates of missing data may jeopardize trial outcome validity. Purpose We determined the rates of missing data over time, by type of data collected and compared demographic and clinical factors associated with missing data among women who participated in two large randomized clinical trials of surgery for stress urinary incontinence, the Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr) and the Trial of Midurethral Sling (TOMUS). Methods The proportions of subjects who attended and missed each follow-up visit were calculated. The chi-squared test, Fisher's exact test and t test were used to compare women with and without missing data, as well as the completeness of the data for each component of the composite primary outcome. Results Data completeness for the primary outcome computation in the TOMUS trial (62.3 %) was nearly double that in the SISTEr trial (35.7 %). The follow-up visit attendance rate decreased over time. A higher proportion of subjects attended all follow-up visits in the TOMUS trial and overall there were fewer missing data for the period that included the primary outcome assessment at 12 months. The highest levels of complete data for the composite outcome variables were for the symptoms questionnaire (SISTEr 100 %, TOMUS 99.8 %) and the urinary stress test (SISTEr 96.1 %, TOMUS 96.7 %). In both studies, the pad test was associated with the lowest levels of complete data (SISTEr 85.1 %, TOMUS 88.3 %) and approximately one in ten subjects had incomplete voiding diaries at the time of primary outcome assessment. Generally, in both studies, a higher proportion of younger subjects had missing data. This analysis lacked a patient perspective as to the reasons for missing data that could have provided additional information on subject burden, motivations for adherence and study design. In addition, we were unable to compare the effects of the different primary outcome assessment time-points in an identically designed trial. Conclusions Missing visits and data increased with time. Questionnaire data and physical outcome data (urinary stress test) that could be assessed during a visit were least prone to missing data, whereas data for variables that required subject effort while away from the research team (pad test, voiding diary) were more likely to be missing. Older subjects were more likely to provide complete data. C1 [Brubaker, Linda] Loyola Univ Chicago, Stritch Sch Med, Dept Obstet Gynecol, Maywood, IL 60153 USA. [Brubaker, Linda] Loyola Univ Chicago, Stritch Sch Med, Dept Urol, Maywood, IL 60153 USA. [Litman, Heather J.] Boston Childrens Hosp, Boston, MA USA. [Kim, Hae-Young; Stoddard, Anne] New England Res Inst, Watertown, MA 02172 USA. [Zimmern, Philippe] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Dyer, Keisha] Univ Calif San Diego, San Diego, CA 92103 USA. [Kusek, John W.] NIDDK, Bethesda, MA USA. [Richter, Holly E.] Univ Alabama Birmingham, Birmingham, AL USA. RP Brubaker, L (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Obstet Gynecol, 2160 South First Ave, Maywood, IL 60153 USA. EM Lbrubaker@lumc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK58225, U01 DK58229, U01 DK58234, U01 DK58231, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, U01 DK60401]; National Institute of Child Health and Human Development and Office of Research in Women's Health FX Supported by cooperative agreements from the National Institute of Diabetes and Digestive and Kidney Diseases: U01 DK58225, U01 DK58229, U01 DK58234, U01 DK58231, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, and U01 DK60401. Also supported by the National Institute of Child Health and Human Development and Office of Research in Women's Health. NR 8 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-3462 EI 1433-3023 J9 INT UROGYNECOL J JI Int. Urogynecol. J. PD AUG PY 2015 VL 26 IS 8 BP 1155 EP 1159 DI 10.1007/s00192-015-2661-5 PG 5 WC Obstetrics & Gynecology; Urology & Nephrology SC Obstetrics & Gynecology; Urology & Nephrology GA CR3JU UT WOS:000361229500010 PM 25800900 ER PT J AU Minster, RL Sanders, JL Singh, J Kammerer, CM Barmada, MM Matteini, AM Zhang, QY Wojczynski, MK Daw, EW Brody, JA Arnold, AM Lunetta, KL Murabito, JM Christensen, K Perls, TT Province, MA Newman, AB AF Minster, Ryan L. Sanders, Jason L. Singh, Jatinder Kammerer, Candace M. Barmada, M. Michael Matteini, Amy M. Zhang, Qunyuan Wojczynski, Mary K. Daw, E. Warwick Brody, Jennifer A. Arnold, Alice M. Lunetta, Kathryn L. Murabito, Joanne M. Christensen, Kaare Perls, Thomas T. Province, Michael A. Newman, Anne B. TI Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Genetics; Epidemiology; Successful aging; Longevity ID LONG-LIFE FAMILY; HUMAN LONGEVITY; MORBIDITY; SURVIVAL; AGE; OLDER; CENTENARIANS; EPIDEMIOLOGY; HERITABILITY; METAANALYSIS AB Background. The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems. Methods. We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts. Results. There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-6)) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest. Conclusions. ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity. C1 [Minster, Ryan L.; Singh, Jatinder; Kammerer, Candace M.; Barmada, M. Michael] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Sanders, Jason L.; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Matteini, Amy M.] Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Zhang, Qunyuan; Wojczynski, Mary K.; Daw, E. Warwick; Province, Michael A.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA. [Brody, Jennifer A.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Arnold, Alice M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02215 USA. [Christensen, Kaare] Univ Southern Denmark, Inst Publ Hlth, Dept Epidemiol, Odense, Denmark. [Perls, Thomas T.] Boston Univ, Boston Sch Med, Dept Med, Sect Geriatr, Boston, MA 02215 USA. [Perls, Thomas T.] Boston Med Ctr, Boston, MA USA. RP Newman, AB (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, A527 Crabtree Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. EM newmana@edc.pitt.edu RI Newman, Anne/C-6408-2013; Christensen, Kaare/C-2360-2009; OI Newman, Anne/0000-0002-0106-1150; Christensen, Kaare/0000-0002-5429-5292; Barmada, M Michael/0000-0002-3604-6460 FU National Institute on Aging [U01AG023712, U01AG023744, U01AG023746, U01AG023749, U01AG023755, AG023629, R01AG29451]; National Heart, Lung, and Blood Institute [HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC25195, N02HL64278]; National Institute of Neurological Disorders and Stroke [HL080295, HL087652, HL105756]; National Center for Advancing Translational Sciences (CTSI) [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center [DK063491]; University of Pittsburgh Claude D. Pepper Older Americans Independence Center [P30AG024827] FX LLFS was supported by the National Institute on Aging (U01AG023712, U01AG023744, U01AG023746, U01AG023749, and U01AG023755). CHS was supported by the National Heart, Lung, and Blood Institute (HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086); the National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke (HL080295, HL087652, and HL105756); the National Institute on Aging (AG023629); the National Center for Advancing Translational Sciences (CTSI grant UL1TR000124); the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DK063491 to the Southern California Diabetes Endocrinology Research Center); and the University of Pittsburgh Claude D. Pepper Older Americans Independence Center (P30AG024827). See also http://chs-nhlbi.org. FHS is supported by the National Institute of Aging (R01AG29451); the National Heart, Lung, and Blood Institute (N01HC25195 to Boston University School of Medicine, N02HL64278 to Affymetrix, Inc., for genotyping services). NR 33 TC 1 Z9 1 U1 1 U2 3 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 2015 VL 70 IS 8 BP 1003 EP 1008 DI 10.1093/gerona/glv006 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CR7MW UT WOS:000361535500012 PM 25758594 ER PT J AU Reinders, I Murphy, RA Koster, A Brouwer, IA Visser, M Garcia, ME Launer, LJ Siggeirsdottir, K Eiriksdottir, G Jonsson, PV Gudnason, V Harris, TB AF Reinders, Ilse Murphy, Rachel A. Koster, Annemarie Brouwer, Ingeborg A. Visser, Marjolein Garcia, Melissa E. Launer, Lenore J. Siggeirsdottir, Kristin Eiriksdottir, Gudny Jonsson, Palmi V. Gudnason, Vilmundur Harris, Tamara B. TI Muscle Quality and Muscle Fat Infiltration in Relation to Incident Mobility Disability and Gait Speed Decline: the Age, Gene/Environment Susceptibility-Reykjavik Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Epidemiology; Functional performance; Muscle; Imaging; Gait ID BODY-COMPOSITION; OLDER-ADULTS; SKELETAL-MUSCLE; PHYSICAL-DISABILITY; COMPUTED-TOMOGRAPHY; STRENGTH; HEALTH; MASS; SARCOPENIA; PERFORMANCE AB Background. Aging is associated with increased risk of reduced mobility. However, data on muscle components in relation to subjective and objective indicators of disability is limited. Methods. Data were from 2,725 participants (43% men) aged 74.8 +/- 4.7 years from the AGES-Reykjavik Study. At baseline, maximal isometric thigh strength (dynamometer chair), and midthigh muscle area and muscle fat infiltration were assessed with computed tomography. Usual 6 m gait speed and mobility disability were assessed at baseline and after 5.2 +/- 0.3 years. Incident mobility disability was defined as having much difficulty or unable to walk 500 m or climb-up 10 steps. A decrease of >= 0.1 m/s in gait speed was considered clinically relevant. Results. Greater strength and area were protective for mobility disability risk and gait speed decline. After adjustment for other muscle components, greater strength was independently associated with lower mobility disability risk in women odds ratios (OR) 0.78 (95% CI 0.62, 0.99), and lower decline in gait speed risk among both men OR 0.64 (0.54, 0.76), and women OR 0.72 (0.62, 0.82). Larger muscle area was independently associated with lower mobility disability risk in women OR 0.67 (0.52, 0.87) and lower decline in gait speed risk in men OR 0.74 (0.61, 0.91). Conclusions. Greater muscle strength and area were independently associated with 15-30% decreased risk of mobility disability in women and gait speed decline in men. Among women, greater muscle strength was also associated with lower risk of gait speed decline. Interventions aimed at maintaining muscle strength and area in old age might delay functional decline. C1 [Reinders, Ilse; Murphy, Rachel A.; Garcia, Melissa E.; Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20814 USA. [Reinders, Ilse; Brouwer, Ingeborg A.; Visser, Marjolein] Vrije Univ Amsterdam, Fac Earth & Life Sci, Dept Hlth Sci, Amsterdam, Netherlands. [Reinders, Ilse; Brouwer, Ingeborg A.; Visser, Marjolein] Vrije Univ Amsterdam, Fac Earth & Life Sci, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Koster, Annemarie] Maastricht Univ, Sch Publ Hlth & Primary Care CAPHRI, Dept Social Med, Maastricht, Netherlands. [Visser, Marjolein] Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Visser, Marjolein] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Siggeirsdottir, Kristin; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Jonsson, Palmi V.] Univ Iceland, Landspitali Natl Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Jonsson, Palmi V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. RP Reinders, I (reprint author), NIA, Lab Epidemiol & Populat Sci, 7201 Wisconsin Ave,3C-309 Gateway Bldg, Bethesda, MD 20814 USA. EM ilse.reinders@nih.gov RI Gudnason, Vilmundur/K-6885-2015; Koster, Annemarie/E-7438-2010 OI Gudnason, Vilmundur/0000-0001-5696-0084; FU National Institutes of Health [N01-AG-12100]; National Institute on Aging Intramural Research Program, Hjartavernd (Icelandic Heart Association); Althingi (Icelandic Parliament) FX This work was supported by National Institutes of Health (N01-AG-12100), the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). NR 37 TC 9 Z9 9 U1 2 U2 5 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 2015 VL 70 IS 8 BP 1030 EP 1036 DI 10.1093/gerona/glv016 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CR7MW UT WOS:000361535500016 PM 25748031 ER PT J AU Petraitiene, R Petraitis, V Bacher, JD Finkelman, MA Walsh, TJ AF Petraitiene, Ruta Petraitis, Vidmantas Bacher, John D. Finkelman, Malcolm A. Walsh, Thomas J. TI Effects of host response and antifungal therapy on serum and BAL levels of galactomannan and (1 -> 3)-beta-D-glucan in experimental invasive pulmonary aspergillosis SO MEDICAL MYCOLOGY LA English DT Article DE aspergillosis; galactomannan; (1 -> 3)-beta-D-glucan; immunosuppression; neutropenia ID LIVER-TRANSPLANT RECIPIENTS; IN-VITRO INTERACTIONS; BETA-D-GLUCAN; ENZYME-IMMUNOASSAY; CYCLOSPORINE-A; CIRCULATING GALACTOMANNAN; FUNGAL-INFECTIONS; AMPHOTERICIN-B; DISEASE BURDEN; MURINE MODEL AB Galactomannan and (1 -> 3)-beta-D-glucan are useful biomarkers of invasive pulmonary aspergillosis (IPA). However, the effects of immunosuppression on levels of galactomannan or (1 -> 3)-beta-D-glucan in IPA are not well understood or quantified. We therefore studied the simultaneous levels of galactomannan and (1 -> 3)-beta-D-glucan in two rabbit models of experimental IPA: (1) AraC-induced neutropenia in untreated (UC-AraC) and liposomal amphotericin B-treated (LAMB-AraC) rabbits; and (2) nonneutropenic cyclosporine-methylprednisolone immunosuppression in untreated (UC-CsA+M) and LAMB-treated (LAMB-CsA+M) rabbits. Simultaneous levels of galactomannan and (1 -> 3)-beta-D-glucan were determined in bronchoalveolar lavage (BAL) fluid and serial serum specimens and correlated with pulmonary host response. Serum galactomannan index (GMI) and (1 -> 3)-beta-D-glucan concentration-time-curves were higher in UC-AraC vs. UC-CsA+M (Mann-Whitney U-test, P < .05). Serum galactomannan and (1 -> 3)-beta-D-glucan in treatment groups demonstrated therapeutic responses with similarly lower levels in comparison to UC (P < .01) in both models. Host differences did not affect BAL fluid GMI or (1 -> 3)-beta-D-glucan but did affect galactomannan and (1 -> 3)-beta-D-glucan levels in serum. The higher serum GMI and (1 -> 3)-beta-D-glucan concentration-time-curves in UC-AraC correlated with extensive pulmonary infiltration by angioinvasive hyphae and minimal inflammation, while the lower concentration-time-curves in UC-CsA+M were associated with shorter and fewer hyphae in lung tissue and an intensive neutrophil response to Aspergillus hyphae. Thus, serum levels of galactomannan and (1 -> 3)-beta-D-glucan in IPA depended upon immunosuppression, which also affected severity of infection and hyphalmorphology, while BAL fluid galactomannan and (1 -> 3)-beta-D-glucan were sensitive biomarkers not affected by host response. C1 [Petraitiene, Ruta; Petraitis, Vidmantas; Walsh, Thomas J.] Cornell Univ, Weill Cornell Med Ctr, Transplantat Oncol Infect Dis Program, Dept Med, New York, NY 10065 USA. [Bacher, John D.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. [Finkelman, Malcolm A.] Associates Cape Cod Inc, East Falmouth, MA USA. [Walsh, Thomas J.] Cornell Univ, Weill Cornell Med Ctr, Dept Pediat, New York, NY 10065 USA. [Walsh, Thomas J.] Cornell Univ, Weill Cornell Med Ctr, Dept Microbiol & Immunol, New York, NY 10065 USA. RP Walsh, TJ (reprint author), Cornell Univ, Weill Cornell Med Ctr, Transplantat Oncol Infect Dis Program, 1300 York Ave,Rm A-421, New York, NY 10065 USA. EM rop2016@med.cornell.edu; thw2003@med.cornell.edu FU Save our Sick Kids Foundation; Astellas; Novartis; Merck; ContraFect; Pfizer; Cubist FX Thomas J. Walsh is a Scholar of the Henry Schueler Foundation and a Scholar of Pediatric Infectious Diseases of the Sharp Family Foundation. He also receives support from the Save our Sick Kids Foundation, as well as research grants for experimental and clinical antimicrobial pharmacotherapeutics from Astellas, Novartis, Merck, ContraFect, Pfizer, and Cubist. He has served as consultant to Astellas, ContraFect, Drais, iCo, Novartis, Pfizer, Methylgene, SigmaTau, and Trius. NR 49 TC 3 Z9 4 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1369-3786 EI 1460-2709 J9 MED MYCOL JI Med. Mycol. PD AUG PY 2015 VL 53 IS 6 BP 558 EP 568 DI 10.1093/mmy/myv034 PG 11 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA CR4JS UT WOS:000361298800003 PM 26129890 ER PT J AU Armstrong, TS Ying, Y Wu, JM Acquaye, AA Vera-Bolanos, E Gilbert, MR Brown, PD Vardy, J Chung, C AF Armstrong, Terri S. Ying, Yuan Wu, Jimin Acquaye, Alvina A. Vera-Bolanos, Elizabeth Gilbert, Mark R. Brown, Paul D. Vardy, Janette Chung, Caroline TI The relationship between corticosteroids and symptoms in patients with primary brain tumors: utility of the Dexamethasone Symptom Questionnaire-Chronic SO NEURO-ONCOLOGY LA English DT Article DE brain tumor; corticosteroids; patient-reported outcomes; symptoms ID GLUCOCORTICOID-RECEPTOR GENE; RADIATION NECROSIS; METASTASES; MANAGEMENT; TOXICITY AB Background. Corticosteroids can have many side effects that impact the patient's quality of life and functional status. The Dexamethasone Symptom Questionnaire-Chronic (DSQ-C) was developed to report corticosteroid side effects. This study's objective was to evaluate the utility of the DSQ-C and report associated signs and symptoms in brain tumor patients. Methods. Data collection included demographic and disease characteristics and the DSQ-C. Descriptive statistics were used to report associations among variables. Linear regression models were applied to assess the effects of the cumulative daily dose (mg/dxtotal d) on DSQ-C scores. Psychometrics included factor analysis to assess construct validity and Cronbach's alpha for internal consistency. Results. Ninety-six adult patients with primary (77%) or metastatic (23%) brain tumors participated, with 74% on corticosteroids. Participants were primarily white (83%) males (65%) between 20 and 75 years of age (median, 53). Median corticosteroid dose duration was 4 mg/day for 1 month (range, 0-26 mo). The DSQ-C scores ranged from 17 to 54 (mean of 27), with 35% reporting increased appetite and trouble sleeping. Factor analysis indicated 6 underlying constructs explaining 53% of variance. DSQ-C internal consistency (reliability) was 0.77. The DSQ-C discriminated between patients who were on steroids and those who were not (P<.01), and cumulative dose predicted DSQ-C scores (P,. 001). Conclusions. This study demonstrated the potential use of the DSQ-C as a screening tool for side effects associated with corticosteroid use in brain tumor patients. Future analyses should include longitudinal evaluation of severity and biologic underpinnings of variability of timing and severity of symptoms. C1 [Armstrong, Terri S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Armstrong, Terri S.; Ying, Yuan; Wu, Jimin; Acquaye, Alvina A.; Vera-Bolanos, Elizabeth; Brown, Paul D.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Gilbert, Mark R.] NIH, Bethesda, MD 20892 USA. [Vardy, Janette] Univ Sydney, Concord Repatriat Gen Hosp, Concord, NSW, Australia. [Chung, Caroline] Univ Toronto, Dept Radiat Oncol, Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. RP Armstrong, TS (reprint author), UTHSC SON, Dept Family Hlth, Oncol Nursing, 6901 Bertner Ave,Room 577, Houston, TX 77030 USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 FU Collaborative Ependymoma Research Foundation (CERN) FX This work was partially supported by the Collaborative Ependymoma Research Foundation (CERN) (grant to A.A.A., E.V-B.). NR 22 TC 2 Z9 3 U1 1 U2 3 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 2015 VL 17 IS 8 BP 1114 EP 1120 DI 10.1093/neuonc/nov054 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CR4MC UT WOS:000361305700009 PM 25862766 ER PT J AU Inamoto, Y Shah, NN Savani, BN Shaw, BE Abraham, AA Ahmed, IA Akpek, G Atsuta, Y Baker, KS Basak, GW Bitan, M DeFilipp, Z Gregory, TK Greinix, HT Hamadani, M Hamilton, BK Hayashi, RJ Jacobsohn, DA Kamble, RT Kasow, KA Khera, N Lazarus, HM Malone, AK Lupo-Stanghellini, MT Margossian, SP Muffly, LS Norkin, M Ramanathan, M Salooja, N Schoemans, H Wingard, JR Wirk, B Wood, WA Yong, A Duncan, CN Flowers, MED Majhail, NS AF Inamoto, Y. Shah, N. N. Savani, B. N. Shaw, B. E. Abraham, A. A. Ahmed, I. A. Akpek, G. Atsuta, Y. Baker, K. S. Basak, G. W. Bitan, M. DeFilipp, Z. Gregory, T. K. Greinix, H. T. Hamadani, M. Hamilton, B. K. Hayashi, R. J. Jacobsohn, D. A. Kamble, R. T. Kasow, K. A. Khera, N. Lazarus, H. M. Malone, A. K. Lupo-Stanghellini, M. T. Margossian, S. P. Muffly, L. S. Norkin, M. Ramanathan, M. Salooja, N. Schoemans, H. Wingard, J. R. Wirk, B. Wood, W. A. Yong, A. Duncan, C. N. Flowers, M. E. D. Majhail, N. S. TI Secondary solid cancer screening following hematopoietic cell transplantation SO BONE MARROW TRANSPLANTATION LA English DT Review ID BONE-MARROW-TRANSPLANTATION; LONG-TERM SURVIVORS; INCREASED RISK; TESTICULAR CANCER; BREAST-CANCER; ENDOMETRIAL CARCINOMA; MALIGNANT NEOPLASMS; CHILDHOOD-CANCER; HPV VACCINATION; CERVICAL-CANCER AB Hematopoietic stem cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers, particularly beyond 5 years after HCT and without reaching a plateau overtime. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to facilitate implementation of cancer screening appropriate to HCT recipients. The working group reviewed guidelines and methods for cancer screening applicable to the general population and reviewed the incidence and risk factors for secondary cancers after HCT. A consensus approach was used to establish recommendations for individual secondary cancers. The most common sites include oral cavity, skin, breast and thyroid. Risks of cancers are increased after HCT compared with the general population in skin, thyroid, oral cavity, esophagus, liver, nervous system, bone and connective tissues. Myeloablative TBI, young age at HCT, chronic GVHD and prolonged immunosuppressive treatment beyond 24 months were well-documented risk factors for many types of secondary cancers. All HCT recipients should be advised of the risks of secondary cancers annually and encouraged to undergo recommended screening based on their predisposition. Here we propose guidelines to help clinicians in providing screening and preventive care for secondary cancers among HCT recipients. C1 [Inamoto, Y.] Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo, Japan. [Shah, N. N.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Savani, B. N.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Shaw, B. E.; Hamadani, M.] Med Coll Wisconsin, Dept Med, CIBMTR, Milwaukee, WI 53226 USA. [Abraham, A. A.; Jacobsohn, D. A.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Div Blood & Marrow Transplantat, Washington, DC 20010 USA. [Ahmed, I. A.] Childrens Mercy Hosp & Clin, Dept Hematol Oncol & Bone Marrow Transplantat, Kansas City, MO USA. [Akpek, G.] Banner MD Anderson Canc Ctr, Sect Hematol Oncol, Gilbert, AZ USA. [Atsuta, Y.] Japanese Data Ctr Hematopoiet Cell Transplantat, Nagoya, Aichi, Japan. [Atsuta, Y.] Nagoya Univ, Grad Sch Med, Nagoya, Aichi 4648601, Japan. [Baker, K. S.; Flowers, M. E. D.] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98104 USA. [Basak, G. W.] Med Univ Warsaw, Dept Hematol Oncol & Internal Dis, Warsaw, Poland. [Bitan, M.] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Pediat Hematol Oncol, IL-69978 Tel Aviv, Israel. [DeFilipp, Z.] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Gregory, T. K.] Presbyterian St Lukes Med Ctr, Colorado Blood Canc Inst, Denver, CO USA. [Greinix, H. T.] Med Univ Vienna, Dept Internal Med 1, Bone Marrow Transplantat Unit, Vienna, Austria. [Hamilton, B. K.; Majhail, N. S.] Cleveland Clin, Taussig Canc Inst, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA. [Hayashi, R. J.] Washington Univ, Sch Med, Dept Pediat, Div Pediat Hematol Oncol, St Louis, MO 63110 USA. [Kamble, R. T.] Baylor Coll Med, Div Hematol & Oncol, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Kasow, K. A.] Univ N Carolina, Dept Pediat, Div Hematol Oncol, Chapel Hill, NC USA. [Khera, N.] Mayo Clin, Dept Hematol Oncol, Phoenix, AZ USA. [Lazarus, H. M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Malone, A. K.] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Lupo-Stanghellini, M. T.] IRCCS San Raffaele Sci Inst, Unit Hematol & Bone Marrow Transplantat, Milan, Italy. [Margossian, S. P.; Duncan, C. N.] Boston Childrens Hosp, Dept Pediat Oncol, Boston, MA USA. [Margossian, S. P.; Duncan, C. N.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Muffly, L. S.] Stanford Univ, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Norkin, M.; Wingard, J. R.] Univ Florida, Dept Med, Div Hematol & Oncol, Gainesville, FL USA. [Ramanathan, M.] Univ Massachusetts, Mem Med Ctr, Dept Med, Div Hematol & Oncol, Worcester, MA USA. [Salooja, N.] Univ London Imperial Coll Sci Technol & Med, London, England. [Schoemans, H.] Univ Hosp Leuven, Leuven, Belgium. [Wirk, B.] SUNY Stony Brook, Med Ctr, Dept Internal Med, Stony Brook, NY 11794 USA. [Wood, W. A.] Univ N Carolina, Dept Med, Div Hematol Oncol, Chapel Hill, NC USA. [Yong, A.] SA Pathol, Royal Adelaide Hosp, Adelaide, SA, Australia. [Yong, A.] Univ Adelaide, Sch Med, Adelaide, SA, Australia. RP Majhail, NS (reprint author), Cleveland Clin, Taussig Canc Inst, Blood & Marrow Transplant Program, 9500 Euclid Ave,R35, Cleveland, OH 44195 USA. EM majhain@ccf.org FU NCI NIH HHS [U24 CA076518, U24-CA76518]; NHLBI NIH HHS [U01 HL069294, 5U01HL069294]; PHS HHS [HHSH234200637015C] NR 85 TC 11 Z9 11 U1 1 U2 6 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 2015 VL 50 IS 8 BP 1013 EP 1023 DI 10.1038/bmt.2015.63 PG 11 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CR2MM UT WOS:000361164200001 PM 25822223 ER PT J AU Heitzeneder, S Zeitlhofer, P Potschger, U Nowak, E Seidel, MG Holzl, M Lawitschka, A Forster-Waldl, E Matthes-Martin, S Heja, D Haas, OA Heitger, A AF Heitzeneder, S. Zeitlhofer, P. Poetschger, U. Nowak, E. Seidel, M. G. Hoelzl, M. Lawitschka, A. Foerster-Waldl, E. Matthes-Martin, S. Heja, D. Haas, O. A. Heitger, A. TI Mannan-binding lectin deficiency attenuates acute GvHD in pediatric hematopoietic stem cell transplantation SO BONE MARROW TRANSPLANTATION LA English DT Letter C1 [Heitzeneder, S.; Poetschger, U.; Hoelzl, M.; Heja, D.; Haas, O. A.; Heitger, A.] St Anna Childrens Hosp, Childrens Canc Res Inst, Transplantat Immunol, A-1090 Vienna, Austria. [Zeitlhofer, P.; Haas, O. A.] Medgen At GmbH, Vienna, Austria. [Nowak, E.; Seidel, M. G.; Lawitschka, A.; Foerster-Waldl, E.; Matthes-Martin, S.; Haas, O. A.; Heitger, A.] Med Univ Vienna, St Anna Kinderspital, Vienna, Austria. [Foerster-Waldl, E.] Med Univ Vienna, Dept Pediat, Vienna, Austria. RP Heitzeneder, S (reprint author), NCI, Pediat Oncol Branch, Bldg 10 CRC,R 1W-3840,10 Ctr Dr, Bethesda, MD 20892 USA. EM sabine.heitzeneder@nih.gov NR 11 TC 0 Z9 0 U1 0 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 2015 VL 50 IS 8 BP 1127 EP 1129 DI 10.1038/bmt.2015.81 PG 3 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CR2MM UT WOS:000361164200017 PM 25961768 ER PT J AU Le, RQ Tian, X Jain, NA Lu, K Ito, S Draper, DA Anandi, P Hourigan, CS Dunavin, N Barrett, AJ Battiwalla, M AF Le, R. Q. Tian, X. Jain, N. A. Lu, K. Ito, S. Draper, D. A. Anandi, P. Hourigan, C. S. Dunavin, N. Barrett, A. John Battiwalla, M. TI Clinical comorbidity predictive measures in ex vivo T-cell-depleted allogeneic hematopoietic stem cell transplantation SO BONE MARROW TRANSPLANTATION LA English DT Letter ID EBMT RISK SCORE; ACUTE-LEUKEMIA; SURVIVAL; INDEX C1 [Le, R. Q.; Jain, N. A.; Lu, K.; Ito, S.; Draper, D. A.; Anandi, P.; Hourigan, C. S.; Dunavin, N.; Barrett, A. John; Battiwalla, M.] NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Tian, X.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Le, RQ (reprint author), NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM minoo.battiwalla@nih.gov RI Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU Intramural NIH HHS NR 13 TC 3 Z9 3 U1 0 U2 2 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 2015 VL 50 IS 8 BP 1138 EP 1140 DI 10.1038/bmt.2015.112 PG 3 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CR2MM UT WOS:000361164200021 PM 25985051 ER PT J AU Moon, YW Rao, G Kim, JJ Shim, HS Park, KS An, SS Kim, B Steeg, PS Sarfaraz, S Lee, LC Voeller, D Choi, EY Luo, J Palmieri, D Chung, HC Kim, JH Wang, Y Giaccone, G AF Moon, Y. W. Rao, G. Kim, J. J. Shim, H-S Park, K-S An, S. S. Kim, B. Steeg, P. S. Sarfaraz, S. Lee, L. Changwoo Voeller, Donna Choi, E. Y. Luo, Ji Palmieri, D. Chung, H. C. Kim, J-H Wang, Y. Giaccone, G. TI LAMC2 enhances the metastatic potential of lung adenocarcinoma SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID SQUAMOUS-CELL CARCINOMA; LAMININ GAMMA-2 CHAIN; TO-MESENCHYMAL TRANSITION; IMMUNOHISTOCHEMICAL ANALYSIS; THERAPEUTIC TARGET; GENE-EXPRESSION; POOR-PROGNOSIS; BREAST-CANCER; BETA-CATENIN; TUMOR-CELLS AB Lung cancer is the number one cancer killer, and metastasis is the main cause of high mortality in lung cancer patients. However, mechanisms underlying the development of lung cancer metastasis remain unknown. Using genome-wide transcriptional analysis in an experimental metastasis model, we identified laminin gamma 2 (LAMC2), an epithelial basement membrane protein, to be significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 increased traction force, migration, and invasion of lung adenocarcinoma cells accompanied by the induction of epithelial-mesenchymal transition (EMT). LAMC2 knockdown decreased traction force, migration, and invasion accompanied by EMT reduction in vitro, and attenuated metastasis in mice. LAMC2 promoted migration and invasion via EMT that was integrin beta 1- and ZEB1-dependent. High LAMC2 was significantly correlated with the mesenchymal marker vimentin expression in lung adenocarcinomas, and with higher risk of recurrence or death in patients with lung adenocarcinoma. We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via EMT and may be a potential therapeutic target. C1 [Moon, Y. W.; Park, K-S; Sarfaraz, S.; Lee, L. Changwoo; Voeller, Donna; Luo, Ji; Wang, Y.; Giaccone, G.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Moon, Y. W.; Chung, H. C.; Kim, J-H] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Div Med Oncol, Seoul, South Korea. [Rao, G.; Park, K-S; Wang, Y.; Giaccone, G.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Kim, J. J.] Johns Hopkins Univ, Dept Bioengn, Baltimore, MD USA. [Shim, H-S] Yonsei Univ, Coll Med, Dept Pathol, Seoul, South Korea. [An, S. S.; Choi, E. Y.] Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Kim, B.] NCI, Pathol Branch, NIH, Bethesda, MD 20892 USA. [Steeg, P. S.; Palmieri, D.] NCI, Womens Cancers Sect, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, Y (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, 3970 Reservoir Rd NW, Washington, DC 20057 USA. EM yw350@georgetown.edu; gg496@georgetown.edu RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU NIH; NIH [P30 CA51008, P50CA103175, U54CA141868, HL107361] FX We thank Dr. Jhingook Kim for providing the GSE8894 data, Dr. Miyazaki for pBOS-CITE-Neo-gamma 2 vector, Dr. Lynn Young for help with expression array data analysis, Yongzhen Qian for help with intracardiac injection, and Dr. Joon-Yong Chung for help with IHC. This study was supported by NIH intramural program and by NIH P30 CA51008 grant. SS An was funded by the NIH P50CA103175, U54CA141868 and HL107361 grants. NR 54 TC 10 Z9 10 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD AUG PY 2015 VL 22 IS 8 BP 1341 EP 1352 DI 10.1038/cdd.2014.228 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CM3QX UT WOS:000357599500011 PM 25591736 ER PT J AU Mascola, JR Ahmed, R AF Mascola, John R. Ahmed, Rafi TI Vaccines: Vaccines for cancer and infectious diseases SO CURRENT OPINION IN IMMUNOLOGY LA English DT Editorial Material C1 [Mascola, John R.] NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. RP Mascola, JR (reprint author), NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. EM jmascola@mail.nih.gov; rahmed@emory.edu NR 2 TC 0 Z9 0 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 2015 VL 35 BP V EP VII DI 10.1016/j.coi.2015.07.009 PG 3 WC Immunology SC Immunology GA CR1HB UT WOS:000361074400001 PM 26275318 ER PT J AU Graham, BS Modjarrad, K McLellan, JS AF Graham, Barney S. Modjarrad, Kayvon McLellan, Jason S. TI Novel antigens for RSV vaccines SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID RESPIRATORY SYNCYTIAL VIRUS; SMALL HYDROPHOBIC PROTEIN; FORMALIN-INACTIVATED RSV; FUSION GLYCOPROTEIN; SUBUNIT VACCINE; F-PROTEIN; NEUTRALIZING ANTIBODY; ENHANCED DISEASE; MONOCLONAL-ANTIBODY; STRUCTURAL BASIS AB Respiratory syncytial virus (RSV) remains a leading global cause of infant mortality and adult morbidity. Infection, which recurs throughout life, elicits only short-lived immunity. The development of a safe and efficacious vaccine has, thus far, been elusive. Recent technological advances, however, have yielded promising RSV vaccine candidates that are based on solving atomic-level structures of surface glycoproteins interacting with neutralizing antibodies. The class I fusion glycoprotein, F, serves as the primary antigenic component of most vaccines, and is the target of the only licensed monoclonal antibody product used to reduce the frequency of severe disease in high-risk neonates. However, success of prior F-based vaccines has been limited by the lack of understanding how the conformational rearrangement between a metastable prefusion F (pre-F) and a stable postfusion F (post-F) affected the epitope content. Neutralizing epitopes reside on both conformations, but those specific to pre-F are far more potent than those previously identified and present on post-F. The solution of the pre-F structure and its subsequent characterization and stabilization illustrates the value of a structure-based approach to vaccine development, and provides hope that a safe and effective RSV vaccine is possible. C1 [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Modjarrad, Kayvon] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Modjarrad, Kayvon] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [McLellan, Jason S.] Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH 03755 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bgraham@nih.gov FU intramural program of the National Institute of Allergy and Infectious Diseases; NIAID [1R43AI112124] FX B.S.G. and K.M. were supported by funding from the intramural program of the National Institute of Allergy and Infectious Diseases. J.S.M. was supported in part by NIAID grant 1R43AI112124. NR 63 TC 13 Z9 15 U1 9 U2 13 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 2015 VL 35 BP 30 EP 38 DI 10.1016/j.coi.2015.04.005 PG 9 WC Immunology SC Immunology GA CR1HB UT WOS:000361074400007 PM 26070108 ER PT J AU Zhou, Y Sullivan, NJ AF Zhou, Yan Sullivan, Nancy J. TI Immunology and evolvement of the adenovirus prime, MVA boost Ebola virus vaccine SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID PROTECTS NONHUMAN-PRIMATES; I CLINICAL-TRIAL; INFECTION; CHALLENGE; IMMUNITY; DISEASE; ANTIGEN; SAFE; GP AB The 2014 Ebola virus outbreak caused an order of magnitude more deaths in a single outbreak than all previous known outbreaks combined, affecting both local and international public health, and threatening the security and economic stability of the countries in West Africa directly confronting the outbreak. The severity of the epidemic lead to a global response to assist with patient care, outbreak control, and deployment of vaccines. The latter was possible due to the long history of basic and clinical research aimed at identifying a safe and effective vaccine to protect against Ebola virus infection. This review highlights the immunology, development, and progress of vaccines based on replication-defective adenovirus vectors, culminating in the successful launch of the first Phase Ill trial of an Ebola virus vaccine. C1 [Zhou, Yan; Sullivan, Nancy J.] NIAID, Biodef Res Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20814 USA. RP Sullivan, NJ (reprint author), NIAID, Biodef Res Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20814 USA. EM nsullivan@nih.gov FU Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health FX The authors thank Dr. Julie Ledgerwood for critical reading of the manuscript and Ms. Brenda Hartman for graphics. This work was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health. NJS declares intellectual property on adenovirus-based Ebola vaccines. NR 34 TC 3 Z9 3 U1 1 U2 11 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 2015 VL 35 BP 131 EP 136 DI 10.1016/j.coi.2015.06.006 PG 6 WC Immunology SC Immunology GA CR1HB UT WOS:000361074400019 PM 26247875 ER PT J AU Jinnah, HA Teller, JK Galpern, WR AF Jinnah, Hyder A. Teller, Jan K. Galpern, Wendy R. TI Recent developments in dystonia SO CURRENT OPINION IN NEUROLOGY LA English DT Review ID PRIMARY TORSION DYSTONIA; GENOTYPE-PHENOTYPE CORRELATIONS; ATAXIA-TELANGIECTASIA; CERVICAL DYSTONIA; BOTULINUM NEUROTOXIN; MOVEMENT-DISORDERS; SPORADIC DYSTONIA; GNAL MUTATIONS; GENE; NEUROLOGY AB Purpose of review The dystonias are a family of related disorders with many different clinical manifestations and causes. This review summarizes recent developments regarding these disorders, focusing mainly on advances with direct clinical relevance from the past 2 years. Recent findings The dystonias are generally defined by their clinical characteristics, rather than by their underlying genetic or neuropathological defects. The many varied clinical manifestations and causes contribute to the fact that they are one of the most poorly recognized of all movement disorders. A series of recent publications has addressed these issues, offering a revised definition and more logical means for classifying the many subtypes. Our understanding of the genetic and neurobiological mechanisms responsible for different types of dystonias also has grown rapidly, creating new opportunities and challenges for diagnosis, and identifying increasing numbers of rare subtypes for which specific treatments are available. Recent advances in describing the clinical phenotypes and determining associated causes have pointed to the need for new strategies for diagnosis, classification, and treatment of the dystonias. C1 [Jinnah, Hyder A.] Emory Univ, Dept Neurol Human Genet & Pediat, Atlanta, GA 30322 USA. [Teller, Jan K.] Dystonia Med Res Fdn, Chicago, IL USA. [Galpern, Wendy R.] NINDS, NIH, Bethesda, MD 20892 USA. RP Jinnah, HA (reprint author), Emory Univ, Dept Neurol, 6300 Woodruff Mem Res Bldg, Atlanta, GA 30322 USA. EM hjinnah@emory.edu FU National Institutes of Health [NS 065701]; Benign Essential Blepharospasm Research Foundation; Cure Dystonia Now; Dystonia Medical Research Foundation FX The authors' work is supported in part by the National Institutes of Health (NS 065701), the Benign Essential Blepharospasm Research Foundation, Cure Dystonia Now, and the Dystonia Medical Research Foundation. NR 49 TC 4 Z9 4 U1 3 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1350-7540 EI 1473-6551 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD AUG PY 2015 VL 28 IS 4 BP 400 EP 405 DI 10.1097/WCO.0000000000000213 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CQ9BF UT WOS:000360905000015 PM 26110799 ER PT J AU Gretebeck, LM Subbarao, K AF Gretebeck, Lisa M. Subbarao, Kanta TI Animal models for SARS and MERS coronaviruses SO CURRENT OPINION IN VIROLOGY LA English DT Article ID ACUTE-RESPIRATORY-SYNDROME; GOLDEN-SYRIAN-HAMSTERS; ANGIOTENSIN-CONVERTING ENZYME-2; DIPEPTIDYL PEPTIDASE 4; MIDDLE-EAST; FUNCTIONAL RECEPTOR; BALB/C MICE; IMMUNE-RESPONSES; RHESUS MACAQUES; LUNG PATHOLOGY AB The emergence of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus (MERS-CoV), two strains of animal coronaviruses that crossed the species barrier to infect and cause severe respiratory infections in humans within the last 12 years, have taught us that coronaviruses represent a global threat that does not recognize international borders. We can expect to see other novel coronaviruses emerge in the future. An ideal animal model should reflect the clinical signs, viral replication and pathology seen in humans. In this review, we present factors to consider in establishing an animal model for the study of novel coronaviruses and compare the different animal models that have been employed to study SARS-CoV and MERS-CoV. C1 [Gretebeck, Lisa M.; Subbarao, Kanta] NIAID, Natl Inst Hlth, Infect Dis Lab, Bethesda, MD 20892 USA. RP Subbarao, K (reprint author), NIAID, Natl Inst Hlth, Infect Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); NIH; Pfizer Inc.; Doris Duke Charitable Foundation; Newport Foundation; American Association for Dental Research; Howard Hughes Medical Institute; Colgate-Palmolive Company FX The authors' research is supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). LMGs research is made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Newport Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/workieducation-training-0/medical-research-scholars-prog ram. NR 66 TC 7 Z9 8 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD AUG PY 2015 VL 13 BP 123 EP 129 DI 10.1016/j.coviro.2015.06.009 PG 7 WC Virology SC Virology GA CR1HA UT WOS:000361074300021 PM 26184451 ER PT J AU Verhein, KC McCaw, Z Gladwell, W Trivedi, S Bushel, PR Kleeberger, SR AF Verhein, Kirsten C. McCaw, Zachary Gladwell, Wesley Trivedi, Shweta Bushel, Pierre R. Kleeberger, Steven R. TI Novel Roles for Notch3 and Notch4 Receptors in Gene Expression and Susceptibility to Ozone-Induced Lung Inflammation in Mice SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID TUMOR-NECROSIS-FACTOR; GAMMA-SECRETASE INHIBITOR; KAPPA-B ACTIVATION; PULMONARY INFLAMMATION; AIRWAY HYPERRESPONSIVENESS; MOUSE LUNG; EOSINOPHILS; RESPONSES; EXPOSURE; CELLS AB BACKGROUND: Ozone is a highly toxic air pollutant and global health concern. Mechanisms of genetic susceptibility to ozone-induced lung inflammation are not completely understood. We hypothesized that Notch3 and Notch4 are important determinants of susceptibility to ozone-induced lung inflammation. METHODS: Wild-type (WT), Notch3 (Notch3(-/-)), and Notch4 (Notch4(-/-)) knockout mice were exposed to ozone (0.3 ppm) or filtered air for 6-72 hr. RESULTS: Relative to air-exposed controls, ozone increased bronchoalveolar lavage fluid (BALF) protein, a marker of lung permeability, in all genotypes, but significantly greater concentrations were found in Notch4(-/-) compared with WT and Notch3(-/-) mice. Significantly greater mean numbers of BALF neutrophils were found in Notch3(-/-) and Notch4(-/-) mice compared with WT mice after ozone exposure. Expression of whole lung Tnf was significantly increased after ozone in Notch3(-/-) and Notch4(-/-) mice, and was significantly greater in Notch3(-/-) compared with WT mice. Statistical analyses of the transcriptome identified differentially expressed gene networks between WT and knockout mice basally and after ozone, and included Trim30, a member of the inflammasome pathway, and Traf6, an inflammatory signaling member. CONCLUSIONS: These novel findings are consistent with Notch3 and Notch4 as susceptibility genes for ozone-induced lung injury, and suggest that Notch receptors protect against innate immune inflammation. C1 [Verhein, Kirsten C.; McCaw, Zachary; Gladwell, Wesley; Kleeberger, Steven R.] NIEHS, Lab Resp Biol, NIH, Dept Hlth & Human Resources DHHS, Res Triangle Pk, NC 27709 USA. [Trivedi, Shweta] N Carolina State Univ, Dept Anim Sci, Raleigh, NC 27695 USA. [Bushel, Pierre R.] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Verhein, KC (reprint author), NIEHS, Lab Resp Biol, 111 TW Alexander Dr,Bldg 101,MD D-201, Res Triangle Pk, NC 27709 USA. EM kirsten.verhein@nih.gov FU Intramural Research Program of NIEHS, NIH, DHHS FX Research was supported by the Intramural Research Program of NIEHS, NIH, DHHS. NR 41 TC 3 Z9 3 U1 0 U2 3 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 2015 VL 123 IS 8 BP 799 EP 805 DI 10.1289/ehp.1408852 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CQ6CX UT WOS:000360693100022 PM 25658374 ER PT J AU Carlin, DJ Larson, TC Pfau, JC Gavett, SH Shukla, A Miller, A Hines, R AF Carlin, Danielle J. Larson, Theodore C. Pfau, Jean C. Gavett, Stephen H. Shukla, Arti Miller, Aubrey Hines, Ronald TI Current Research and Opportunities to Address Environmental Asbestos Exposures SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID LIBBY AMPHIBOLE EXPOSURE; ANTINUCLEAR AUTOANTIBODIES; MALIGNANT MESOTHELIOMA; CARDIOVASCULAR-DISEASE; FIBROBLAST PHENOTYPE; RADIOGRAPHIC CHANGES; RESPIRATORY-DISEASE; FISCHER-344 RATS; IRON OVERLOAD; C57BL/6 MICE AB Asbestos-related diseases continue to result in approximately 120,000 deaths every year in the United States and worldwide. Although extensive research has been conducted on health effects of occupational exposures to asbestos, many issues related to environmental asbestos exposures remain unresolved. For example, environmental asbestos exposures associated with a former mine in Libby, Montana, have resulted in high rates of nonoccupational asbestos-related disease. Additionally, other areas with naturally occurring asbestos deposits near communities in the United States and overseas are undergoing investigations to assess exposures and potential health risks. Some of the latest public health, epidemiological, and basic research findings were presented at a workshop on asbestos at the 2014 annual meeting of the Society of Toxicology in Phoenix, Arizona. The following focus areas were discussed: a) mechanisms resulting in fibrosis and/or tumor development; b) relative toxicity of different forms of asbestos and other hazardous elongated mineral particles (EMPs); c) proper dose metrics (e.g., mass, fiber number, or surface area of fibers) when interpreting asbestos toxicity; d) asbestos exposure to susceptible populations; and e) using toxicological findings for risk assessment and remediation efforts. The workshop also featured asbestos research supported by the National Institute of Environmental Health Sciences, the Agency for Toxic Substances and Disease Registry, and the U.S. Environmental Protection Agency. Better protection of individuals from asbestos-related health effects will require stimulation of new multidisciplinary research to further our understanding of what constitutes hazardous exposures and risk factors associated with toxicity of asbestos and other hazardous EMPs (e.g., nanomaterials). C1 [Carlin, Danielle J.] NIEHS, Div Extramural Res & Training, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Larson, Theodore C.] ATSDR, Div Toxicol & Human Hlth Sci, Atlanta, GA USA. [Pfau, Jean C.] Idaho State Univ, Dept Biol Sci, Pocatello, ID 83209 USA. [Gavett, Stephen H.; Hines, Ronald] US EPA, Environm Publ Hlth Div, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Shukla, Arti] Univ Vermont, Coll Med, Dept Pathol & Lab Med, Burlington, VT USA. [Miller, Aubrey] NIEHS, Off Director, NIH, DHHS, Bethesda, MD USA. RP Carlin, DJ (reprint author), NIEHS, Div Extramural Res & Training, NIH, 530 Davis Dr,Rm 3102, Morrisville, NC 27560 USA. EM danielle.carlin@nih.gov FU NIEHS NIH HHS [R01 ES021110]; NIGMS NIH HHS [P20 GM103408] NR 57 TC 3 Z9 3 U1 5 U2 24 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 2015 VL 123 IS 8 BP A194 EP A197 DI 10.1289/ehp.1409662 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CQ6CX UT WOS:000360693100001 PM 26230287 ER PT J AU Shevtsov, A Ramanculov, E Shevtsova, E Kairzhanova, A Tarlykov, P Filipenko, M Dymova, M Abisheva, G Jailbekova, A Kamalova, D Chsherbakov, A Tulegenov, S Akhmetova, A Sytnik, I Karibaev, T Mukanov, K AF Shevtsov, Alexandr Ramanculov, Erlan Shevtsova, Elena Kairzhanova, Alma Tarlykov, Pavel Filipenko, Maxim Dymova, Maya Abisheva, Gulzada Jailbekova, Aygul Kamalova, Dinara Chsherbakov, Andrei Tulegenov, Samat Akhmetova, Assel Sytnik, Igor Karibaev, Talgat Mukanov, Kasim TI Genetic diversity of Brucella abortus and Brucella melitensis in Kazakhstan using MLVA-16 SO INFECTION GENETICS AND EVOLUTION LA English DT Article DE Multi-locus variable number tandem repeat analysis (MLVA); Brucella melitensis; Brucella abortus; Genotyping; Kazakhstan ID MULTIPLEX PCR; ASSAY; STRAINS; IDENTIFICATION; DISEASE; LOCI; SPP. AB Brucellosis is an endemic disease in Central Asia characterized by high infection rates in humans and animals. Currently, little is known about the genetic diversity of Brucella spp. circulating in the region, despite the high prevalence of brucellosis. This study aimed to analyze the genetic diversity of Brucella melitensis and Brucella abortus strains circulating in the Republic of Kazakhstan. We genotyped 128 B. melitensis and 124 B. abortus strains collected in regions with the highest prevalence of brucellosis. Genotyping was performed using multi-locus variable-number tandem-repeat analysis (MLVA). Analysis of a subset of 8 loci (MLVA-8) of 128 B. melitensis strains identified genotypes 42 (n = 108), 43 (n = 2), and 63 (n = 19) related to the 'East Mediterranean' group. An MLVA-16 assay sorted 128 B. melitensis strains into 25 different genotypes. Excluding one variable locus, MLVA-15 of B. melitensis was distinct from strains originating in the Mediterranean region; however, 77% of them were identical to strains isolated in China. A minimum spanning tree for B. melitensis using MLVA-15 analysis clustered the local strains together with strains previously collected in China. MLVA-8 analysis of 124 B. abortus strains identified them as genotype 36, suggesting Eurasian distribution of this lineage. Complete MLVA-16 assay analysis clustered the strains into five genotypes, revealing little diversity of B. abortus when compared on the global scale. A minimum spanning tree for B. abortus obtained using MLVA-15 analysis clustered the 2 most prevalent genotypes (n = 117) together with strains previously collected in China. Thus, MLVA analysis was used to characterize 252 strains of Brucella collected in Kazakhstan. The analysis revealed genetic homogeneity among the strains. Interestingly, identical MLVA-15 profiles were found in seemingly unrelated outbreaks in China, Turkey, and Kazakhstan. Further analysis is needed for better understanding of the epidemiology of brucellosis in Asia. (C) 2015 Elsevier B.V. All rights reserved. C1 [Shevtsov, Alexandr; Ramanculov, Erlan; Shevtsova, Elena; Kairzhanova, Alma; Tarlykov, Pavel; Filipenko, Maxim; Abisheva, Gulzada; Kamalova, Dinara; Mukanov, Kasim] Natl Biotechnol Ctr, Astana 010000, Kazakhstan. [Ramanculov, Erlan] Nazarbayev Univ, Sch Sci & Technol, Astana 010000, Kazakhstan. [Filipenko, Maxim; Dymova, Maya] Inst Chem Biol & Fundamental Med, Novosibirsk 630000, Russia. [Filipenko, Maxim; Dymova, Maya] Novosibirsk State Univ, Novosibirsk 630090, Russia. [Jailbekova, Aygul; Chsherbakov, Andrei; Tulegenov, Samat; Akhmetova, Assel; Sytnik, Igor; Karibaev, Talgat] Natl Reference Ctr Vet, Astana 010000, Kazakhstan. RP Shevtsov, A (reprint author), Natl Biotechnol Ctr, 13-1 Valikhanov Str, Astana 010000, Kazakhstan. EM ncbshevtsov@gmail.com; ramanculov@biocenter.kz; pavel.tarlykov@gmail.com; mlfilipenko@gmail.com; gu.nzmr@mail.ru; mukanov@biocenter.kz OI Shevtsov, Alexandr/0000-0002-7576-2750; Dymova, Maya/0000-0002-7281-9096; Tarlykov, Pavel/0000-0003-2075-307X FU Ministry of Education and Science of the Republic of Kazakhstan [N0113RK00302] FX This work was supported by funding received from the Ministry of Education and Science of the Republic of Kazakhstan, Grant No. N0113RK00302. We would like to thank Gilles Vergnaud for assistance with the data deposition into MLVA bank. We are thankful to all personnel of the National Reference Center for Veterinary who isolated the bacterial strains. NR 41 TC 3 Z9 3 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-1348 EI 1567-7257 J9 INFECT GENET EVOL JI Infect. Genet. Evol. PD AUG PY 2015 VL 34 BP 173 EP 180 DI 10.1016/j.meegid.2015.07.008 PG 8 WC Infectious Diseases SC Infectious Diseases GA CQ9AJ UT WOS:000360902400022 PM 26160544 ER PT J AU Prasad, V Kim, C Burotto, M Vandross, A AF Prasad, Vinay Kim, Chul Burotto, Mauricio Vandross, Andrae TI The Strength of Association Between Surrogate End Points and Survival in Oncology A Systematic Review of Trial-Level Meta-analyses SO JAMA INTERNAL MEDICINE LA English DT Review ID PROGRESSION-FREE SURVIVAL; METASTATIC BREAST-CANCER; CELL LUNG-CANCER; RANDOMIZED CONTROLLED-TRIALS; INDIVIDUAL PATIENT DATA; DISEASE-FREE SURVIVAL; ARRHYTHMIA SUPPRESSION TRIAL; ADVANCED COLORECTAL-CANCER; CLINICAL-TRIALS; POTENTIAL SURROGATE AB IMPORTANCE The strength of association between surrogate end points and survival in oncology is important to understand because surrogate end points are frequently used in oncology clinical trials, supporting US Food and Drug Administration approvals and National Comprehensive Cancer Network guideline recommendations. OBJECTIVE To identify and evaluate trial-levelmeta-analyses of randomized clinical trials quantifying the association between a surrogate end point and overall survival in medical oncology. Trial-level correlations test whether treatments that improve the surrogate end point also improve the final end point and are widely considered the strongest evidence to validate a surrogate end point. EVIDENCE REVIEW Our literature search was built on earlier reported data sets and updated with Google Scholar and MEDLINE searches conducted on December 26, 2014. For MEDLINE, search terms included ("regression" or "correlation") and "surrogate" and "end point [or endpoint]" and ("oncology" or "cancer"). For Google scholar, search terms included ("regression" or "correlation") and "surrogate end point [or endpoint]" and "overall survival" and "trial level." A total of 108 abstracts were retrieved, and 62 articles were read in full in addition to articles identified through prior reviews. FINDINGS We found 36 articles in which 65 specific correlations between a surrogate end point and survival were identified. Surrogate end points were studied in the neoadjuvant, adjuvant, locally advanced, and metastatic settings. The most common sources for trials included in the 36 articles were systematic reviews of the published literature (10 of 36; 28%), and published literature and meeting abstracts (14 of 36; 39%). Four meta-analyses (11%) used a convenience sample, and only 5 studies (14%) attempted to include unpublished trials by surveying clinical trial registries. Among these 5 studies, only 352 of 684 eligible trials (51.1%) were included in the analyses. More than half of reported correlations (34 of 65; 52%) were of low strength (r <= 0.7). Approximately a quarter (16 of 65; 25%) were of medium strength (r > 0.7 tor < 0.85), and 15 of 65 (23%) were highly correlated (r >= 0.85) with survival. CONCLUSIONS AND RELEVANCE Most trial-level validation studies of surrogate end points in oncology find low correlations with survival. All validation studies use only a subset of available trials. The evidence supporting the use of surrogate end points in oncology is limited. C1 [Prasad, Vinay; Kim, Chul; Burotto, Mauricio] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Vandross, Andrae] Univ Calif Los Angeles, Div Med Oncol, Los Angeles, CA USA. RP Prasad, V (reprint author), NCI, NIH, 10 Ctr Dr,10-12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov OI Prasad, Vinay/0000-0002-6110-8221 NR 102 TC 26 Z9 27 U1 1 U2 12 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 2015 VL 175 IS 8 BP 1389 EP 1398 DI 10.1001/jamainternmed.2015.2829 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CR1BL UT WOS:000361057700029 PM 26098871 ER PT J AU Blackstock, OJ Frew, P Bota, D Vo-Green, L Parker, K Franks, J Hodder, SL Justman, J Golin, CE Haley, DF Kuo, I Adimora, AA Rompalo, A Soto-Torres, L Wang, J Mannheimer, SB AF Blackstock, Oni J. Frew, Paula Bota, Dorothy Vo-Green, Linda Parker, Kim Franks, Julie Hodder, Sally L. Justman, Jessica Golin, Carol E. Haley, Danielle F. Kuo, Irene Adimora, Adaora A. Rompalo, Anne Soto-Torres, Lydia Wang, Jing Mannheimer, Sharon B. TI Perceptions of Community HIV/STI Risk Among U.S Women Living in Areas with High Poverty and HIV Prevalence Rates SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE HIV; sexually transmitted infections; risk perception; women; community ID AFRICAN-AMERICAN WOMEN; CONSPIRACY BELIEFS; PERCEIVED RISK; UNITED-STATES; PREEXPOSURE PROPHYLAXIS; HIV/AIDS PREVALENCE; SEXUAL RISK; AIDS RISK; PREVENTION; INFECTION AB Although studies have consistently demonstrated that women at high risk for HIV and non-HIV sexually transmitted infections (STIs) tend to underestimate their individual risk, little is known about how women at risk perceive their community's HIV/STI risk. We explored perceptions of community HIV/STI risk among U.S. women living in areas with high poverty and HIV prevalence rates as part of a qualitative substudy of the Women's HIV SeroIncidence Study. Semi-structured focus groups were conducted. Data were coded and analyzed using the constant comparative method. Participants expressed the perception that their communities were at elevated HIV/STI risk, mostly due to contextual and structural factors such as lack of access to health care and education. Findings suggest that HIV prevention messages that target U.S. women at high risk for HIV may be strengthened by addressing the high perceived community HIV/STI risk driven by structural factors. C1 [Blackstock, Oni J.] Albert Einstein Coll Med, Dept Med, Montefiore Med Ctr, Bronx, NY 10467 USA. [Frew, Paula; Bota, Dorothy; Vo-Green, Linda; Haley, Danielle F.] Rollins Sch Publ Health, Dept Med, Emory Sch Med, Atlanta, GA 30307 USA. [Parker, Kim] Texas Womans Univ, Dept Hlth Studies, Denton, TX USA. [Franks, Julie; Justman, Jessica] Columbia Univ, ICAP, New York, NY 10027 USA. [Golin, Carol E.] Univ N Carolina, Dept Med, Chapel Hill, NC 27515 USA. [Golin, Carol E.] Univ N Carolina, Dept Hlth Behav & Hlth Educ, Chapel Hill, NC 27515 USA. [Wang, Jing] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA USA. [Mannheimer, Sharon B.] Columbia Univ, ICAP, Mailman Sch Publ Hlth, New York, NY 10027 USA. [Mannheimer, Sharon B.] Columbia Univ, Dept Med, Harlem Hosp Ctr, New York, NY 10027 USA. [Hodder, Sally L.] Rutgers New Jersey Med School, Dept Med, Newark, NJ USA. [Kuo, Irene] George Washington Univ, Dept Epidemiol & Biostat, Milken Inst Sch Publ Hlth & Hlth Services, Washington, DC 20052 USA. [Adimora, Adaora A.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27515 USA. [Rompalo, Anne] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Soto-Torres, Lydia] NAID, Div Acquired Immunodeficiency Syndrome, NIH, Phoenix, AZ USA. RP Blackstock, OJ (reprint author), Albert Einstein Coll Med, Div Gen Internal Med, Dept Med, Montefiore Med Ctr, Bronx, NY 10467 USA. EM oblackst@montefiore.org FU Centers for Innovative Research to Control AIDS, Mailman School of Public Health, Columbia University [5U1Al069466]; University of North Carolina Clinical Trials Unit [AI069423]; University of North Carolina Clinical Trials Research Center of the Clinical and Translational Science Award [RR 025747]; University of North Carolina Center for AIDS Research [AI050410]; Emory University HIV/AIDS Clinical Trials Unit [5UO1AI069418]; Center for AIDS Research [P30 AI050409]; Clinical and Translational Science Award [UL1 RR025008]; Terry Beirn Community Programs for Clinical Research on AIDS Clinical Trials Unit [5 UM1 AI069503-07]; Johns Hopkins Adult AIDS Clinical Trial Unit [AI069465]; Johns Hopkins Clinical and Translational Science Award [UL1 RR 25005]; HPTN Scholars Program - National Institute of Allergy and Infectious Disease; National Institute of Mental Health [K23MH103129, UM1 AI068619, UM 1AI068617, UM1-AI068613]; National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse FX The views expressed herein are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health, the National Institutes of Health, the HPTN, or its funders. The authors thank the study participants, community stakeholders, and staff from each study site. In particular, they acknowledge Lynda Emel, Jonathan Lucas, Nirupama Sista, Kathy Hinson, Elizabeth DiNenno, Ann O'Leary, Lisa Diane White, Waheedah Shabaaz-El, Quarraisha Abdool-Karim, and Sten Vermund, LeTanya Johnson-Lewis, James Peterson, Shelita Merchant, Tracy Hunt, Stephanie Lykes, Charlene Wylie, Adongo Tia-Okwee, Sharon Parker, Genda Dockery, Margarita Velasco, and Lorenna Rodriguez. Funding for this study was provided by the National Institute of Allergy and Infectious Diseases, National Institute on Drug Abuse, and National Institute of Mental Health (cooperative agreement no. UM1 AI068619, UM 1AI068617, and UM1-AI068613); Centers for Innovative Research to Control AIDS, Mailman School of Public Health, Columbia University (5U1Al069466); University of North Carolina Clinical Trials Unit (AI069423); University of North Carolina Clinical Trials Research Center of the Clinical and Translational Science Award (RR 025747); University of North Carolina Center for AIDS Research (AI050410); Emory University HIV/AIDS Clinical Trials Unit (5UO1AI069418), Center for AIDS Research (P30 AI050409), and Clinical and Translational Science Award (UL1 RR025008); The Terry Beirn Community Programs for Clinical Research on AIDS Clinical Trials Unit(5 UM1 AI069503-07) and; The Johns Hopkins Adult AIDS Clinical Trial Unit (AI069465) and The Johns Hopkins Clinical and Translational Science Award (UL1 RR 25005). The primary author's work on this manuscript was supported through the HPTN Scholars Program funded by the National Institute of Allergy and Infectious Disease and grant K23MH103129 from the National Institute of Mental Health. NR 38 TC 2 Z9 2 U1 3 U2 8 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD AUG PY 2015 VL 26 IS 3 BP 811 EP 823 PG 13 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CQ9EP UT WOS:000360915400020 PM 26320916 ER PT J AU Persoskie, A Leyva, B AF Persoskie, Alexander Leyva, Bryan TI Blacks Smoke Less (and More) than Whites: Simpson's Paradox in US Smoking Rates, 2008 to 2012 SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Editorial Material DE Smoking rates; race; education; SES; disparity; Simpson's Paradox; reversal of association ID DISPARITIES; EPIDEMIOLOGY; VARIABLES; HEALTH AB In what is known as Simpson's Paradox, a statistical association present within different groups becomes reversed when the groups are aggregated. Because race is confounded with socioeconomic status (SES) in the U.S., the overall smoking rate among Blacks may exceed that among Whites, even while the reverse is true within SES strata (or when adjusting for SES). Indeed, in the most recent five iterations of the Behavioral Risk Factor Surveillance System (2008-2012), a nationwide dataset, unadjusted models found that non-Hispanic Blacks were more likely than non-Hispanic Whites to report current smoking (e.g., in 2012: OR=1.14, p<.0001). However, Blacks were less likely than Whites to report smoking across all five years when models adjusted for income (e.g., in 2012: OR=0.85, p<.0001) and in 2008-2010 when models adjusted for education. This reversal of association reflects racial disparities in SES, which cause Black Americans to be disproportionately affected by smoking risk factors associated with low income and education. C1 [Persoskie, Alexander; Leyva, Bryan] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Persoskie, A (reprint author), Bldg 75,Off 4472,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM alexander.persoskie@fda.hhs.gov NR 21 TC 3 Z9 3 U1 0 U2 1 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD AUG PY 2015 VL 26 IS 3 BP 951 EP 956 DI 10.1353/hpu.2015.0085 PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CQ9EP UT WOS:000360915400029 PM 26320925 ER PT J AU Fedorova, OV Emelianov, IV Bagrov, KA Grigorova, YN Wei, W Juhasz, O Frolova, EV Marshall, CA Lakatta, EG Konradi, AO Bagrov, AY AF Fedorova, Olga V. Emelianov, Igor V. Bagrov, Konstantin A. Grigorova, Yulia N. Wei, Wen Juhasz, Ondrej Frolova, Elena V. Marshall, Courtney A. Lakatta, Edward G. Konradi, Alexandra O. Bagrov, Alexei Y. TI Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists SO JOURNAL OF HYPERTENSION LA English DT Article ID ENDOGENOUS CARDIOTONIC STEROIDS; CHRONIC-RENAL-FAILURE; BLOOD-PRESSURE; MONOCLONAL-ANTIBODY; ARTERIAL STIFFNESS; UREMIC PATIENTS; NA+/K+-ATPASE; CANRENONE; HYPERTENSION; ALDOSTERONE AB Objective: Endogenous cardiotonic steroids, including marinobufagenin (MBG), stimulate vascular synthesis of collagen. Because mineralocorticoid antagonists competitively antagonize effect of cardiotonic steroids on the Na/K-ATPase, we hypothesized that spironolactone would reverse the profibrotic effects of MBG. Methods: Experiment 1: Explants of thoracic aortae and aortic vascular smooth muscle cells from Wistar rats were cultured for 24 h in the presence of vehicle or MBG (100 nmol/l) with or without canrenone (10 mu mol/l), an active metabolite of spironolactone. Experiment 2: In 16 patients (56 +/- 2 years) with resistant hypertension on a combined (lisinopril/amlodipine/hydrochlorothiazide) therapy, we determined arterial pressure, pulse wave velocity, plasma MBG, and erythrocyte Na/K-ATPase before and 6 months after addition of placebo (n = 8) or spironolactone (50 mg/day; n = 8) to the therapy. Results: In rat aortic explants and in vascular smooth muscle cells, pretreatment with MBG resulted in a two-fold rise in collagen-1, and a marked reduction in the sensitivity of the aortic rings to the vasorelaxant effect of sodium nitroprusside following endothelin-1-induced constriction (EC50 = 480 +/- 67 vs. 23 +/- 3 nmol/l in vehicle-treated rings; P < 0.01). Canrenone blocked effects of MBG on collagen synthesis and restored sensitivity of vascular rings to sodium nitroprusside (EC50 = 17 +/- 1 nmol/l). Resistant hypertension patients exhibited elevated plasma MBG (0.42 +/- 0.07 vs. 0.24 +/- 0.03 nmol/l; P = 0.01) and reduced Na/K-ATPase activity (1.9 +/- 0.15 vs. 2.8 +/- 0.2 mu mol Pi/ml per h, P < 0.01) vs. seven healthy individuals. Six-month administration of spironolactone, unlike placebo treatment, was associated with a decrease in pulse wave velocity and arterial pressure, and with restoration of Na/K-ATPase activity in the presence of unchanged MBG levels. Conclusion: MBG-induced vascular fibrosis is a likely target for spironolactone. C1 [Fedorova, Olga V.; Grigorova, Yulia N.; Wei, Wen; Juhasz, Ondrej; Marshall, Courtney A.; Lakatta, Edward G.; Bagrov, Alexei Y.] NIA, NIH, Baltimore, MD 21224 USA. [Emelianov, Igor V.; Bagrov, Konstantin A.; Grigorova, Yulia N.; Konradi, Alexandra O.] Almazov Fed Heart Blood & Endocrinol Ctr, Inst Heart & Vessels, St Petersburg, Russia. [Bagrov, Konstantin A.] Technion Israel Inst Technol, Dept Biotechnol, Haifa, Israel. [Frolova, Elena V.] Russian Acad Sci, Sechenov Inst Evolutionary Physiol & Biochem, St Petersburg 196140, Russia. RP Bagrov, AY (reprint author), NIA, Lab Cardiovasc Sci, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM BagrovA@mail.nih.gov OI Konradi, Alexandra/0000-0001-8169-7812 FU National Institute on Aging, National Institutes of Health; Ministry of Science and Education of Russian Federation [14.740.11.0928] FX Source of funding: Supported by Intramural Research Program, National Institute on Aging, National Institutes of Health (O.V.F., O.J., W.W., C.A.M., E.G.L., A.Y.B.), and by a grant from Ministry of Science and Education of Russian Federation Nr. 14.740.11.0928 (I.V.E., Y.N.G., A.O.K.). NR 34 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD AUG PY 2015 VL 33 IS 8 BP 1602 EP 1610 DI 10.1097/HJH.0000000000000591 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CQ8JN UT WOS:000360853900018 PM 26136067 ER PT J AU Hyde, RK Zhao, L Alemu, L Liu, PP AF Hyde, R. K. Zhao, L. Alemu, L. Liu, P. P. TI Runx1 is required for hematopoietic defects and leukemogenesis in Cbfb-MYH11 knock-in mice SO LEUKEMIA LA English DT Article ID ACUTE MYELOID-LEUKEMIA; CBF-BETA-SMMHC; BINDING-FACTOR-BETA; MYOSIN HEAVY-CHAIN; ACUTE MYELOMONOCYTIC LEUKEMIA; FETAL LIVER HEMATOPOIESIS; TRANSCRIPTION FACTOR; GENE CBFB-MYH11; FUSION PROTEIN; IDENTIFICATION AB CBF beta-SMMHC (core-binding factor beta-smooth muscle myosin heavy chain), the fusion protein generated by the chromosome 16 inversion fusion gene, CBFB-MYH11, is known to initiate leukemogenesis. However, the mechanism through which CBF beta-SMMHC contributes to leukemia development is not well understood. Previously, it was proposed that CBF beta-SMMHC acts by dominantly repressing the transcription factor RUNX1 (Runt-related protein 1), but we recently showed that CBF beta-SMMHC has activities that are independent of RUNX1 repression. In addition, we showed that a modified CBF beta-SMMHC with decreased RUNX1-binding activity accelerates leukemogenesis. These results raise questions about the importance of RUNX1 in leukemogenesis by CBF beta-SMMHC. To test this, we generated mice expressing Cbfb-MYH11 in a Runx1-deficient background, resulting from either homozygous Runx1-null alleles (Runx1(-/-)) or a single dominant-negative Runx1 allele (Runx1(+/lz)). We found that loss of Runx1 activity rescued the differentiation defects induced by Cbfb-MYH11 during primitive hematopoiesis. During definitive hematopoiesis, RUNX1 loss also significantly reduced the proliferation and differentiation defects induced by Cbfb-MYH11. Importantly, Cbfb-MYH11-induced leukemia had much longer latency in Runx1(+/lz) mice than in Runx1-sufficient mice. These data indicate that Runx1 activity is critical for Cbfb-MYH11-induced hematopoietic defects and leukemogenesis. C1 [Hyde, R. K.; Zhao, L.; Alemu, L.; Liu, P. P.] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. RP Hyde, RK (reprint author), Univ Nebraska Med Ctr, Nebraska Med Ctr 985870, Dept Biochem & Mol Biol, Durham Res Bldg 1,Room 7008, Omaha, NE 68198 USA. EM kate.hyde@unmc.edu; pliu@mail.nih.gov FU Intramural Research Program of National Human Genome Research Institute, National Institutes of Health; National Institutes of Health [R00CA148963] FX This work was supported by the Intramural Research Program of National Human Genome Research Institute, National Institutes of Health and National Institutes of Health Grant R00CA148963 (RKH). NR 33 TC 5 Z9 5 U1 0 U2 0 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 2015 VL 29 IS 8 BP 1771 EP 1778 DI 10.1038/leu.2015.58 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA CQ9LU UT WOS:000360937200017 PM 25742748 ER PT J AU Maggio, M de Vita, F Lauretani, F Bandinelli, S Semba, RD Bartali, B Cherubini, A Cappola, AR Ceda, GP Ferrucci, L AF Maggio, Marcello de Vita, Francesca Lauretani, Fulvio Bandinelli, Stefania Semba, Richard D. Bartali, Benedetta Cherubini, Antonio Cappola, Anne R. Ceda, Gian Paolo Ferrucci, Luigi TI Relationship between Carotenoids, Retinol, and Estradiol Levels in Older Women SO NUTRIENTS LA English DT Article ID BREAST-CANCER CELLS; BETA-CAROTENE; IN-VITRO; PLASMA CAROTENOIDS; ALPHA-TOCOPHEROL; VITAMIN-A; ESTROGEN; RISK; EXPRESSION; LYCOPENE AB Background. In vitro evidence suggests anti-estrogenic properties for retinol and carotenoids, supporting a chemo-preventive role of these phytochemicals in estrogen-dependent cancers. During aging there are significant reductions in retinol and carotenoid concentrations, whereas estradiol levels decline during menopause and progressively increase from the age of 65. We aimed to investigate the hypothesis of a potential relationship between circulating levels of retinol, carotenoids, and estradiol (E2) in a cohort of late post-menopausal women. Methods. We examined 512 women >= 65 years from the InCHIANTI study. Retinol, alpha-caroten, beta-caroten, beta-criptoxantin, lutein, zeaxanthin, and lycopene levels were assayed at enrollment (1998-2000) by High-Performance Liquid Chromatography. Estradiol and testosterone (T) levels were assessed by Radioimmunometry (RIA) and testosterone-to-estradiol ratio (T/E2), as a proxy of aromatase activity, was also calculated. General linear models adjusted for age (Model 1) and further adjusted for other confounders including Body Mass Index (BMI) BMI, smoking, intake of energy, lipids, and vitamin A; C-Reactive Protein, insulin, total cholesterol, liver function, and testosterone (Model 2) were used to investigate the relationship between retinol, carotenoids, and E2 levels. To address the independent relationship between carotenoids and E2 levels, factors significantly associated with E2 in Model 2 were also included in a fully adjusted Model 3. Results. After adjustment for age, alpha-carotene (beta +/- SE = -0.01 +/- 0.004, p = 0.02) and beta-carotene (beta +/- SE = -0.07 +/- 0.02, p = 0.0007) were significantly and inversely associated with E2 levels. alpha-Carotene was also significantly and positively associated with T/E2 ratio (beta +/- SE = 0.07 +/- 0.03, p = 0.01). After adjustment for other confounders (Model 2), the inverse relationship between alpha-carotene (beta +/- SE = -1.59 +/- 0.61, p = 0.01), beta-carotene (beta +/- SE = -0.29 +/- 0.08, p = 0.0009), and E2 persisted whereas the relationship between alpha-carotene and T/E2 ratio was attenuated (beta +/- SE = 0.22 +/- 0.12, p = 0.07). In a fully adjusted model (Model 3), only beta-carotene (beta +/- SE = -0.05 +/- 0.02, p = 0.03) was significantly and inversely associated with E2 levels independent of alpha-carotene. No association was found between retinol, total non-pro-vitamin A carotenoids, lutein, zeaxanthin, and lycopene, and E2 levels. Conclusions: In older women, beta-carotene levels are independently and inversely associated with E2. C1 [Maggio, Marcello; de Vita, Francesca; Ceda, Gian Paolo] Univ Parma, Dept Clin & Expt Med, I-43126 Parma, Italy. [Maggio, Marcello; Lauretani, Fulvio; Ceda, Gian Paolo] Univ Hosp Parma, Geriatr Rehabil Dept, I-43126 Parma, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, I-50100 Florence, Italy. [Semba, Richard D.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21225 USA. [Bartali, Benedetta] New England Res Inst, Watertown, MA 02472 USA. [Cherubini, Antonio] IRCCS INRCA, Geriatr, I-60127 Ancona, Italy. [Cappola, Anne R.] Univ Penn, Perelman Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Ferrucci, Luigi] NIA, NIH, Harbor Hosp, Baltimore, MD 21225 USA. RP de Vita, F (reprint author), Univ Parma, Dept Clin & Expt Med, Via Gramsci 14, I-43126 Parma, Italy. EM marcellomaggio2001@yahoo.it; francy_devita@hotmail.it; flauretani@ao.pr.it; stefania.bandinelli@asf.toscana.it; rdsemba@jhmi.edu; bbartali@neriscience.com; A.CHERUBINI@inrca.it; acappola@mail.med.upenn.edu; gpceda@unipr.it; ferruccilu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295; Cherubini, Antonio/0000-0003-0261-9897 FU Italian Ministry of Health [ICS 110.1/RS97.71]; US National Institute on Aging [N01-AG-916413, N01-AG-821336, AG-020727]; Intramural Research Program of the US National Institute on Aging [263 MD 9164 13, 263 MD 821336] FX The InCHIANTI Study was supported as a "targeted project" (ICS 110.1/RS97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (Contracts N01-AG-916413 and N01-AG-821336 and AG-020727), and by the Intramural Research Program of the US National Institute on Aging (Contracts 263 MD 9164 13 and 263 MD 821336). None of the sponsoring institutions interfered with the collection, analysis, presentation, or interpretation of the data reported here. NR 34 TC 0 Z9 0 U1 1 U2 10 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD AUG PY 2015 VL 7 IS 8 BP 6506 EP 6519 DI 10.3390/nu7085296 PG 14 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CQ4PQ UT WOS:000360587500027 PM 26251919 ER PT J AU Tsuji, PA Carlson, BA Anderson, CB Seifried, HE Hatfield, DL Howard, MT AF Tsuji, Petra A. Carlson, Bradley A. Anderson, Christine B. Seifried, Harold E. Hatfield, Dolph L. Howard, Michael T. TI Dietary Selenium Levels Affect Selenoprotein Expression and Support the Interferon-gamma and IL-6 Immune Response Pathways in Mice SO NUTRIENTS LA English DT Article ID SELENOCYSTEINE TRANSFER-RNA; GENE-EXPRESSION; PHYSIOLOGICAL ROLES; UGA CODONS; DISEASE; DEFICIENCY; MUSCLE; SUPPLEMENTATION; METHYLATION; MACROPHAGES AB Selenium is an essential element that is required to support a number of cellular functions and biochemical pathways. The objective of this study was to examine the effects of reduced dietary selenium levels on gene expression to assess changes in expression of non-selenoprotein genes that may contribute to the physiological consequences of selenium deficiency. Mice were fed diets that were either deficient in selenium or supplemented with selenium in the form of sodium selenite for six weeks. Differences in liver mRNA expression and translation were measured using a combination of ribosome profiling, RNA-Seq, microarrays, and qPCR. Expression levels and translation of mRNAs encoding stress-related selenoproteins were shown to be up-regulated by increased selenium status, as were genes involved in inflammation and response to interferon-gamma. Changes in serum cytokine levels were measured which confirmed that interferon-gamma, as well as IL-6, were increased in selenium adequate mice. Finally, microarray and qPCR analysis of lung tissue demonstrated that the selenium effects on immune function are not limited to liver. These data are consistent with previous reports indicating that adequate selenium levels can support beneficial immune responses, and further identify the IL-6 and interferon-gamma pathways as being responsive to dietary selenium intake. C1 [Tsuji, Petra A.] Towson Univ, Dept Biol Sci, Towson, MD 21252 USA. [Carlson, Bradley A.; Hatfield, Dolph L.] NIH, Mol Biol Selenium Sect, Mouse Canc Genet Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Anderson, Christine B.; Howard, Michael T.] Univ Utah, Human Genet, Salt Lake City, UT 84112 USA. [Seifried, Harold E.] NCI, Nutr Sci Res Grp, Rockville, MD 20892 USA. RP Howard, MT (reprint author), Univ Utah, Human Genet, Salt Lake City, UT 84112 USA. EM ptsuji@towson.edu; carlsonb@mail.nih.gov; anderson@genetics.utah.edu; seifrieh@mail.nih.gov; hatfield@mail.nih.gov; mhoward@genetics.utah.edu FU NIH [NS083884, GM1142391]; National Institutes of Health; National Cancer Institute, Center for Cancer Research; Fisher Endowed Chair funds FX The authors would like to acknowledge Brian Dalley (University of Utah, High Throughput Genomics Core, Salt Lake City, UT, USA for his technical support and assistance with deep-sequencing of ribosome profiling and RNA-Seq samples. We would also like to thank Liang Cao and Yunkai Yu (National Institutes of Health) for assistance with the cytokine analysis. This work was funded by NIH grants NS083884 and GM1142391 (Michael T. Howard), the Intramural Research Program of the National Institutes of Health (Dolph L. Hatfield, Bradley A. Carlson), National Cancer Institute, Center for Cancer Research to Dolph L. Hatfield, as well as Fisher Endowed Chair funds (Petra A. Tsuji). NR 57 TC 8 Z9 8 U1 3 U2 12 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD AUG PY 2015 VL 7 IS 8 BP 6529 EP 6549 DI 10.3390/nu7085297 PG 21 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CQ4PQ UT WOS:000360587500029 PM 26258789 ER PT J AU Flaherty, KT Hamilton, BK Rosen, MA Amaravadi, RK Schuchter, LM Gallagher, M Chen, H Sehgal, C O'Dwyer, PJ AF Flaherty, Keith T. Hamilton, Betty K. Rosen, Mark A. Amaravadi, Ravi K. Schuchter, Lynn M. Gallagher, Maryann Chen, Helen Sehgal, Chandra O'Dwyer, Peter J. TI Phase I/II Trial of Imatinib and Bevacizumab in Patients With Advanced Melanoma and Other Advanced Cancers SO ONCOLOGIST LA English DT Article DE Melanoma; Bevacizumab; Imatinib; Vascular endothelial growth factor; Platelet-derived growth factor ID ENDOTHELIAL-GROWTH-FACTOR; RENAL-CELL CARCINOMA; PROGRESSION-FREE SURVIVAL; ANTI-VEGF TREATMENT; II CLINICAL-TRIALS; MALIGNANT-MELANOMA; TYROSINE KINASE; IN-VIVO; METASTATIC MELANOMA; TUMOR ANGIOGENESIS AB Background. Vascular endothelial growth factor and platelet-derived growth factor signaling in the tumor microenvironment appear to cooperate in promoting tumor angiogenesis. Patients and Methods. We conducted a phase I trial combining bevacizumab (i.v. every 2 weeks) and imatinib (oral daily). Once a recommended phase II dose combination was established, a phase II trial was initiated in patients with metastatic melanoma. A Simon 2-stage design was used with 23 patients required in the first stage and 41 patients in total should the criteria to proceed be met. We required that 50% of the patients be progression-free at 16 weeks. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and power Doppler ultrasonography were performed in patients with metastatic tumors amenable to imaging with these methods at baseline and after 4 weeks. Results. A total of 17 patients were accrued to 4 dose and combination levels. Bevacizumab 10 mg/kg every 2 weeks could be safely combined with imatinib 800 mg daily. Common toxicities included fatigue, nausea, vomiting, edema, proteinuria, and anemia, but were not commonly severe. A total of 23 patients with metastatic melanoma (48% with American Joint Commission on Cancer stage M1c; median age, 63 years) were enrolled in the first stage of phase II. The 16-week progression-free survival rate was 35%, leading to termination of phase II after the first stage. In the small subset of patients who remained on study with lesions evaluable by DCE-MRI, significant decreases in tumor vascular permeability were noted, despite early disease progression using the Response Evaluation Criteria In Solid Tumors. Conclusion. Bevacizumab and imatinib can be safely combined at the maximum doses used for each agent. We did not observe significant clinical activity with this regimen in melanoma patients. C1 [Flaherty, Keith T.; Hamilton, Betty K.; Rosen, Mark A.; Amaravadi, Ravi K.; Schuchter, Lynn M.; Gallagher, Maryann; Sehgal, Chandra; O'Dwyer, Peter J.] Univ Penn, Abramson Canc Ctr, Dev Therapeut Program, Philadelphia, PA 19104 USA. [Chen, Helen] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Flaherty, KT (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM kflaherty@partners.org FU NIH (Bethesda, MD) [K23 CA104884-02] FX This study was supported by Grant K23 CA104884-02 from the NIH (Bethesda, MD). NR 53 TC 7 Z9 7 U1 0 U2 6 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD AUG PY 2015 VL 20 IS 8 BP 952 EP 959 DI 10.1634/theoncologist.2015-0108 PG 8 WC Oncology SC Oncology GA CQ9YR UT WOS:000360973500020 PM 26084808 ER PT J AU McWhirter, KK Morrow, AS Lee, BA Bishu, S Zametkin, AJ Balkin, TJ Smith, CB Picchioni, D AF McWhirter, Kelly K. Morrow, Anne S. Lee, Beth A. Bishu, Shrinivas Zametkin, Alan J. Balkin, Thomas J. Smith, Carolyn B. Picchioni, Dante TI A PILOT STUDY ON THE ENCODING OF A PERCEPTUAL LEARNING TASK FOLLOWING SLEEP DEPRIVATION SO PERCEPTUAL AND MOTOR SKILLS LA English DT Article ID DISCRIMINATION; MEMORY; DETERIORATION; IMPROVEMENT; PLASTICITY; BENEFITS AB Memory encoding sometimes must occur during a period of sleep deprivation. The question was whether one night of sleep deprivation inhibits encoding on a perceptual learning task (the texture discrimination task). The sample was 18 human participants (M age = 22.1 yr., SEM = 0.5; 8 men). The participants were randomized to a sleep deprivation or sleep control condition and, after the manipulation, were given two administrations of the texture discrimination task. All participants were given an opportunity for a 90 min. nap between the two administrations. Performance was measured by the interpolated stimulus-to-mask-onset asynchrony (i.e., the inter-stimulus interval), at which the percentage of correct responses for the stimuli in the participant's peripheral vision fell below 80%. Offline consolidation was defined as a decrease in this index between the two administrations. Participants who were sleep deprived prior to encoding exhibited similar offline consolidation (M = -5.3 msec., SEM = 2.3) compared to participants who were not sleep deprived prior to encoding (M = -6.2 msec., SEM = 3.9); the two-way interaction between time and condition was not significant. In light of reports in the literature, these results indicate encoding following sleep deprivation may be influenced by both the type of task encoded and the brain regions involved in memory processing. C1 [McWhirter, Kelly K.; Balkin, Thomas J.; Picchioni, Dante] Walter Reed Army Inst Res, Silver Spring, MD USA. [Morrow, Anne S.; Lee, Beth A.; Bishu, Shrinivas; Zametkin, Alan J.; Smith, Carolyn B.] NIH, Bethesda, MD 20892 USA. RP Picchioni, D (reprint author), NIH, Intramural Res Program, 10 Ctr Dr, Bethesda, MD 20892 USA. EM dante.picchioni@nih.gov FU National Institute of Mental Health Intramural Research Program; U.S. Army Medical Research and Materiel Command FX This research was supported by the National Institute of Mental Health Intramural Research Program and the U.S. Army Medical Research and Materiel Command. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Army nor the U.S. Government. The ClinicalTrials.gov Identifier is NCT00884702, and the National Institutes of Health Institutional Review Board Protocol Number is 09-M-0123. NR 25 TC 0 Z9 0 U1 1 U2 5 PU AMMONS SCIENTIFIC, LTD PI MISSOULA PA PO BOX 9229, MISSOULA, MT 59807-9229 USA SN 0031-5125 J9 PERCEPT MOTOR SKILL JI Percept. Mot. Skills PD AUG PY 2015 VL 121 IS 1 BP 80 EP 93 DI 10.2466/23.PMS.121c11x9 PG 14 WC Psychology, Experimental SC Psychology GA CQ9PH UT WOS:000360946600006 PM 26226287 ER PT J AU Ponce-Alvarez, A He, BYJ Hagmann, P Deco, G AF Ponce-Alvarez, Adrian He, Biyu J. Hagmann, Patric Deco, Gustavo TI Task-Driven Activity Reduces the Cortical Activity Space of the Brain: Experiment and Whole-Brain Modeling SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PRIMARY VISUAL-CORTEX; FUNCTIONAL CONNECTIVITY; WORKING-MEMORY; VARIABILITY; ARCHITECTURE; NETWORKS; DYNAMICS; SIGNAL; SPIKING; FLUCTUATIONS AB How a stimulus or a task alters the spontaneous dynamics of the brain remains a fundamental open question in neuroscience. One of the most robust hallmarks of task/stimulus-driven brain dynamics is the decrease of variability with respect to the spontaneous level, an effect seen across multiple experimental conditions and in brain signals observed at different spatiotemporal scales. Recently, it was observed that the trial-to-trial variability and temporal variance of functional magnetic resonance imaging (fMRI) signals decrease in the task-driven activity. Here we examined the dynamics of a large-scale model of the human cortex to provide a mechanistic understanding of these observations. The model allows computing the statistics of synaptic activity in the spontaneous condition and in putative tasks determined by external inputs to a given subset of brain regions. We demonstrated that external inputs decrease the variance, increase the covariances, and decrease the autocovariance of synaptic activity as a consequence of single node and large-scale network dynamics. Altogether, these changes in network statistics imply a reduction of entropy, meaning that the spontaneous synaptic activity outlines a larger multidimensional activity space than does the task-driven activity. We tested this model's prediction on fMRI signals from healthy humans acquired during rest and task conditions and found a significant decrease of entropy in the stimulus-driven activity. Altogether, our study proposes a mechanism for increasing the information capacity of brain networks by enlarging the volume of possible activity configurations at rest and reliably settling into a confined stimulus-driven state to allow better transmission of stimulus-related information. C1 [Ponce-Alvarez, Adrian; Deco, Gustavo] Univ Pompeu Fabra, Dept Informat & Commun Technol, Computat Neurosci Grp, Ctr Brain & Cognit, Barcelona, Spain. [He, Biyu J.] NINDS, NIH, Bethesda, MD 20892 USA. [Hagmann, Patric] Univ Lausanne Hosp, Dept Radiol, Lausanne, Switzerland. [Hagmann, Patric] Univ Lausanne CHUV UNIL, Lausanne, Switzerland. [Hagmann, Patric] Ecole Polytech Fed Lausanne, Signal Proc Lab 5, Lausanne, Switzerland. [Deco, Gustavo] Univ Pompeu Fabra, Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain. RP Ponce-Alvarez, A (reprint author), Univ Pompeu Fabra, Dept Informat & Commun Technol, Computat Neurosci Grp, Ctr Brain & Cognit, Barcelona, Spain. EM adrian.ponce@upf.edu RI Deco, Gustavo/A-6341-2008; OI Deco, Gustavo/0000-0002-8995-7583; He, Biyu/0000-0003-1549-1351 FU SEMAINE ERA-Net NEURON Project; ERC Advanced Grant: DYSTRUCTURE [295129]; FP7-ICT BrainScales; Leenaards Foundation; Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke FX APA was supported by SEMAINE ERA-Net NEURON Project. GD was supported by the ERC Advanced Grant: DYSTRUCTURE (n. 295129), and the FP7-ICT BrainScales. PH was supported by Leenaards Foundation. BJH was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 3 Z9 3 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD AUG PY 2015 VL 11 IS 8 AR e1004445 DI 10.1371/journal.pcbi.1004445 PG 26 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CQ7ZC UT WOS:000360824500043 PM 26317432 ER PT J AU Striegel, DA Hara, M Periwal, V AF Striegel, Deborah A. Hara, Manami Periwal, Vipul TI The Beta Cell in Its Cluster: Stochastic Graphs of Beta Cell Connectivity in the Islets of Langerhans SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PANCREATIC B-CELLS; INSULIN-SECRETION; GAP-JUNCTIONS; IN-VIVO; GLUCOSE; MASS; ARCHITECTURE; EXPRESSION; RELEASE; DIFFERENTIATION AB Pancreatic islets of Langerhans consist of endocrine cells, primarily alpha, beta and delta cells, which secrete glucagon, insulin, and somatostatin, respectively, to regulate plasma glucose. beta cells form irregular locally connected clusters within islets that act in concert to secrete insulin upon glucose stimulation. Due to the central functional significance of this local connectivity in the placement of beta cells in an islet, it is important to characterize it quantitatively. However, quantification of the seemingly stochastic cytoarchitecture of beta cells in an islet requires mathematical methods that can capture topological connectivity in the entire beta-cell population in an islet. Graph theory provides such a framework. Using large-scale imaging data for thousands of islets containing hundreds of thousands of cells in human organ donor pancreata, we show that quantitative graph characteristics differ between control and type 2 diabetic islets. Further insight into the processes that shape and maintain this architecture is obtained by formulating a stochastic theory of beta-cell rearrangement in whole islets, just as the normal equilibrium distribution of the Ornstein-Uhlenbeck process can be viewed as the result of the interplay between a random walk and a linear restoring force. Requiring that rearrangements maintain the observed quantitative topological graph characteristics strongly constrained possible processes. Our results suggest that beta-cell rearrangement is dependent on its connectivity in order to maintain an optimal cluster size in both normal and T2D islets. C1 [Striegel, Deborah A.; Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Hara, Manami] Univ Chicago, Dept Med, Chicago, IL 60637 USA. RP Striegel, DA (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM vipulp@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, NIDDK FX This work was supported by Intramural Research Program of the National Institutes of Health, NIDDK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 2 Z9 2 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD AUG PY 2015 VL 11 IS 8 AR e1004423 DI 10.1371/journal.pcbi.1004423 PG 29 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CQ7ZC UT WOS:000360824500034 PM 26266953 ER PT J AU Tamerius, J Viboud, C Shaman, J Chowell, G AF Tamerius, James Viboud, Cecile Shaman, Jeffrey Chowell, Gerardo TI Impact of School Cycles and Environmental Forcing on the Timing of Pandemic Influenza Activity in Mexican States, May-December 2009 SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID A H1N1 VIRUS; ABSOLUTE-HUMIDITY; A/H1N1 INFLUENZA; UNITED-STATES; TRANSMISSION; IMMUNITY; INFECTION; CLOSURE; WAVE; DYNAMICS AB While a relationship between environmental forcing and influenza transmission has been established in inter-pandemic seasons, the drivers of pandemic influenza remain debated. In particular, school effects may predominate in pandemic seasons marked by an atypical concentration of cases among children. For the 2009 A/H1N1 pandemic, Mexico is a particularly interesting case study due to its broad geographic extent encompassing temperate and tropical regions, well-documented regional variation in the occurrence of pandemic outbreaks, and coincidence of several school breaks during the pandemic period. Here we fit a series of transmission models to daily laboratory-confirmed influenza data in 32 Mexican states using MCMC approaches, considering a meta-population framework or the absence of spatial coupling between states. We use these models to explore the effect of environmental, school-related and travel factors on the generation of spatially-heterogeneous pandemic waves. We find that the spatial structure of the pandemic is best understood by the interplay between regional differences in specific humidity (explaining the occurrence of pandemic activity towards the end of the school term in late May-June 2009 in more humid southeastern states), school vacations (preventing influenza transmission during July-August in all states), and regional differences in residual susceptibility (resulting in large outbreaks in early fall 2009 in central and northern Mexico that had yet to experience fully-developed outbreaks). Our results are in line with the concept that very high levels of specific humidity, as present during summer in southeastern Mexico, favor influenza transmission, and that school cycles are a strong determinant of pandemic wave timing. C1 [Tamerius, James] Univ Iowa, Dept Geog & Sustainabil Sci, Iowa City, IA 52242 USA. [Viboud, Cecile] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Shaman, Jeffrey] Columbia Univ, Environm Hlth Sci, New York, NY USA. [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. RP Tamerius, J (reprint author), Univ Iowa, Dept Geog & Sustainabil Sci, Iowa City, IA 52242 USA. EM james-tamerius@uiowa.edu FU NIH [1U54GM088558]; NIEHS Center grant [ES009089]; RAPIDD program of the Science and Technology Directorate, US Department of Homeland Security; Fogarty International Center, NIH; Office of Global Affairs' International Influenza Unit, Office of the Secretary, US Department of Health and Human Services FX Funding was provided by the NIH Models of Infectious Disease Agent Study program through cooperative agreement 1U54GM088558 (JT, JS), as well as NIEHS Center grant ES009089 (JS), the RAPIDD program of the Science and Technology Directorate, US Department of Homeland Security (JS), and the in-house influenza research program of the Fogarty International Center, NIH, funded by the Office of Global Affairs' International Influenza Unit, Office of the Secretary, US Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 3 Z9 3 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD AUG PY 2015 VL 11 IS 8 AR e1004337 DI 10.1371/journal.pcbi.1004337 PG 17 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CQ7ZC UT WOS:000360824500012 PM 26291446 ER PT J AU Yang, PY Zheng, XF Jayaswal, V Hu, G Yang, JYH Jothi, R AF Yang, Pengyi Zheng, Xiaofeng Jayaswal, Vivek Hu, Guang Yang, Jean Yee Hwa Jothi, Raja TI Knowledge-Based Analysis for Detecting Key Signaling Events from Time-Series Phosphoproteomics Data SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID GENE-EXPRESSION DATA; SPECTROMETRY-BASED PROTEOMICS; MEANS CLUSTERING-ALGORITHM; EMBRYONIC STEM-CELLS; PROTEIN-PHOSPHORYLATION; MASS-SPECTROMETRY; QUANTITATIVE PHOSPHOPROTEOMICS; IN-VIVO; POSTTRANSLATIONAL MODIFICATIONS; NETWORK MEDICINE AB Cell signaling underlies transcription/epigenetic control of a vast majority of cell-fate decisions. A key goal in cell signaling studies is to identify the set of kinases that underlie key signaling events. In a typical phosphoproteomics study, phosphorylation sites (substrates) of active kinases are quantified proteome-wide. By analyzing the activities of phosphorylation sites over a time-course, the temporal dynamics of signaling cascades can be elucidated. Since many substrates of a given kinase have similar temporal kinetics, clustering phosphorylation sites into distinctive clusters can facilitate identification of their respective kinases. Here we present a knowledge-based CLUster Evaluation (CLUE) approach for identifying the most informative partitioning of a given temporal phosphoproteomics data. Our approach utilizes prior knowledge, annotated kinase-substrate relationships mined from literature and curated databases, to first generate biologically meaningful partitioning of the phosphorylation sites and then determine key kinases associated with each cluster. We demonstrate the utility of the proposed approach on two time-series phosphoproteomics datasets and identify key kinases associated with human embryonic stem cell differentiation and insulin signaling pathway. The proposed approach will be a valuable resource in the identification and characterizing of signaling networks from phosphoproteomics data. C1 [Yang, Pengyi; Zheng, Xiaofeng; Hu, Guang; Jothi, Raja] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, Durham, NC 27713 USA. [Yang, Pengyi; Jothi, Raja] NIEHS, Biostat Branch, NIH, Durham, NC USA. [Jayaswal, Vivek; Yang, Jean Yee Hwa] Univ Sydney, Sch Math & Stat, Ctr Math Biol, Sydney, NSW 2006, Australia. RP Yang, PY (reprint author), NIEHS, Epigenet & Stem Cell Biol Lab, NIH, Durham, NC 27713 USA. EM pengyi.yang@nih.gov; jothi@mail.nih.gov RI Yang, Pengyi/B-1002-2010; Hu, Guang/E-7474-2016 OI Yang, Pengyi/0000-0003-1098-3138; Hu, Guang/0000-0003-0437-4723 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [1ZIAES102625] FX This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (RJ: 1ZIAES102625). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 2 Z9 2 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD AUG PY 2015 VL 11 IS 8 AR e1004403 DI 10.1371/journal.pcbi.1004403 PG 18 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CQ7ZC UT WOS:000360824500025 PM 26252020 ER PT J AU Iyengar, SK Sedor, JR Freedman, BI Kao, WHL Kretzler, M Keller, BJ Abboud, HE Adler, SG Best, LG Bowden, DW Burlock, A Chen, YDI Cole, SA Comeau, ME Curtis, JM Divers, J Drechsler, C Duggirala, R Elston, RC Guo, XQ Huang, HT Hoffmann, MM Howard, BV Ipp, E Kimmel, PL Klag, MJ Knowler, WC Kohn, OF Leak, TS Leehey, DJ Li, M Malhotra, A Marz, W Nair, V Nelson, RG Nicholas, SB O'Brien, SJ Pahl, MV Parekh, RS Pezzolesi, MG Rasooly, RS Rotimi, CN Rotter, JI Schelling, JR Seldin, MF Shah, VO Smiles, AM Smith, MW Taylor, KD Thameem, F Thornley-Brown, DP Truitt, BJ Wanner, C Weil, EJ Winkler, CA Zager, PG Igo, RP Hanson, RL Langefeld, CD AF Iyengar, Sudha K. Sedor, John R. Freedman, Barry I. Kao, W. H. Linda Kretzler, Matthias Keller, Benjamin J. Abboud, Hanna E. Adler, Sharon G. Best, Lyle G. Bowden, Donald W. Burlock, Allison Chen, Yii-Der Ida Cole, Shelley A. Comeau, Mary E. Curtis, Jeffrey M. Divers, Jasmin Drechsler, Christiane Duggirala, Ravi Elston, Robert C. Guo, Xiuqing Huang, Huateng Hoffmann, Michael Marcus Howard, Barbara V. Ipp, Eli Kimmel, Paul L. Klag, Michael J. Knowler, William C. Kohn, Orly F. Leak, Tennille S. Leehey, David J. Li, Man Malhotra, Alka Maerz, Winfried Nair, Viji Nelson, Robert G. Nicholas, Susanne B. O'Brien, Stephen J. Pahl, Madeleine V. Parekh, Rulan S. Pezzolesi, Marcus G. Rasooly, Rebekah S. Rotimi, Charles N. Rotter, Jerome I. Schelling, Jeffrey R. Seldin, Michael F. Shah, Vallabh O. Smiles, Adam M. Smith, Michael W. Taylor, Kent D. Thameem, Farook Thornley-Brown, Denyse P. Truitt, Barbara J. Wanner, Christoph Weil, E. Jennifer Winkler, Cheryl A. Zager, Philip G. Igo, Robert P., Jr. Hanson, Robert L. Langefeld, Carl D. CA Family Investigat Nephropathy & D TI Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND) SO PLOS GENETICS LA English DT Article ID STAGE RENAL-DISEASE; GLOMERULAR-FILTRATION-RATE; AFRICAN-AMERICANS; PROTEIN; TYPE-1; LOCI; ALBUMINURIA; POPULATIONS; EXPRESSION; RECEPTOR AB Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10(-9)). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10(-8)), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD. C1 [Iyengar, Sudha K.; Elston, Robert C.; Truitt, Barbara J.; Igo, Robert P., Jr.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Sedor, John R.; Schelling, Jeffrey R.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Sedor, John R.] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA. [Freedman, Barry I.] Wake Forest Sch Med, Dept Internal Med, Nephrol Sect, Winston Salem, NC USA. [Kao, W. H. Linda] Johns Hopkins Univ, Dept Epidemiol & Med, Baltimore, MD USA. [Kretzler, Matthias; Keller, Benjamin J.; Leak, Tennille S.; Nair, Viji] Univ Michigan, Dept Internal Med Nephrol, Ann Arbor, MI 48109 USA. [Abboud, Hanna E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med Nephrol, San Antonio, TX USA. [Adler, Sharon G.] Harbor UCLA Med Ctr, Dept Med, Div Nephrol & Hypertens, Torrance, CA 90509 USA. [Best, Lyle G.] Missouri Breaks Ind Res, Timber Lake, SD USA. [Bowden, Donald W.] Wake Forest Sch Med, Ctr Human Gen, Dept Biochem, Winston Salem, NC USA. [Chen, Yii-Der Ida; Guo, Xiuqing; Rotter, Jerome I.; Taylor, Kent D.; Langefeld, Carl D.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Cole, Shelley A.; Duggirala, Ravi] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Comeau, Mary E.; Divers, Jasmin] Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC USA. [Comeau, Mary E.; Divers, Jasmin] Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Curtis, Jeffrey M.; Knowler, William C.; Malhotra, Alka; Nelson, Robert G.; Weil, E. Jennifer; Hanson, Robert L.] NIDDK, NIH, Phoenix, AZ USA. [Drechsler, Christiane] Univ Hosp Wurzburg, Div Renal, Wurzburg, Germany. [Drechsler, Christiane] Univ Hosp Wurzburg, Comprehens Heart Failure Ctr, Wurzburg, Germany. [Huang, Huateng] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Hoffmann, Michael Marcus] Univ Med Ctr, Dept Clin Chem, Freiburg, Germany. [Howard, Barbara V.] MedStar Hlth Res Inst, Hyattsville, MD USA. [Ipp, Eli] Harbor UCLA Med Ctr, Dept Med, Sect Diabet & Metab, Torrance, CA 90509 USA. [Kimmel, Paul L.] NIDDK, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. [Klag, Michael J.] Johns Hopkins Sch Med, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kohn, Orly F.] Univ Chicago Med, Dept Med, Chicago, IL USA. [Leehey, David J.] Loyola Sch Med, Dept Med, Maywood, IL USA. [Li, Man] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Maerz, Winfried] Heidelberg Univ, Graz, Austria. [Maerz, Winfried] Graz Univ, Synlab Acad, Graz, Austria. [Nicholas, Susanne B.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [O'Brien, Stephen J.] Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg, Russia. [O'Brien, Stephen J.] Nova SE Univ, Oceanog Ctr, Ft Lauderdale, FL 33314 USA. [Pahl, Madeleine V.] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Parekh, Rulan S.] Univ Hlth Network, Hosp Sick Children, Dept Paediat & Med, Toronto, ON, Canada. [Parekh, Rulan S.] Univ Toronto, Toronto, ON, Canada. [Pezzolesi, Marcus G.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Med, Boston, MA 02115 USA. [Rasooly, Rebekah S.] Natl Inst Diabet & Digest Dis, NIH, Bethesda, MD USA. [Rotimi, Charles N.] Ctr Res Genom & Global Hlth, Bethesda, MD USA. [Seldin, Michael F.] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Davis, CA USA. [Shah, Vallabh O.] Univ New Mexico, Dept Biochem & Mol Biol, Albuquerque, NM 87131 USA. [Smiles, Adam M.] Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA. [Smith, Michael W.] NHGRI, Rockville, MD USA. [Thameem, Farook] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Thornley-Brown, Denyse P.] Univ Alabama Birmingham, Nephrol, Birmingham, AL USA. [Wanner, Christoph] Univ Hosp Wurzburg, Div Nephrol, Dept Med, Wurzburg, Germany. [Winkler, Cheryl A.] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Zager, Philip G.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. RP Iyengar, SK (reprint author), Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. EM ski@case.edu; jrs4@case.edu; bfreedma@wakehealth.edu RI Hoffmann, Michael/D-4074-2015; Hanson, Robert/O-3238-2015; OI Hoffmann, Michael/0000-0001-8459-6080; Hanson, Robert/0000-0002-4252-7068; Rasooly, Rebekah/0000-0002-6357-5528 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, U01DK57304]; NIDDK; National Heart, Lung and Blood Institute [U01HL065520, U01HL041654, U01HL041652]; National Cancer Institute, National Institutes of Health (NIH) [N01-CO-12400]; NIH, National Cancer Institute, Center for Cancer Research; National Center for Research Resources [M01-RR-000080, M01-RR-07122, M01-RR-00425, M01-RR-00827-29, HSC M01-RR-00997, M01-RR-01346] FX This study was supported by grants U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, and U01DK57304 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and, in part, by the Intramural Research Program of the NIDDK. Support was also received from the National Heart, Lung and Blood Institute grants U01HL065520, U01HL041654, and U01HL041652. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contract N01-CO-12400 and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This work was also supported by the National Center for Research Resources for the General Clinical Research Center grants: Case Western Reserve University, M01-RR-000080; Wake Forest University, M01-RR-07122; Harbor-University of California, Los Angeles Medical Center, M01-RR-00425; College of Medicine, University of California, Irvine, M01-RR-00827-29; University of New Mexico, HSC M01-RR-00997; and Frederic C. Bartter, M01-RR-01346. Computing resources were provided, in part, by the Wake Forest School of Medicine Center for Public Health Genomics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 12 Z9 13 U1 5 U2 10 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 2015 VL 11 IS 8 AR e1005352 DI 10.1371/journal.pgen.1005352 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA CQ7YP UT WOS:000360823100004 PM 26305897 ER PT J AU Robinson, A McDonald, JP Caldas, VEA Patel, M Wood, EA Punter, CM Ghodke, H Cox, MM Woodgate, R Goodman, MF van Oijen, AM AF Robinson, Andrew McDonald, John P. Caldas, Victor E. A. Patel, Meghna Wood, Elizabeth A. Punter, Christiaan M. Ghodke, Harshad Cox, Michael M. Woodgate, Roger Goodman, Myron F. van Oijen, Antoine M. TI Regulation of Mutagenic DNA Polymerase V Activation in Space and Time SO PLOS GENETICS LA English DT Article ID ESCHERICHIA-COLI; RECA PROTEIN; REPLICATION MACHINERY; GENETIC REQUIREMENTS; CYCLOBUTANE DIMER; SOS MUTAGENESIS; IMAGE-ANALYSIS; POL V; UMUD; REPLISOME AB Spatial regulation is often encountered as a component of multi-tiered regulatory systems in eukaryotes, where processes are readily segregated by organelle boundaries. Well-characterized examples of spatial regulation are less common in bacteria. Low-fidelity DNA polymerase V (UmuD'C-2) is produced in Escherichia coli as part of the bacterial SOS response to DNA damage. Due to the mutagenic potential of this enzyme, pol V activity is controlled by means of an elaborate regulatory system at transcriptional and posttranslational levels. Using single-molecule fluorescence microscopy to visualize UmuC inside living cells in space and time, we now show that pol V is also subject to a novel form of spatial regulation. After an initial delay (similar to 45 min) post UV irradiation, UmuC is synthesized, but is not immediately activated. Instead, it is sequestered at the inner cell membrane. The release of UmuC into the cytosol requires the RecA* nucleoprotein filament-mediated cleavage of UmuD -> UmuD'. Classic SOS damage response mutants either block [umuD(K97A)] or constitutively stimulate [recA(E38K)] UmuC release from the membrane. Foci of mutagenically active pol V Mut (UmuD'C-2-RecA-ATP) formed in the cytosol after UV irradiation do not co-localize with pol III replisomes, suggesting a capacity to promote translesion DNA synthesis at lesions skipped over by DNA polymerase III. In effect, at least three molecular mechanisms limit the amount of time that pol V has to access DNA: (1) transcriptional and posttranslational regulation that initially keep the intracellular levels of pol V to a minimum; (2) spatial regulation via transient sequestration of UmuC at the membrane, which further delays pol V activation; and (3) the hydrolytic activity of a recently discovered pol V Mut ATPase function that limits active polymerase time on the chromosomal template. C1 [Robinson, Andrew; Caldas, Victor E. A.; Punter, Christiaan M.; Ghodke, Harshad; van Oijen, Antoine M.] Univ Groningen, Ctr Synthet Biol, Zernike Inst Adv Mat, Groningen, Netherlands. [McDonald, John P.; Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. [Patel, Meghna; Goodman, Myron F.] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Patel, Meghna; Goodman, Myron F.] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. [Wood, Elizabeth A.; Cox, Michael M.] Univ Wisconsin, Dept Biochem, Madison, WI 53705 USA. RP Robinson, A (reprint author), Univ Groningen, Ctr Synthet Biol, Zernike Inst Adv Mat, Groningen, Netherlands. RI Caldas, Victor/L-4383-2013; OI Caldas, Victor/0000-0002-4263-0786; Ghodke, Harshad/0000-0002-6628-876X; Robinson, Andrew/0000-0002-3544-0976; van Oijen, Antoine/0000-0002-1794-5161 FU National Institute of Health [ES012259, GM21422, GM32335]; Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health Intramural Research Program; Netherlands Organization for Scientific Research (NWO) [Vici 680-47-607]; European Research Council (ERC Starting) [281098] FX This work was supported by National Institute of Health (http://grants.nih.gov) grants to MFG (ES012259; GM21422) and to MMC (GM32335); funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health Intramural Research Program (https://www.nichd.nih.gov/grants-funding) to RW; funds from the Netherlands Organization for Scientific Research (NWO; www.nwo.nl/en/funding; Vici 680-47-607) and the European Research Council (erc.europa.eu/funding-and-grants; ERC Starting 281098). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 8 Z9 8 U1 0 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 2015 VL 11 IS 8 AR e1005482 DI 10.1371/journal.pgen.1005482 PG 30 WC Genetics & Heredity SC Genetics & Heredity GA CQ7YP UT WOS:000360823100057 PM 26317348 ER PT J AU Tkatchenko, AV Tkatchenko, TV Guggenheim, JA Verhoeven, VJM Hysi, PG Wojciechowski, R Singh, PK Kumar, A Thinakaran, G Williams, C AF Tkatchenko, Andrei V. Tkatchenko, Tatiana V. Guggenheim, Jeremy A. Verhoeven, Virginie J. M. Hysi, Pirro G. Wojciechowski, Robert Singh, Pawan Kumar Kumar, Ashok Thinakaran, Gopal Williams, Cathy CA Consortium Refractive Error Myopia TI APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; HIGH-GRADE MYOPIA; FORM-DEPRIVATION MYOPIA; PRECURSOR PROTEIN APP; DOMINANT HIGH MYOPIA; QUALITY-OF-LIFE; SET ENRICHMENT ANALYSIS; IN-SITU HYBRIDIZATION; RECESSIVE HIGH MYOPIA; ISOLATED RAT RETINA AB Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained ("missing heritability"). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5'-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 x 10(-4)) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 x 10(-3)). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 x 10(-3)). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+ 11.5 +/- 2.2 D, p < 1.0 x 10(-4)) compared to both heterozygous (-0.8 +/- 2.0 D, p < 1.0 x 10(-4)) and wild-type (+ 0.3 +/- 2.2 D, p < 1.0 x 10(-4)) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 x 10(-4)). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 x 10(-4)) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the "missing" myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development. C1 [Tkatchenko, Andrei V.; Tkatchenko, Tatiana V.] Columbia Univ, Dept Ophthalmol, New York, NY 10027 USA. [Tkatchenko, Andrei V.] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10027 USA. [Guggenheim, Jeremy A.] Cardiff Univ, Sch Optometry & Vis Sci, Cardiff CF10 3AX, S Glam, Wales. [Verhoeven, Virginie J. M.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Verhoeven, Virginie J. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hysi, Pirro G.] Kings Coll London, Sch Med, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wojciechowski, Robert] NHGRI, Stat Genet Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Singh, Pawan Kumar; Kumar, Ashok] Wayne State Univ, Dept Ophthalmol, Detroit, MI USA. [Kumar, Ashok] Wayne State Univ, Dept Anat & Cell Biol, Detroit, MI USA. [Thinakaran, Gopal] Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA. [Thinakaran, Gopal] Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. [Thinakaran, Gopal] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Williams, Cathy] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. RP Tkatchenko, AV (reprint author), Columbia Univ, Dept Ophthalmol, New York, NY 10027 USA. EM avt2130@cumc.columbia.edu OI Wojciechowski, Robert/0000-0002-9593-4652 FU US National Institutes of Health (NIH) [R21EY018902, R01EY023839]; Midwest Eye-Banks; UK Medical Research Council; Wellcome Trust [102215/2/13/2]; University of Bristol; National Eye Research Centre, Bristol [SCIAD053]; NIHR; Hong Kong Polytechnic University [Z0GM]; NIH [R01AG019070, K08EY022943, R01EY019888]; 23andMe FX This work was supported by grants R21EY018902 and R01EY023839 from the US National Institutes of Health (NIH) and research grants from the Midwest Eye-Banks to AVT. The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC; this research was supported specifically by the National Eye Research Centre, Bristol (SCIAD053); CW is supported by an NIHR Fellowship. JAG was supported by grant Z0GM from the Hong Kong Polytechnic University. GT is supported by grant R01AG019070, RW is supported by grant K08EY022943, AK is supported by grant R01EY019888 from NIH. We thank 23andMe for funding the generation of the ALSPAC GWA data. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 146 TC 6 Z9 6 U1 1 U2 13 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 2015 VL 11 IS 8 AR e1005432 DI 10.1371/journal.pgen.1005432 PG 25 WC Genetics & Heredity SC Genetics & Heredity GA CQ7YP UT WOS:000360823100024 PM 26313004 ER PT J AU Rafati, S Kamhawi, S Valenzuela, JG Ghanei, M AF Rafati, Sima Kamhawi, Shaden Valenzuela, Jesus G. Ghanei, Mostafa TI Building Research and Development Capacity for Neglected Tropical Diseases Impacting Leishmaniasis in the Middle East and North Africa: A Case Study SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Editorial Material ID EFFICACY C1 [Rafati, Sima] Pasteur Inst Iran, Dept Immunotherapy & Leishmania Vaccine Res, Tehran, Iran. [Kamhawi, Shaden; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Ghanei, Mostafa] Pasteur Inst Iran, Director Off, Tehran, Iran. RP Rafati, S (reprint author), Pasteur Inst Iran, Dept Immunotherapy & Leishmania Vaccine Res, Tehran, Iran. EM s_rafati@yahoo.com NR 15 TC 0 Z9 1 U1 0 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 2015 VL 9 IS 8 AR e0003695 DI 10.1371/journal.pntd.0003695 PG 4 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CQ6IO UT WOS:000360708200001 PM 26313269 ER PT J AU Cho, MK Taylor, H McCormick, JB Anderson, N Barnard, D Boyle, MB Capron, AM Dorfman, E Havard, K Reider, C Sadler, J Schwartz, P Sharp, RR Danis, M Wilfond, BS AF Cho, Mildred K. Taylor, Holly McCormick, Jennifer B. Anderson, Nick Barnard, David Boyle, Mary B. Capron, Alexander M. Dorfman, Elizabeth Havard, Kathryn Reider, Carson Sadler, John Schwartz, Peter Sharp, Richard R. Danis, Marion Wilfond, Benjamin S. TI Building a Central Repository for Research Ethics Consultation Data: A Proposal for a Standard Data Collection Tool SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE ethics; FDA; biostatistics; quality improvement; consultation AB Clinical research ethics consultation services have been established across academic health centers over the past decade. This paper presents the results of collaboration within the CTSA consortium to develop a standard approach to the collection of research ethics consultation information to serve as a foundation for quality improvement, education, and research efforts. This approach includes categorizing and documenting descriptive information about the requestor, research project, the ethical question, the consult process, and describing the basic structure for a consult note. This paper also explores challenges in determining how to share some of this information between collaborating institutions related to concerns about confidentially, data quality, and informatics. While there is much still to be learned to improve the process of clinical research ethics consultation, these tools can advance these efforts, which, in turn, can facilitate the ethical conduct of research. C1 [Cho, Mildred K.] Stanford Univ, Stanford, CA 94305 USA. [Taylor, Holly] Johns Hopkins Univ, Baltimore, MD USA. [McCormick, Jennifer B.; Sharp, Richard R.] Mayo Clin, Rochester, MN USA. [Anderson, Nick] Univ Calif Davis, Davis, CA 95616 USA. [Barnard, David] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Boyle, Mary B.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Capron, Alexander M.] Univ So Calif, Los Angeles, CA USA. [Dorfman, Elizabeth; Wilfond, Benjamin S.] Univ Washington, Seattle, WA 98195 USA. [Havard, Kathryn] Univ Cincinnati, Cincinnati, OH USA. [Reider, Carson] Ohio State Univ, Columbus, OH 43210 USA. [Sadler, John] Univ Texas Dallas, Dallas, TX 75230 USA. [Schwartz, Peter] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Danis, Marion] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Wilfond, Benjamin S.] Seattle Childrens Res Inst, Seattle, WA USA. RP Wilfond, BS (reprint author), Univ Washington, Seattle, WA 98195 USA. EM benjamin.wilfond@seattlechildrens.org FU National Center for Advancing Translational Sciences of the NIH [UL1 RR025014-04S1] FX Mary Ellen Michel was a member of the working group. Ellen Kuwana provided editorial assistance. This work was supported by the National Center for Advancing Translational Sciences of the NIH to the Institute of Translational Health Sciences: UL1 RR025014-04S1 (Research Bioethics Consultation Standardization and Data Sharing). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The members of the working group were part of the following CTSAs: The Stanford Center for Clinical and Translational Research and Education (UL1 TR001085), Johns Hopkins Institute for Clinical and Translational (UL1 TR001079), Mayo Center for Translational Science Activities (UL1 TR000135), Southern California Clinical and Translational Science Institute (UL1 TR000130), Institute of Translational Health Sciences (UL1 TR000423), The Ohio State University Center for Clinical and Translational Science (UL1 TR001105), UT Southwestern Center for Translational Medicine (UL1TR001105), and Indiana Clinical and Translational Science Institute (UL TR001108). NR 8 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-8054 EI 1752-8062 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD AUG PY 2015 VL 8 IS 4 BP 376 EP 387 DI 10.1111/cts.12268 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CQ4OU UT WOS:000360585200024 PM 25758372 ER PT J AU Presnell, JS Schnitzler, CE Browne, WE AF Presnell, Jason S. Schnitzler, Christine E. Browne, William E. TI KLF/SP Transcription Factor Family Evolution: Expansion, Diversification, and Innovation in Eukaryotes SO GENOME BIOLOGY AND EVOLUTION LA English DT Article DE C2H2 zinc fingers; domain shuffling; domain architecture; domain co-occurrence network; domain evolution; low-complexity regions ID KRUPPEL-LIKE FACTOR; CTENOPHORE MNEMIOPSIS-LEIDYI; GENOME PROVIDES INSIGHTS; WELL CONSERVED FAMILIES; LOW-COMPLEXITY REGIONS; ZINC-FINGER PROTEINS; BOX-BINDING-PROTEIN; FUNCTIONAL-ANALYSIS; MOLECULAR-CLONING; GENE-EXPRESSION AB The Kruppel-like factor and specificity protein (KLF/SP) genes play key roles in critical biological processes including stem cell maintenance, cell proliferation, embryonic development, tissue differentiation, and metabolism and their dysregulation has been implicated in a number of human diseases and cancers. Although many KLF/SP genes have been characterized in a handful of bilaterian lineages, little is known about the KLF/SP gene family in nonbilaterians and virtually nothing is known outside the metazoans. Here, we analyze and discuss the origins and evolutionary history of the KLF/SP transcription factor family and associated transactivation/repression domains. We have identified and characterized the complete KLF/SP gene complement from the genomes of 48 species spanning the Eukarya. We have also examined the phylogenetic distribution of transactivation/repression domains associated with this gene family. We report that the origin of the KLF/SP gene family predates the divergence of the Metazoa. Furthermore, the expansion of the KLF/SP gene family is paralleled by diversification of transactivation domains via both acquisitions of pre-existing ancient domains as well as by the appearance of novel domains exclusive to this gene family and is strongly associated with the expansion of cell type complexity. C1 [Presnell, Jason S.; Browne, William E.] Univ Miami, Dept Biol, Coral Gables, FL 33124 USA. [Schnitzler, Christine E.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD USA. RP Browne, WE (reprint author), Univ Miami, Dept Biol, Coral Gables, FL 33124 USA. EM wbrowne@bio.miami.edu RI Browne, William/D-4267-2013 OI Browne, William/0000-0001-8200-6489 FU University of Miami College of Arts and Sciences; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This work was supported by startup funds from the University of Miami College of Arts and Sciences to W.E.B. J.S.P. was supported by the University of Miami College of Arts and Sciences. C.E.S. was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The authors thank James Baker, Allie Graham, Isaac Skromne, Lauren Vandepas, members of the Browne laboratory, and two anonymous reviewers for their thoughtful comments and critical reading of the manuscript. NR 138 TC 4 Z9 4 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1759-6653 J9 GENOME BIOL EVOL JI Genome Biol. Evol. PD AUG PY 2015 VL 7 IS 8 BP 2289 EP 2309 DI 10.1093/gbe/evv141 PG 21 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA CQ7XI UT WOS:000360819300016 PM 26232396 ER PT J AU Halladay, LR Blair, HT AF Halladay, Lindsay R. Blair, Hugh T. TI Distinct ensembles of medial prefrontal cortex neurons are activated by threatening stimuli that elicit excitation vs. inhibition of movement SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE medial prefrontal cortex; periaqueductal gray; fear conditioning; prelimbic; infralimbic ID DORSOLATERAL PERIAQUEDUCTAL GRAY; FEAR EXTINCTION; CONDITIONED FEAR; PRELIMBIC CORTEX; DISSOCIABLE ROLES; DEFENSE REACTIONS; CINGULATE CORTEX; AMYGDALA; EXPRESSION; MEMORY AB Neural circuits controlling defensive behavior were investigated by recording single units in medial prefrontal cortex (mPFC) and dorsolateral periaqueductal gray (dlPAG) while rats expressed conditioned fear responses to an auditory conditioned stimulus (CS; 20-s train of white noise pips) previously paired with an aversive unconditioned stimulus (US; 2-s train of periorbital shocks). The CS elicited conditioned movement inhibition (CMI; characterized by decreased movement speed and freezing) when rats had not recently encountered the US, whereas the CS elicited conditioned movement excitation (CME; characterized by increased movement speed and flight behavior) after recent US encounters. Many mPFC neurons were "strategy-selective" cells that changed their firing rates only when the CS elicited CME (15/71) or CMI (13/71) responses, whereas few mPFC cells (4/71) responded nonselectively to the CS during either response. By contrast, many dlPAG neurons (20/74) responded nonselectively to the CS, but most (40/74) were excited by the CS selectively during CME trials (and none during CMI trials). CME-selective neurons in dlPAG responded phasically after CS pips that elicited CME responses, whereas CME-selective neurons in mPFC showed tonically elevated activity before and after pips that evoked CME responses. These findings suggest that, at the time when the CS occurs, tonic firing rates of CME- and CMI-selective mPFC neurons may bias the rat's choice of whether to express CME vs. CMI responses, perhaps via projections to downstream structures (such as amygdala and PAG) that influence how sensory stimuli are mapped onto motor circuits that drive the expression of competing behaviors. C1 [Halladay, Lindsay R.; Blair, Hugh T.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. RP Halladay, LR (reprint author), NIAAA, NIH, 5625 Fishers Ln,Rm 2N09, Rockville, MD 20852 USA. EM lindsay.halladay@nih.gov FU NIH [R01 MH073700, 5 T32 NS058280-03] FX This work was supported by NIH R01 MH073700 awarded to H. T. Blair and by NIH training grant 5 T32 NS058280-03 to L. R. Halladay. NR 54 TC 5 Z9 5 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG 1 PY 2015 VL 114 IS 2 BP 793 EP 807 DI 10.1152/jn.00656.2014 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA CQ4DI UT WOS:000360554100004 PM 25972588 ER PT J AU Thirugnanasambandam, N Khera, R Wang, H Kukke, SN Hallett, M AF Thirugnanasambandam, Nivethida Khera, Rohan Wang, Han Kukke, Sahana N. Hallett, Mark TI Distinct interneuronal networks influence excitability of the surround during movement initiation SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE transcranial magnetic stimulation; premotor-motor interaction; surround inhibition; MEP recruitment curve ID FOCAL HAND DYSTONIA; TRANSCRANIAL MAGNETIC STIMULATION; PRIMARY MOTOR CORTEX; VENTRAL PREMOTOR CORTEX; I-WAVES; COIL ORIENTATION; INHIBITION; SYSTEM; MODULATION; ACTIVATION AB Surround inhibition (SI) is a feature of motor control in which activation of task-related muscles is associated with inhibition of neighboring, nonprotagonist muscles, allowing selective motor control. The physiological basis for SI still remains unknown. In all previous studies, SI in the motor system was measured during movement initiation by using transcranial magnetic stimulation (TMS) to deliver a posteroanterior current at a single suprathreshold intensity. To expand our understanding of SI, we explored this phenomenon at a wide range of intensities and by stimulating motor cortex with currents along anteroposterior and lateromedial directions. Fifteen healthy volunteers performed a brief isometric index finger flexion on hearing a tone. Electromyography was recorded from the synergist and surround finger muscles. Single-pulse TMS was applied to stimulate the surround muscle at different intensities at rest or movement initiation. The motor evoked potential (MEP) amplitudes were then plotted against stimulation intensities to obtain the MEP recruitment curves for the rest and movement initiation conditions and for the three current directions for every subject. From the recruitment curves, we found that surround inhibition could be elicited only by the posteroanterior current. Hence, we postulate that surround inhibition is mediated by intracortical circuits in the motor cortex. Also, for the first time, we observed surround facilitation when the motor cortex was stimulated with anteroposterior current. Further studies are needed to investigate the mechanisms underlying both these phenomena individually in healthy subjects and patients with dystonia and other movement disorders. C1 [Thirugnanasambandam, Nivethida; Khera, Rohan; Wang, Han; Kukke, Sahana N.; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Wang, Han] Beijing Union Med Coll Hosp, Dept Neurol, Beijing, Peoples R China. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, 10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov RI Khera, Rohan/H-9029-2012 OI Khera, Rohan/0000-0001-9467-6199 FU National Institute of Neurological Disorders and Stroke Intramural Research Program FX This study was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. NR 32 TC 2 Z9 2 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG 1 PY 2015 VL 114 IS 2 BP 1102 EP 1108 DI 10.1152/jn.00791.2014 PG 7 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA CQ4DI UT WOS:000360554100032 PM 26041828 ER PT J AU Kazemian, M Ren, M Lin, JX Liao, W Spolski, R Leonard, WJ AF Kazemian, Majid Ren, Min Lin, Jian-Xin Liao, Wei Spolski, Rosanne Leonard, Warren J. TI Comprehensive assembly of novel transcripts from unmapped human RNA-Seq data and their association with cancer SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE cancer-associated transcripts; long noncoding RNAs; unmapped sequencing reads ID LONG NONCODING RNAS; GENE-EXPRESSION; HUMAN GENOME; HISTONE MODIFICATIONS; BREAST-CANCER; ALIGNMENT; PROJECT; CHROMATIN; CELLS; SEQUENCES AB Crucial parts of the genome including genes encoding microRNAs and noncoding RNAs went unnoticed for years, and even now, despite extensive annotation and assembly of the human genome, RNA-sequencing continues to yield millions of unmappable and thus uncharacterized reads. Here, we examined >300 billion reads from 536 normal donors and 1,873 patients encompassing 21 cancer types, identified similar to 300 million such uncharacterized reads, and using a distinctive approach de novo assembled 2,550 novel human transcripts, which mainly represent long noncoding RNAs. Of these, 230 exhibited relatively specific expression or non-expression in certain cancer types, making them potential markers for those cancers, whereas 183 exhibited tissue specificity. Moreover, we used lentiviral-mediated expression of three selected transcripts that had higher expression in normal than in cancer patients and found that each inhibited the growth of HepG2 cells. Our analysis provides a comprehensive and unbiased resource of unmapped human transcripts and reveals their associations with specific cancers, providing potentially important new genes for therapeutic targeting. C1 [Leonard, Warren J.] NHLBI, NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. NHLBI, NIH, Ctr Immunol, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, NIH, Lab Mol Immunol, Bldg 10, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health; NIH [K22- KHL125593A] FX The results shown here are in part based upon data generated by the TCGA Research Network (http://cancergenome.nih.gov/) and Genotype-Tissue Expression (GTEx) program. We also thank Genome Reference and Human Genome Sequencing consortiums for their contribution to human genome sequencing and assembly. We thank Drs. Claudia Kemper and Peng Li for valuable discussions and critical comments. This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health and grant to MK from NIH (K22- KHL125593A). This study utilized the high-performance computing facility, helix/biowulf (http://biowulf.nih.gov/), at the National Institutes of Health. NR 53 TC 1 Z9 1 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD AUG PY 2015 VL 11 IS 8 AR 826 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CQ7EW UT WOS:000360766800003 PM 26253570 ER PT J AU Tinaz, S Malone, P Hallett, M Horovitz, SG AF Tinaz, Sule Malone, Patrick Hallett, Mark Horovitz, Silvina G. TI Role of the Right Dorsal Anterior Insula in the Urge to Tic in Tourette Syndrome SO MOVEMENT DISORDERS LA English DT Article DE functional MRI; resting-state; graph theory; network; interoception ID FUNCTIONAL-ORGANIZATION; PREMONITORY URGES; CINGULATE CORTEX; NEURAL CIRCUITS; BASAL GANGLIA; STIMULATION; SUPPRESSION; INHIBITION; GENERATION; AWARENESS AB Background: The mid-posterior part of the insula is involved in processing bodily sensations and urges and is activated during tic generation in Tourette syndrome. The dorsal anterior part of the insula, however, integrates sensory and emotional information with cognitive valuation and is implicated in interoception. The right dorsal anterior insula also participates in urge suppression in healthy subjects. This study examined the role of the right dorsal anterior insula in the urge to tic in Tourette syndrome. Methods: Resting-state functional magnetic resonance imaging was performed in 13 adult Tourette patients and 13 matched controls. The role of the right dorsal anterior insula within the urge-tic network was investigated using graph theory-based neural network analysis. The functional connectivity of the right dorsal anterior insula was also correlated with urge and tic severity. Results: Even though the patients did not exhibit any overt tics, the right dorsal anterior insula demonstrated higher connectivity, especially with the frontostriatal nodes of the urge-tic network in patients compared with controls. The functional connectivity between the right dorsal anterior insula and bilateral supplementary motor area also correlated positively with urge severity in patients. Conclusions: These results suggest that the right dorsal anterior insula is part of the urge-tic network and could influence the urge- and tic-related cortico-striato-thalamic regions even during rest in Tourette syndrome. It might be responsible for heightened awareness of bodily sensations generating premonitory urges in Tourette syndrome. (C) 2015 International Parkinson and Movement Disorder Society C1 [Tinaz, Sule; Hallett, Mark; Horovitz, Silvina G.] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Malone, Patrick] NINDS, NIH, Bethesda, MD 20892 USA. RP Tinaz, S (reprint author), 10 Ctr Dr MSC 1428,Bldg 10,Room 7D42, Bethesda, MD 20892 USA. EM aysesule.tinaz@nih.gov FU NINDS FX This study was supported by the NINDS Intramural Program. NR 46 TC 7 Z9 7 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG PY 2015 VL 30 IS 9 BP 1190 EP 1197 DI 10.1002/mds.26230 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CQ7BY UT WOS:000360759000005 PM 25855089 ER PT J AU Vermulst, M Denney, AS Lang, MJ Hung, CW Moore, S Mosely, AM Thompson, WJ Madden, V Gauer, J Wolfe, KJ Summers, D Schleit, J Sutphin, GL Haroon, S Holczbauer, A Caine, J Jorgenson, J Cyr, D Kaeberlein, M Strathern, JN Duncan, MC Erie, DA AF Vermulst, Marc Denney, Ashley S. Lang, Michael J. Hung, Chao-Wei Moore, Stephanie Mosely, Arthur M. Thompson, William J. Madden, Victoria Gauer, Jacob Wolfe, Katie J. Summers, DanielW. Schleit, Jennifer Sutphin, George L. Haroon, Suraiya Holczbauer, Agnes Caine, Joanne Jorgenson, James Cyr, Douglas Kaeberlein, Matt Strathern, Jeffrey N. Duncan, Mara C. Erie, Dorothy A. TI Transcription errors induce proteotoxic stress and shorten cellular lifespan SO NATURE COMMUNICATIONS LA English DT Article ID RNA-POLYMERASE-II; ELECTRON-MICROSCOPY; PROTEIN; FIDELITY; CELLS; YEAST; CHAPERONE; DISEASE; POLYGLUTAMINE; AGGREGATION AB Transcription errors occur in all living cells; however, it is unknown how these errors affect cellular health. To answer this question, we monitor yeast cells that are genetically engineered to display error-prone transcription. We discover that these cells suffer from a profound loss in proteostasis, which sensitizes them to the expression of genes that are associated with protein-folding diseases in humans; thus, transcription errors represent a new molecular mechanism by which cells can acquire disease phenotypes. We further find that the error rate of transcription increases as cells age, suggesting that transcription errors affect proteostasis particularly in aging cells. Accordingly, transcription errors accelerate the aggregation of a peptide that is implicated in Alzheimer's disease, and shorten the lifespan of cells. These experiments reveal a previously unappreciated role for transcriptional fidelity in cellular health and aging. C1 [Vermulst, Marc; Moore, Stephanie; Jorgenson, James; Erie, Dorothy A.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. [Vermulst, Marc; Haroon, Suraiya; Holczbauer, Agnes] Childrens Hosp Philadelphia, Ctr Mitochondrial & Epigen Med, Philadelphia, PA 19104 USA. [Denney, Ashley S.] Univ Colorado, Sch Med, Denver, CO 80217 USA. [Lang, Michael J.; Duncan, Mara C.] Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. [Hung, Chao-Wei; Gauer, Jacob] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Mosely, Arthur M.; Thompson, William J.] Duke Univ, Prote Core Facil, Durham, NC 27710 USA. [Madden, Victoria] Univ N Carolina, Sch Med, Microscopy Serv Lab, Chapel Hill, NC 27599 USA. [Wolfe, Katie J.; Cyr, Douglas] Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA. [Summers, DanielW.] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA. [Summers, DanielW.] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA. [Schleit, Jennifer; Sutphin, George L.; Kaeberlein, Matt] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Caine, Joanne] CSIRO, Dept Mat Sci & Engn, Parkville, Vic 3052, Australia. [Strathern, Jeffrey N.] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Erie, Dorothy A.] Univ N Carolina, Dept Chem, Curriculum Appl Sci & Engn, Chapel Hill, NC 27599 USA. RP Vermulst, M (reprint author), Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. EM vermulstm@email.chop.edu; derie@unc.edu OI lang, michael/0000-0003-3544-5221 FU NIH [GM092741, R01GM56981, R01AG039390, T32AG000057, T32ES007032]; NIA [11006596]; National Institutes of Health, National Cancer Institute; Center for Cancer Research; [R01 GM079480]; [GM 080294] FX We thank Kerry Bloom and Jolien Verdaasdonk for extensive help with fluorescent microscopy. We thank the lab of Douglas Wallace, Liming Pei, Gary Pielak and Kevin Weeks for the use of their equipment and Dr Richard Gardner for plasmids carrying toxic alanine repeats. We thank Eeva-Liisa Eskelinen, Greg Odorizzi, Daniel Klionsky and his laboratory for the help interpreting the electron microscopy images. M. C. D. was supported by NIH grant GM092741 (M. C. D.), and M. V. was supported by NIA grant 11006596. A. S. D. and J. S. were supported in part by the intramural Research Program of the National Institutes of Health, National Cancer Institute and the Center for Cancer Research. D. C. was supported by NIH grant R01GM56981. M. K. was supported by NIH grant R01AG039390. G. L. S. was supported by NIH training grant T32AG000057. J. N. S. was supported by NIH training grant T32ES007032. D. A. E. was supported by R01 GM079480 and GM 080294. NR 41 TC 8 Z9 8 U1 2 U2 17 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 2015 VL 6 AR 8065 DI 10.1038/ncomms9065 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CQ1JH UT WOS:000360353000002 PM 26304740 ER PT J AU Roederer, M AF Roederer, Mario TI Parsimonious Determination of the Optimal Infectious Dose of a Pathogen for Nonhuman Primate Models SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY VIRUS SIVMAC239; T-CELL RESPONSES; CHALLENGE EXPERIMENTS; IMMUNE-RESPONSES; RHESUS-MONKEYS; SIV CHALLENGE; MACAQUES; VACCINE; TRANSMISSION; PROTECTION AB The nonhuman primate (NHP) model is often the best experimental model for testing interventions designed to block infection by human pathogens, such as HIV, tuberculosis, and malaria. A physiological model may require the use of a limiting dose of the infectious agent, where only a fraction of animals become infected upon any given challenge. Determining the challenge dose of the pathogen in such experiments is critical to the success of the experiment: using too-high or too-low a challenge dose may lead to false negative results and an excessive use of animals. Here I define an optimized protocol for defining the dose of pathogen that infects 50% of the time (AID(50)); other challenge doses, e.g. AID(80), can be easily calculated from the same data. This protocol minimizes the number of animals, as well as resources and procedures, while providing an estimate of the AID(50) within 1.5-fold of the true value. C1 NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Roederer, M (reprint author), NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Roederer@nih.gov FU Intramural Research Program of the Vaccine Research Center, NIAID, NIH FX This work was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2015 VL 11 IS 8 AR e1005100 DI 10.1371/journal.ppat.1005100 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CQ7VD UT WOS:000360812500032 PM 26285041 ER PT J AU Sionov, E Mayer-Barber, KD Chang, YC Kauffman, KD Eckhaus, MA Salazar, AM Barber, DL Kwon-Chung, KJ AF Sionov, Edward Mayer-Barber, Katrin D. Chang, Yun C. Kauffman, Keith D. Eckhaus, Michael A. Salazar, Andres M. Barber, Daniel L. Kwon-Chung, Kyung J. TI Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNE-DEFICIENCY-SYNDROME; CD8+ T-CELLS; HOST-DEFENSE; POLYRIBOCYTIDYLIC ACID; NEOFORMANS INFECTION; OPPORTUNISTIC INFECTIONS; ASPERGILLUS-FUMIGATUS; INTERFERON-PRODUCTION; LUNG INFECTION AB Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to be a critical risk factor for developing cryptococcosis. However, the role of HIV-induced innate inflammation in susceptibility to cryptococcosis has not been evaluated. Thus, we sought to determine the role of Type I IFN induction in host defense against cryptococci by treatment of C. neoformans (H99) infected mice with poly-ICLC (pICLC), a dsRNA virus mimic. Unexpectedly, pICLC treatment greatly extended survival of infected mice and reduced fungal burdens in the brain. Protection from cryptococcosis by pICLC-induced Type I IFN was mediated by MDA5 rather than TLR3. PICLC treatment induced a large, rapid and sustained influx of neutrophils and Ly6C(high) monocytes into the lung while suppressing the development of eosinophilia. The pICLC-mediated protection against H99 was CD4 T cell dependent and analysis of CD4 T cell polyfunctionality showed a reduction in IL-5 producing CD4 T cells, marginal increases in Th1 cells and dramatic increases in ROR gamma t+ Th17 cells in pICLC treated mice. Moreover, the protective effect of pICLC against H99 was diminished in IFN gamma KO mice and by IL-17A neutralization with blocking mAbs. Furthermore, pICLC treatment also significantly extended survival of C. gattii infected mice with reduced fungal loads in the lungs. These data demonstrate that induction of type I IFN dramatically improves host resistance against the etiologic agents of cryptococcosis by beneficial alterations in both innate and adaptive immune responses. C1 [Sionov, Edward; Chang, Yun C.; Kwon-Chung, Kyung J.] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Mayer-Barber, Katrin D.] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Kauffman, Keith D.; Barber, Daniel L.] NIAID, T Lymphocyte Biol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Eckhaus, Michael A.] NIAID, Div Vet Resources, Off Res Serv, Off Director,NIH, Bethesda, MD 20892 USA. [Salazar, Andres M.] Oncovir Inc, Washington, DC USA. RP Sionov, E (reprint author), Agr Res Org, Volcani Ctr, Inst Postharvest & Food Sci, Dept Food Qual & Safety, IL-50250 Bet Dagan, Israel. EM barberd@niaid.nih.gov; jkchung@niaid.nih.gov FU NIAID, NIH; Division of Veterinary Resources, NIH FX The funding source for ES, KDMB, YCC, KDK, DLB, and KJKC is the Intramural Research Program of NIAID, NIH. The funding source for MAE is the Division of Veterinary Resources, NIH. AMS received no specific funding for this work. The funders had no role in study design, data collection and analysis, or preparation of the manuscript. NR 72 TC 7 Z9 7 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2015 VL 11 IS 8 AR e1005040 DI 10.1371/journal.ppat.1005040 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CQ7VD UT WOS:000360812500010 PM 26252005 ER PT J AU Tuero, I Mohanram, V Musich, T Miller, L Vargas-Inchaustegui, DA Demberg, T Venzon, D Kalisz, I Kalyanaraman, VS Pal, R Ferrari, MG LaBranche, C Montefiori, DC Rao, M Vaccari, M Franchini, G Barnett, SW Robert-Guroff, M AF Tuero, Iskra Mohanram, Venkatramanan Musich, Thomas Miller, Leia Vargas-Inchaustegui, Diego A. Demberg, Thorsten Venzon, David Kalisz, Irene Kalyanaraman, V. S. Pal, Ranajit Ferrari, Maria Grazia LaBranche, Celia Montefiori, David C. Rao, Mangala Vaccari, Monica Franchini, Genoveffa Barnett, Susan W. Robert-Guroff, Marjorie TI Mucosal B Cells Are Associated with Delayed SIV Acquisition in Vaccinated Female but Not Male Rhesus Macaques Following SIVmac251 Rectal Challenge SO PLOS PATHOGENS LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; DEPENDENT CELLULAR CYTOTOXICITY; ESTROGEN-RECEPTOR-BETA; IMMUNE-RESPONSES; NONHUMAN-PRIMATES; FC-GLYCOSYLATION; HIV-1 INFECTION; NONNEUTRALIZING ANTIBODIES; ENVELOPE PROTEIN; SEX-DIFFERENCES AB Many viral infections, including HIV, exhibit sex-based pathogenic differences. However, few studies have examined vaccine-related sex differences. We compared immunogenicity and protective efficacy of monomeric SIV gp120 with oligomeric SIV gp140 in a pre-clinical rhesus macaque study and explored a subsequent sex bias in vaccine outcome. Each immunization group (16 females, 8 males) was primed twice mucosally with replication-competent Ad-recombinants encoding SIV(smH4)env/rev, SIV(239)gag and SIV(239)nef Delta(1-13) and boosted twice intramuscularly with SIVmac239 monomeric gp120 or oligomeric gp140 in MF59 adjuvant. Controls (7 females, 5 males) received empty Ad and MF59. Up to 9 weekly intrarectal challenges with low-dose SIVmac251 were administered until macaques became infected. We assessed vaccine-induced binding, neutralizing, and non-neutralizing antibodies, Env-specific memory B cells and plasmablasts/plasma cells (PB/PC) in bone marrow and rectal tissue, mucosal Env-specific antibodies, and Env-specific T-cells. Post-challenge, only one macaque (gp140-immunized) remained uninfected. However, SIV acquisition was significantly delayed in vaccinated females but not males, correlated with Env-specific IgA in rectal secretions, rectal Env-specific memory B cells, and PC in rectal tissue. These results extend previous correlations of mucosal antibodies and memory B cells with protective efficacy. The gp140 regimen was more immunogenic, stimulating elevated gp140 and cyclic V2 binding antibodies, ADCC and ADCP activities, bone marrow Env-specific PB/PC, and rectal gp140-specific IgG. However, immunization with gp120, the form of envelope immunogen used in RV144, the only vaccine trial to show some efficacy, provided more significant acquisition delay. Further over 40 weeks of follow-up, no gp120 immunized macaques met euthanasia criteria in contrast to 7 gp140-immunized and 2 control animals. Although males had higher binding antibodies than females, ADCC and ADCP activities were similar. The complex challenge outcomes may reflect differences in IgG subtypes, Fc glycosylation, Fc-R polymorphisms, and/or the microbiome, key areas for future studies. This first demonstration of a sex-difference in SIV vaccine-induced protection emphasizes the need for sex-balancing in vaccine trials. Our results highlight the importance of mucosal immunity and memory B cells at the SIV exposure site for protection. C1 [Tuero, Iskra; Mohanram, Venkatramanan; Musich, Thomas; Miller, Leia; Vargas-Inchaustegui, Diego A.; Demberg, Thorsten; Robert-Guroff, Marjorie] NCI, Immune Biol Retroviral Infect Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Kalisz, Irene; Kalyanaraman, V. S.; Pal, Ranajit; Ferrari, Maria Grazia] Adv Biosci Labs Inc, Rockville, MD USA. [LaBranche, Celia; Montefiori, David C.] Duke Univ, Med Ctr, Durham, NC USA. [Rao, Mangala] Walter Reed Army Inst Res, USMHRP, Silver Spring, MD USA. [Vaccari, Monica; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Barnett, Susan W.] Novartis Vaccines, Cambridge, MA USA. RP Tuero, I (reprint author), NCI, Immune Biol Retroviral Infect Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov RI Mohanram, Venkatramanan/I-3652-2016 FU NIH [HHSN27201100016C]; NIH grant [5 PO1 AI066287-02]; Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This study was supported in part by NIH contract HHSN27201100016C to DCM, in part by NIH grant 5 PO1 AI066287-02 to SWB, and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 13 Z9 13 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2015 VL 11 IS 8 AR e1005101 DI 10.1371/journal.ppat.1005101 PG 28 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CQ7VD UT WOS:000360812500033 PM 26267144 ER PT J AU Feldman, SA Assadipour, Y Kriley, I Goff, SL Rosenberg, SA AF Feldman, Steven A. Assadipour, Yasmine Kriley, Isaac Goff, Stephanie L. Rosenberg, Steven A. TI Adoptive Cell Therapy-Tumor-Infiltrating Lymphocytes, T-Cell Receptors, and Chimeric Antigen Receptors SO SEMINARS IN ONCOLOGY LA English DT Review ID METASTATIC MELANOMA PATIENTS; HIGH-DOSE INTERLEUKIN-2; ACTIVATED KILLER-CELLS; CARBONIC-ANHYDRASE-IX; DETUDE-DES-LYMPHOMES; NON-HODGKIN-LYMPHOMA; ANTITUMOR-ACTIVITY; CANCER REGRESSION; PHASE-I; MONOCLONAL-ANTIBODY C1 [Feldman, Steven A.; Assadipour, Yasmine; Kriley, Isaac; Goff, Stephanie L.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, Ctr Canc Res, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM sar@nih.gov NR 98 TC 14 Z9 14 U1 2 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2015 VL 42 IS 4 BP 626 EP 639 DI 10.1053/j.seminoncol.2015.05.005 PG 14 WC Oncology SC Oncology GA CQ7KF UT WOS:000360782200011 PM 26320066 ER PT J AU Kramer, CM Appelbaum, E Desai, MY Desvigne-Nickens, P DiMarco, JP Friedrich, MG Geller, N Heckler, S Ho, CY Jerosch-Herold, M Ivey, EA Keleti, J Kim, DY Kolm, P Kwong, RY Maron, MS Schulz-Menger, J Piechnik, S Watkins, H Weintraub, WS Wu, P Neubauer, S AF Kramer, Christopher M. Appelbaum, Evan Desai, Milind Y. Desvigne-Nickens, Patrice DiMarco, John P. Friedrich, Matthias G. Geller, Nancy Heckler, Sarahfaye Ho, Carolyn Y. Jerosch-Herold, Michael Ivey, Elizabeth A. Keleti, Julianna Kim, Dong-Yun Kolm, Paul Kwong, Raymond Y. Maron, Martin S. Schulz-Menger, Jeanette Piechnik, Stefan Watkins, Hugh Weintraub, William S. Wu, Pan Neubauer, Stefan TI Hypertrophic Cardiomyopathy Registry: The rationale and design of an international, observational study of hypertrophic cardiomyopathy SO AMERICAN HEART JOURNAL LA English DT Article ID CARDIOVASCULAR MAGNETIC-RESONANCE; MYOCARDIAL FIBROSIS; TASK-FORCE; PROGNOSTIC VALUE; GENE-MUTATIONS; SUDDEN-DEATH; PREVALENCE; PREVENTION; GUIDELINES; DIAGNOSIS AB Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease with a frequency as high as 1 in 200. In many cases, HCM is caused by mutations in genes encoding the different components of the sarcomere apparatus. Hypertrophic cardiomyopathy is characterized by unexplained left ventricular hypertrophy, myofibrillar disarray, and myocardial fibrosis. The phenotypic expression is quite variable. Although most patients with HCM are asymptomatic, serious consequences are experienced in a subset of affected individuals who present initially with sudden cardiac death or progress to refractory heart failure. The Hypertrophic Cardiomyopathy Registry study is a National Heart, Lung, and Blood Institute-sponsored 2,750-patient, 44-site, international registry and natural history study designed to address limitations in extant evidence to improve prognostication in HCM (NCT01915615). In addition to the collection of standard demographic, clinical, and echocardiographic variables, patients will undergo state-of-the-art cardiac magnetic resonance for assessment of left ventricular mass and volumes as well as replacement scarring and interstitial fibrosis. In addition, genetic and biomarker analyses will be performed. The Hypertrophic Cardiomyopathy Registry has the potential to change the paradigm of risk stratification in HCM, using novel markers to identify those at higher risk. C1 [Kramer, Christopher M.; DiMarco, John P.] Univ Virginia Hlth Syst, Charlottesville, VA 22908 USA. [Appelbaum, Evan] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Desai, Milind Y.] Cleveland Clin, Cleveland, OH 44106 USA. [Desvigne-Nickens, Patrice; Geller, Nancy; Keleti, Julianna; Kim, Dong-Yun] NHLBI, Bethesda, MD 20892 USA. [Friedrich, Matthias G.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Heckler, Sarahfaye; Ivey, Elizabeth A.; Kolm, Paul; Weintraub, William S.; Wu, Pan] Christiana Ctr Hlth Outcomes, Newark, DE USA. [Ho, Carolyn Y.; Jerosch-Herold, Michael; Kwong, Raymond Y.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Maron, Martin S.] Tufts Univ New England Med Ctr, Boston, MA USA. [Schulz-Menger, Jeanette] Charite Campus Busch, Berlin, Germany. [Piechnik, Stefan; Watkins, Hugh; Neubauer, Stefan] Univ Oxford, Oxford, England. RP Kramer, CM (reprint author), Univ Virginia Hlth Syst, Dept Med, Lee St,Box 800170, Charlottesville, VA 22908 USA. EM ckramer@virginia.edu OI Piechnik, Stefan K./0000-0002-0268-5221; Watkins, Hugh/0000-0002-5287-9016 FU National Heart, Lung, and Blood Institute [U01HL117006-01A1]; National Institute of General Medical Sciences [U54-GM10494]; Oxford NIHR Biomedical Research Centre FX National Heart, Lung, and Blood Institute U01HL117006-01A1, National Institute of General Medical Sciences U54-GM10494, and Oxford NIHR Biomedical Research Centre. NR 29 TC 9 Z9 9 U1 1 U2 3 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 2015 VL 170 IS 2 BP 223 EP 230 DI 10.1016/j.ahj.2015.05.013 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CQ1LV UT WOS:000360360100008 PM 26299218 ER PT J AU Weatherspoon, DJ Chattopadhyay, A Boroumand, S Garcia, I AF Weatherspoon, Darien J. Chattopadhyay, Amit Boroumand, Shahdokht Garcia, Isabel TI Oral cavity and oropharyngeal cancer incidence trends and disparities in the United States: 2000-2010 SO CANCER EPIDEMIOLOGY LA English DT Review DE Mouth neoplasms; Healthcare disparities; Carcinoma; Squamous cell; Oral health ID SQUAMOUS-CELL CARCINOMAS; PAPILLOMAVIRUS-ASSOCIATED CANCERS; EPIDEMIC; HEAD; PREVALENCE; SURVIVAL; SEX AB Background: Changes in the incidence of oral cancer based on anatomic location and demographic factors over time have been reported in the United States. The purpose of this study was to use recent data to examine oral cancer incidence trends and disparities by demographic factors and anatomic location. Methods: Surveillance, Epidemiology, and End Results (SEER) incidence data from 2000 to 2010 were used to characterize and analyze oral cancer incidence trends by anatomic region and subsite, age at diagnosis, gender, race/ethnicity, and stage at diagnosis. Poisson regression was used to compare incidence risk by select demographic factors. Results: About 75,468 incident oral cancer cases were diagnosed from 2000 to 2010. The tonsil was the most frequently diagnosed anatomic subsite (23.1%) and the subsite with the greatest contribution to the overall, age-standardized cumulative incidence rate of 8.4 cases per 100,000 (95% confidence interval (CI): 8.3, 8.4). An increasing incidence trend was observed for cancers in the oropharyngeal region, in contrast to a decreasing trend seen in the oral cavity region. In the Poisson regression model, all race/ethnicity groups showed a lower incidence risk relative to whites for oral cavity and oropharyngeal cancer, and white males displayed the highest incidence rate of all race/ethnicity-gender groups during the study period (14.1 per 100,000; 95% CI: 14.0, 14.2). Conclusions: This study's epidemiological findings are especially important for oral health care providers, patient education, and the identification of risk profiles associated with oral cancer. The distinct epidemiological trends of oral cavity and oropharyngeal cancers dictate that oral cancer can no longer be viewed as a discrete entity. Oral health providers should have a strong understanding of the different risk factors associated with oral cavity and oropharyngeal cancers and educate their patients accordingly. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Weatherspoon, Darien J.] Univ Illinois, Chicago Coll Dent, Dept Pediat Dent, Div Prevent & Publ Hlth Sci, Chicago, IL 60612 USA. [Chattopadhyay, Amit] Mohammad Bin Rashid Univ Med & Hlth Sci, Dubai Healthcare City, Dubai, U Arab Emirates. [Boroumand, Shahdokht] Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. [Garcia, Isabel] Univ Florida, Coll Dent, Gainesville, FL 32610 USA. RP Weatherspoon, DJ (reprint author), Univ Illinois, Chicago Coll Dent, Dept Pediat Dent, Div Prevent & Publ Hlth Sci, MC 621,801 S Paulina St,Room 204-C, Chicago, IL 60612 USA. EM dweath3@uic.edu; Amit.Chattopadhyay@dhcc.ae; boroumands@mail.nih.gov; agarcia2@dental.ufl.edu FU National Institute of Dental and Craniofacial Research FX This study was supported by the National Institute of Dental and Craniofacial Research. The authors thank Drs Margo Adesanya and Timothy Iafolla, National Institute of Dental and Craniofacial Research, for their comments and suggestions as well as Dr Linda Morris Brown, RTI International, and Dr Lynn Ries, National Cancer Institute, for their input related to SEER data. NR 30 TC 7 Z9 8 U1 0 U2 12 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 2015 VL 39 IS 4 BP 497 EP 504 DI 10.1016/j.canep.2015.04.007 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CP7BX UT WOS:000360043300002 PM 25976107 ER PT J AU Stolzenberg-Solomon, RZ Amundadottir, LT AF Stolzenberg-Solomon, Rachael Z. Amundadottir, Laufey T. TI Epidemiology and Inherited Predisposition for Sporadic Pancreatic Adenocarcinoma SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Pancreatic cancer; Diabetes; Etiology; Genome-wide association studies ID GENOME-WIDE ASSOCIATION; ABO BLOOD-GROUP; CASE-CONTROL CONSORTIUM; BODY-MASS INDEX; CANCER SUSCEPTIBILITY LOCI; PROSPECTIVE EPIC COHORT; GLYCATION END-PRODUCTS; FRANCISCO BAY AREA; PROSTATE-CANCER; POOLED ANALYSIS AB Given the changing demographics of Western populations, the numbers of pancreatic cancer cases are projected to increase during the next decade. Diabetes, recent cigarette smoking, and excess body weight are the cancer's most consistent risk factors. The search for common and rare germline variants that influence risk of pancreatic cancer through genome-wide association studies and high-throughput-sequencing based studies is under-way and holds the promise of increasing the knowledge of variants and genes that play a role in inherited susceptibility of this disease. Research reported in this review has advanced the understanding of pancreatic cancer. C1 [Stolzenberg-Solomon, Rachael Z.] NCI, NIH, Div Canc Epidemiol & Genet, Nutrit Epidemiol Branch, Rockville, MD 20850 USA. [Amundadottir, Laufey T.] NCI, NIH, Div Canc Epidemiol & Genet, Lab Translat Gen, Bethesda, MD 20892 USA. RP Stolzenberg-Solomon, RZ (reprint author), NCI, NIH, Nutrit Epidemiol Branch, Bethesda, MD 20892 USA. EM rs221z@nih.gov; amundadottirl@mail.nih.gov FU National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services FX This work was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services. NR 156 TC 2 Z9 2 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 EI 1558-1977 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD AUG PY 2015 VL 29 IS 4 BP 619 EP + DI 10.1016/j.hoc.2015.04.009 PG 23 WC Oncology; Hematology SC Oncology; Hematology GA CQ2FS UT WOS:000360416000004 PM 26226901 ER PT J AU Klion, AD Ogbogu, PU AF Klion, Amy D. Ogbogu, Princess U. TI Preface SO IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA LA English DT Editorial Material C1 [Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Ogbogu, Princess U.] Ohio State Univ, Sect Allergy & Immunol, Div Pulm Allergy Crit Care & Sleep Med, Wexner Med Ctr, Columbus, OH 43210 USA. RP Klion, AD (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM AKLION@niaid.nih.gov; Princess.0gbogu@osumc.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8561 EI 1557-8607 J9 IMMUNOL ALLERGY CLIN JI Immunol. Allerg. Clin. North Am. PD AUG PY 2015 VL 35 IS 3 BP XI EP XII DI 10.1016/j.iac.2015.06.001 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA CP8ZD UT WOS:000360182600001 PM 26209902 ER PT J AU O'Connell, EM Nutman, TB AF O'Connell, Elise M. Nutman, Thomas B. TI Eosinophilia in Infectious Diseases SO IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA LA English DT Article DE Eosinophilia; Infection; Fever; Travel; Immigrant; Refugee ID SCHISTOSOMA-HAEMATOBIUM INFECTION; VISCERAL LARVA MIGRANS; STRONGYLOIDES-STERCORALIS INFECTION; OPISTHORCHIS-VIVERRINI INFECTION; TROPICAL PULMONARY EOSINOPHILIA; NORTH-AMERICAN PARAGONIMIASIS; TRICHURIS DYSENTERY SYNDROME; ISOSPORA-BELLI INFECTION; LOA-LOA FILARIASIS; OF-THE-LITERATURE AB In determining the etiology of eosinophilia, it is necessary to consider the type of patient, including previous travel and exposure history, comorbidities, and symptoms. In this review, we discuss the approach to the patient with eosinophilia from an infectious diseases perspective based on symptom complexes. C1 [O'Connell, Elise M.; Nutman, Thomas B.] NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP O'Connell, EM (reprint author), NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, 4 Ctr Dr,Bldg 4,Room B105, Bethesda, MD 20892 USA. EM oconnellem@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. NR 235 TC 3 Z9 3 U1 2 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8561 EI 1557-8607 J9 IMMUNOL ALLERGY CLIN JI Immunol. Allerg. Clin. North Am. PD AUG PY 2015 VL 35 IS 3 BP 493 EP + DI 10.1016/j.iac.2015.05.003 PG 31 WC Allergy; Immunology SC Allergy; Immunology GA CP8ZD UT WOS:000360182600008 PM 26209897 ER PT J AU Williams, KW Milner, JD Freeman, AF AF Williams, Kelli W. Milner, Joshua D. Freeman, Alexandra F. TI Eosinophilia Associated with Disorders of Immune Deficiency or Immune Dysregulation SO IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA LA English DT Article DE Eosinophilia; Immune; Deficiency; Dysregulation ID HYPER-IGE SYNDROME; WISKOTT-ALDRICH-SYNDROME; SEVERE COMBINED IMMUNODEFICIENCY; STEM-CELL TRANSPLANTATION; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; ADENOSINE-DEAMINASE DEFICIENCY; CYTOKINESIS 8 DOCK8; CHRONIC MUCOCUTANEOUS CANDIDIASIS; BONE-MARROW-TRANSPLANTATION; LINKED IPEX SYNDROME AB Increased serum eosinophil levels have been associated with multiple disorders of immune deficiency or immune dysregulation. Although primary immunodeficiency diseases are rare, it is important to consider these in the differential diagnosis of patients with eosinophilia. In this review, the clinical features, laboratory findings, diagnosis, and genetic basis of disease of several disorders of immune deficiency or dysregulation are discussed. The article includes autosomal dominant hyper IgE syndrome, DOCK8 deficiency, phosphoglucomutase 3 deficiency, ADA-SCID, Omenn syndrome, Wiskott-Aldrich syndrome, Loeys-Dietz syndrome, autoimmune lymphoproliferative syndrome, immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, Comel-Netherton syndrome, and severe dermatitis, multiple allergies, and metabolic wasting syndrome. C1 [Williams, Kelli W.; Freeman, Alexandra F.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Freeman, AF (reprint author), NIAID, Lab Clin Infect Dis, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 12C103, Bethesda, MD 20892 USA. EM freemaal@mail.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 146 TC 7 Z9 9 U1 2 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8561 EI 1557-8607 J9 IMMUNOL ALLERGY CLIN JI Immunol. Allerg. Clin. North Am. PD AUG PY 2015 VL 35 IS 3 BP 523 EP + DI 10.1016/j.iac.2015.05.004 PG 24 WC Allergy; Immunology SC Allergy; Immunology GA CP8ZD UT WOS:000360182600009 PM 26209898 ER PT J AU Cole-Lewis, H Varghese, A Sanders, A Schwarz, M Pugatch, J Augustson, E AF Cole-Lewis, Heather Varghese, Arun Sanders, Amy Schwarz, Mary Pugatch, Jillian Augustson, Erik TI Assessing Electronic Cigarette-Related Tweets for Sentiment and Content Using Supervised Machine Learning SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article ID SOCIAL MEDIA; PERCEPTIONS; BEHAVIOR; ADULTS AB Background: Electronic cigarettes (e-cigarettes) continue to be a growing topic among social media users, especially on Twitter. The ability to analyze conversations about e-cigarettes in real-time can provide important insight into trends in the public's knowledge, attitudes, and beliefs surrounding e-cigarettes, and subsequently guide public health interventions. Objective: Our aim was to establish a supervised machine learning algorithm to build predictive classification models that assess Twitter data for a range of factors related to e-cigarettes. Methods: Manual content analysis was conducted for 17,098 tweets. These tweets were coded for five categories: e-cigarette relevance, sentiment, user description, genre, and theme. Machine learning classification models were then built for each of these five categories, and word groupings (n-grams) were used to define the feature space for each classifier. Results: Predictive performance scores for classification models indicated that the models correctly labeled the tweets with the appropriate variables between 68.40% and 99.34% of the time, and the percentage of maximum possible improvement over a random baseline that was achieved by the classification models ranged from 41.59% to 80.62%. Classifiers with the highest performance scores that also achieved the highest percentage of the maximum possible improvement over a random baseline were Policy/Government (performance: 0.94; % improvement: 80.62%), Relevance (performance: 0.94; % improvement: 75.26%), Ad or Promotion (performance: 0.89; % improvement: 72.69%), and Marketing (performance: 0.91; % improvement: 72.56%). The most appropriate word-grouping unit (n-gram) was 1 for the majority of classifiers. Performance continued to marginally increase with the size of the training dataset of manually annotated data, but eventually leveled off. Even at low dataset sizes of 4000 observations, performance characteristics were fairly sound. Conclusions: Social media outlets like Twitter can uncover real-time snapshots of personal sentiment, knowledge, attitudes, and behavior that are not as accessible, at this scale, through any other offline platform. Using the vast data available through social media presents an opportunity for social science and public health methodologies to utilize computational methodologies to enhance and extend research and practice. This study was successful in automating a complex five-category manual content analysis of e-cigarette-related content on Twitter using machine learning techniques. The study details machine learning model specifications that provided the best accuracy for data related to e-cigarettes, as well as a replicable methodology to allow extension of these methods to additional topics. C1 [Cole-Lewis, Heather; Varghese, Arun; Sanders, Amy; Schwarz, Mary; Pugatch, Jillian] ICF Int, Rockville, MD USA. [Augustson, Erik] NCI, Tobacco Control Res Branch, Bethesda, MD 20892 USA. RP Augustson, E (reprint author), NCI, Tobacco Control Res Branch, 9609 Med Ctr Dr,MSC 9761, Bethesda, MD 20892 USA. EM augustse@mail.nih.gov OI Pugatch, Jillian/0000-0001-9103-5484; Schwarz, Mary/0000-0003-0482-7323 FU National Institutes of Health, National Cancer Institute [HHSN261200900022C, D6-ICF-1] FX This research was funded by the National Institutes of Health, National Cancer Institute HHSN261200900022C, Subcontract Number D6-ICF-1. The authors would like to thank Shinett Boggan, Alex Feith-Tiongson, Samantha Letizia, Thomas Madden, and Delsie Sequiera for their contributions to the study. NR 31 TC 6 Z9 6 U1 1 U2 11 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD AUG PY 2015 VL 17 IS 8 AR e208 DI 10.2196/jmir.4392 PG 11 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA CQ0SG UT WOS:000360306600011 PM 26307512 ER PT J AU Holmes, A AF Holmes, A. TI Corticostriatal control of rewarded learning SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 25th Biennial Meeting of the International-Society-for-Neurochemistry Jointly with the 13th Meeting of the Asian-Pacific-Society-for-Neurochemistry in Conjunction with the 35th Meeting of the Australasian-Neuroscience-Society CY AUG 23-27, 2015 CL Cairns, AUSTRALIA SP Int Soc Neurochemistry, Asian Pacific Soc Neurochemistry, Australasian Neuroscience Soc C1 [Holmes, A.] NIAAA, LBGN, Rockville, MD 20852 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 2015 VL 134 SU 1 SI SI MA S15-03 BP 35 EP 35 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CP9IA UT WOS:000360206300067 ER PT J AU Fields, D AF Fields, D. TI White matter plasticity in response to functional activity SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 25th Biennial Meeting of the International-Society-for-Neurochemistry Jointly with the 13th Meeting of the Asian-Pacific-Society-for-Neurochemistry in Conjunction with the 35th Meeting of the Australasian-Neuroscience-Society CY AUG 23-27, 2015 CL Cairns, AUSTRALIA SP Int Soc Neurochemistry, Asian Pacific Soc Neurochemistry, Australasian Neuroscience Soc C1 [Fields, D.] NICHD, NIH, Silver Spring, 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 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2015 VL 134 SU 1 SI SI MA S17-01 BP 39 EP 39 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CP9IA UT WOS:000360206300073 ER PT J AU Wu, LG AF Wu, L-G TI Modes of EXO- and endocytosis in secretory cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 25th Biennial Meeting of the International-Society-for-Neurochemistry Jointly with the 13th Meeting of the Asian-Pacific-Society-for-Neurochemistry in Conjunction with the 35th Meeting of the Australasian-Neuroscience-Society CY AUG 23-27, 2015 CL Cairns, AUSTRALIA SP Int Soc Neurochemistry, Asian Pacific Soc Neurochemistry, Australasian Neuroscience Soc C1 [Wu, L-G] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2015 VL 134 SU 1 SI SI MA S35-02 BP 74 EP 74 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CP9IA UT WOS:000360206300146 ER PT J AU Agam, G Sade, Y Toker, L Rapoport, SI Belmaker, RH AF Agam, G. Sade, Y. Toker, L. Rapoport, S. I. Belmaker, R. H. TI IP3 AND/OR inositol levels changes are separate effects of lithium that may mediate its induced behavioral and cellular changes SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 25th Biennial Meeting of the International-Society-for-Neurochemistry Jointly with the 13th Meeting of the Asian-Pacific-Society-for-Neurochemistry in Conjunction with the 35th Meeting of the Australasian-Neuroscience-Society CY AUG 23-27, 2015 CL Cairns, AUSTRALIA SP Int Soc Neurochemistry, Asian Pacific Soc Neurochemistry, Australasian Neuroscience Soc C1 [Agam, G.; Sade, Y.; Toker, L.; Belmaker, R. H.] Ben Gurion Univ Negev, Fac Hlth Sci, Dept Clin Biochem & Pharmacol, Beer Sheva, Israel. [Rapoport, S. I.] NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2015 VL 134 SU 1 SI SI MA MTU08-01 BP 167 EP 167 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CP9IA UT WOS:000360206300393 ER PT J AU Gonzalez, B Jayanthi, S Muniz, J Cadet, J Garia-Rill, E Urbano, F Bisagno, V AF Gonzalez, B. Jayanthi, S. Muniz, J. Cadet, J. Garia-Rill, E. Urbano, F. Bisagno, V. TI Differential effects of modafinil and methamphetamine on epigenetic and glutamatergic markers expression in the prefrontal cortex SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 25th Biennial Meeting of the International-Society-for-Neurochemistry Jointly with the 13th Meeting of the Asian-Pacific-Society-for-Neurochemistry in Conjunction with the 35th Meeting of the Australasian-Neuroscience-Society CY AUG 23-27, 2015 CL Cairns, AUSTRALIA SP Int Soc Neurochemistry, Asian Pacific Soc Neurochemistry, Australasian Neuroscience Soc C1 [Gonzalez, B.; Muniz, J.; Bisagno, V.] CNR, ININFA, Buenos Aires, DF, Argentina. [Urbano, F.] CNR, IFIByNE, Buenos Aires, DF, Argentina. [Jayanthi, S.; Cadet, J.] NIDA, Intramural Program, Mol Neuropsychiat Res Branch, Baltimore, MD USA. [Garia-Rill, E.] UAMS Ctr Translat Neurosci Neurobiol & Dev Sci, Little Rock, AR USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2015 VL 134 SU 1 SI SI MA MTU12-07 BP 213 EP 213 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CP9IA UT WOS:000360206300520 ER PT J AU Ali, S Rosas-Hernandez, H Cuevas, E Lantz-McPeak, S Paule, M Gonzalez, C Rice, K Gannon, B Fantegrossi, W AF Ali, S. Rosas-Hernandez, H. Cuevas, E. Lantz-McPeak, S. Paule, M. Gonzalez, C. Rice, K. Gannon, B. Fantegrossi, W. TI Methamphetamine, MDMA and bath salts induce cytotoxic effects in bovine brain microvessel endothelial cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 25th Biennial Meeting of the International-Society-for-Neurochemistry Jointly with the 13th Meeting of the Asian-Pacific-Society-for-Neurochemistry in Conjunction with the 35th Meeting of the Australasian-Neuroscience-Society CY AUG 23-27, 2015 CL Cairns, AUSTRALIA SP Int Soc Neurochemistry, Asian Pacific Soc Neurochemistry, Australasian Neuroscience Soc C1 [Ali, S.; Cuevas, E.; Lantz-McPeak, S.; Paule, M.] Natl Ctr Toxicol Res, Div Neuroroxicol HFT 132, Jefferson, AR 72079 USA. [Rosas-Hernandez, H.; Gonzalez, C.] Univ Autonoma San Luis Potosi, Fac Ciencias Quim, Slp, Mexico. [Rice, K.] NIAAA, NIDA, Chem Biol Res Br Drug Design & Synth Sect, Baltimore, MD USA. [Gannon, B.; Fantegrossi, W.] UAMS, Dept Pharmacol, Little Rock, AR USA. NR 0 TC 0 Z9 0 U1 1 U2 7 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 2015 VL 134 SU 1 SI SI MA MTU12-26 BP 220 EP 220 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CP9IA UT WOS:000360206300539 ER PT J AU Shin, DM Park, S Kim, MS Muallem, S AF Shin, D. M. Park, S. Kim, M. S. Muallem, S. TI Increased glutamate release in TRPML1 knock-out mice SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 25th Biennial Meeting of the International-Society-for-Neurochemistry Jointly with the 13th Meeting of the Asian-Pacific-Society-for-Neurochemistry in Conjunction with the 35th Meeting of the Australasian-Neuroscience-Society CY AUG 23-27, 2015 CL Cairns, AUSTRALIA SP Int Soc Neurochemistry, Asian Pacific Soc Neurochemistry, Australasian Neuroscience Soc C1 [Shin, D. M.; Park, S.] Yonsei Univ, Coll Dent, Oral Biol, Seoul 120749, South Korea. [Kim, M. S.] Wonkwang Univ, Lab Oral Biol, Physiol, Coll Dent, Iksan, South Korea. [Muallem, S.] NIDCR, NIH, Physiol & Therapeut Branch 2Mol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2015 VL 134 SU 1 SI SI MA WTH13-41 BP 344 EP 345 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CP9IA UT WOS:000360206300884 ER PT J AU Underhill, S Amara, S AF Underhill, S. Amara, S. TI Regulation of a neuronal glutamate transporter by methamphetamine SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 25th Biennial Meeting of the International-Society-for-Neurochemistry Jointly with the 13th Meeting of the Asian-Pacific-Society-for-Neurochemistry in Conjunction with the 35th Meeting of the Australasian-Neuroscience-Society CY AUG 23-27, 2015 CL Cairns, AUSTRALIA SP Int Soc Neurochemistry, Asian Pacific Soc Neurochemistry, Australasian Neuroscience Soc C1 [Underhill, S.; Amara, S.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2015 VL 134 SU 1 SI SI MA WTH14-25 BP 356 EP 356 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CP9IA UT WOS:000360206300916 ER PT J AU Adams, MJ Majolo, B Ostner, J Schuelke, O De Marco, A Thierry, B Engelhardt, A Widdig, A Gerald, MS Weiss, A AF Adams, Mark James Majolo, Bonaventura Ostner, Julia Schuelke, Oliver De Marco, Arianna Thierry, Bernard Engelhardt, Antje Widdig, Anja Gerald, Melissa S. Weiss, Alexander TI Personality Structure and Social Style in Macaques SO JOURNAL OF PERSONALITY AND SOCIAL PSYCHOLOGY LA English DT Article DE Old World monkey; social style; fuzzy set; comparative; dominance ID 5-FACTOR MODEL; RHESUS MACAQUES; CHIMPANZEE PERSONALITY; ZOOLOGICAL PARKS; MACACA; EVOLUTION; PRIMATE; PHYLOGENY; BEHAVIOR; TRAITS AB Why regularities in personality can be described with particular dimensions is a basic question in differential psychology. Nonhuman primates can also be characterized in terms of personality structure. Comparative approaches can help reveal phylogenetic constraints and social and ecological patterns associated with the presence or absence of specific personality dimensions. We sought to determine how different personality structures are related to interspecific variation in social style. Specifically, we examined this question in 6 different species of macaques, because macaque social style is well characterized and can be categorized on a spectrum of despotic (Grade 1) versus tolerant (Grade 4) social styles. We derived personality structures from adjectival ratings of Japanese (Macaca fuscata; Grade 1), Assamese (M. assamensis; Grade 2), Barbary (M. sylvanus; Grade 3), Tonkean (M. tonkeana; Grade 4), and crested (M. nigra; Grade 4) macaques and compared these species with rhesus macaques (M. mulatta; Grade 1) whose personality was previously characterized. Using a nonparametric method, fuzzy set analysis, to identify commonalities in personality dimensions across species, we found that all but 1 species exhibited consistently defined Friendliness and Openness dimensions, but that similarities in personality dimensions capturing aggression and social competence reflect similarities in social styles. These findings suggest that social and phylogenetic relationships contribute to the origin, maintenance, and diversification of personality. C1 [Adams, Mark James] Univ Edinburgh, Dept Psychiat, Edinburgh EH8 9YL, Midlothian, Scotland. [Majolo, Bonaventura] Lincoln Univ, Sch Psychol, Lincoln, England. [Ostner, Julia; Schuelke, Oliver] Univ Gottingen, Courant Res Ctr Evolut Social Behav, Gottingen, Germany. [De Marco, Arianna] Fdn Ethoikos, Poggio San Lorenzo, Reti, Italy. [Thierry, Bernard] CNRS, Strasbourg, France. [Engelhardt, Antje] German Primate Ctr, Gottingen, Germany. [Widdig, Anja] Max Planck Inst Evolutionary Anthropol, Leipzig, Germany. [Widdig, Anja] Univ Leipzig, Fac Biosci Pharm & Psychol, D-04109 Leipzig, Germany. [Gerald, Melissa S.] NIA, Bethesda, MD 20892 USA. [Weiss, Alexander] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland. RP Adams, MJ (reprint author), Univ Edinburgh Psychiat, Royal Edinburgh Hosp, Edinburgh EH10 5HF, Midlothian, Scotland. EM m@differentialist.info RI Engelhardt, Antje/A-2660-2013; OI De Marco, Arianna/0000-0002-3681-0254; Adams, Mark James/0000-0002-3599-6018; Majolo, Bonaventura/0000-0002-0235-3040 FU Great Britain Sasakawa Foundation [3591]; Max Planck Society; German Initiative of Excellence; German Research Council; Federal Ministry for Economic Cooperation and Development [EN 916/1,2]; German Academic Exchange Service; University of Puerto Rico, Medical Sciences Campus; National Center for Research Resources (NCRR); Office of Research Infrastructure Programs (ORIP) of National Institutes of Health (NIH) [5P40OD012217] FX The authors express our thanks to the many raters who provided their impressions of the monkeys. We thank Miho Inoue-Murayama, Hideki Sugiura, Michael Huffman, and Takafumi Suzumura for facilitating data collection on Japanese macaques, supported by a grant from the Great Britain Sasakawa Foundation (3591) to MJA. Research of wild Assamese macaques was carried out under permission of the Department of National Parks and Wildlife Conservation as well as the National Research Council of Thailand (permit nr. 0004.3/3618, 0002.3/2647) and funded by the Max Planck Society and the German Initiative of Excellence to the University of Gottingen. We thank Professor Mohamed Qarro (Ecole Nationale Forestiere d'Ingenieurs, Morocco) and the Haut Commissariat aux Eaux et Forets et a la Lutte Contre la Desertification of Morocco for research permission to collect data on the wild Barbary macaques. We gratefully acknowledge the permission of the Indonesian State Ministry of Research and Technology, the Directorate General of Forest Protection and Nature Conservation and the Department for the Conservation of Natural Resources, North Sulawesi to conduct research on crested macaques. We sincerely thank all former and current members of the Macaca Nigra Project that contributed personality ratings. Research on crested macaques was funded by the German Research Council, partly together with the Federal Ministry for Economic Cooperation and Development, (EN 916/1,2) and the German Academic Exchange Service. The rhesus macaque population of Cayo Santiago is supported by the University of Puerto Rico, Medical Sciences Campus and by the National Center for Research Resources (NCRR) and the Office of Research Infrastructure Programs (ORIP) of the National Institutes of Health (NIH) through Grant 5P40OD012217 award to the CPRC. The content of this publication is solely the responsibility of all of the authors and does not necessarily represent the official views of NIH or the United States Government. NR 95 TC 4 Z9 4 U1 19 U2 58 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-3514 EI 1939-1315 J9 J PERS SOC PSYCHOL JI J. Pers. Soc. Psychol. PD AUG PY 2015 VL 109 IS 2 BP 338 EP 353 DI 10.1037/pspp0000041 PG 16 WC Psychology, Social SC Psychology GA CQ2PN UT WOS:000360443600009 PM 26030054 ER PT J AU Reinders, I Murphy, RA Martin, KR Brouwer, IA Visser, M White, DK Newman, AB Houston, DK Kanaya, AM Nagin, DS Harris, TB AF Reinders, Ilse Murphy, Rachel A. Martin, Kathryn R. Brouwer, Ingeborg A. Visser, Marjolein White, Daniel K. Newman, Anne B. Houston, Denise K. Kanaya, Alka M. Nagin, Daniel S. Harris, Tamara B. CA Hlth Aging Body Composition Study TI Body Mass Index Trajectories in Relation to Change in Lean Mass and Physical Function: The Health, Aging and Body Composition Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; body mass index; lean mass; physical function; trajectories ID FAT-FREE MASS; OLDER-ADULTS; WEIGHT-LOSS; MUSCLE MASS; AGE; OVERWEIGHT; PATTERNS; ABC AB ObjectivesTo examine body mass index (BMI) trajectories with change in lean mass and physical function in old age. DesignProspective cohort study. SettingHealth, Aging and Body Composition Study. ParticipantsBlack and white men (n=482) and women (n=516) aged 73.12.7 and initially free of disability. MeasurementsA group-based trajectory model was used to determine BMI trajectories, the path a person's BMI followed over 9years. Lean mass, gait speed, grip strength, and knee extension strength were assessed at baseline and after 9years, and relative changes were calculated. Multivariable linear regression was used to determine associations between trajectories and relative change in lean mass and physical function. ResultsFour BMI trajectories were identified for men and four for women. Although all demonstrated a decline in BMI, the rate of decline differed according to trajectory for women only. Men in Trajectory 4 (mean BMI at baseline 33.9 +/- 2.3kg/m(2)) declined more than those in Trajectory 1 (mean BMI at baseline 22.9 +/- 1.6kg/m(2)) in gaitspeed (-9.91%, 95% confidence interval (CI)=-15.15% to -4.67%) and leg strength (-8.63%, 95% CI=-15.62% to -1.64%). Women in Trajectory 4 (mean BMI at baseline 34.9 +/- 3.0kg/m(2)) had greater losses than those in Trajectory 1 (mean BMI at baseline 20.5 +/- 1.6kg/m(2)) in lean mass in the arms (-3.19%, 95% CI=-6.16% to -0.23%). No other associations were observed. ConclusionObese men had the highest risk of decline in physical function despite similar weight loss between trajectories, whereas overweight and obese women who lost the most weight had the greatest risk of lean mass loss. The weight at which a person enters old age is informative for predicting loss in lean mass and physical function, illustrating the importance of monitoring weight. C1 [Reinders, Ilse; Murphy, Rachel A.; Martin, Kathryn R.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20814 USA. [Reinders, Ilse; Brouwer, Ingeborg A.; Visser, Marjolein] Vrije Univ Amsterdam, Dept Hlth Sci, Amsterdam, Netherlands. [Reinders, Ilse; Brouwer, Ingeborg A.; Visser, Marjolein] Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Martin, Kathryn R.] Univ Aberdeen, Sch Med & Dent, Epidemiol Grp, Aberdeen, Scotland. [Visser, Marjolein] Vrije Univ Amsterdam Med Ctr, Dept Nutr & Dietet, Internal Med, Amsterdam, Netherlands. [White, Daniel K.] Univ Delaware, Dept Phys Therapy, Newark, DE USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. [Houston, Denise K.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Sticht Ctr Aging,Sect Gerontol & Geriatr Med, Winston Salem, NC 27103 USA. [Kanaya, Alka M.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Nagin, Daniel S.] Carnegie Mellon Univ, Heinz Coll, Pittsburgh, PA 15213 USA. RP Reinders, I (reprint author), NIA, Lab Epidemiol & Populat Sci, 7201 Wisconsin Ave,3C-309 Gateway Bldg, Bethesda, MD 20814 USA. EM ilse.reinders@nih.gov RI Newman, Anne B./C-6408-2013 OI Newman, Anne B./0000-0002-0106-1150 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050]; National Institute on Nursing Research [R01-NR012459]; Intramural Research Program of the National Institutes of Health, NIA FX This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; NIA Grant R01-AG028050; and National Institute on Nursing Research Grant R01-NR012459. This research was supported in part by the Intramural Research Program of the National Institutes of Health, NIA. NR 28 TC 2 Z9 2 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2015 VL 63 IS 8 BP 1615 EP 1621 DI 10.1111/jgs.13524 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CP9IG UT WOS:000360207000016 PM 26289686 ER PT J AU Xu, ZY Bagci, U Foster, B Mansoor, A Udupa, JK Mollura, DJ AF Xu, Ziyue Bagci, Ulas Foster, Brent Mansoor, Awais Udupa, Jayaram K. Mollura, Daniel J. TI A hybrid method for airway segmentation and automated measurement of bronchial wall thickness on CT SO MEDICAL IMAGE ANALYSIS LA English DT Article DE Airway wall thickness estimation; Fuzzy connectedness; Random walk; Full width at half maximum; Phase congruency ID RESOLUTION COMPUTED-TOMOGRAPHY; IMAGE SEGMENTATION; FUZZY CONNECTEDNESS; PET-CT; QUANTIFICATION; IDENTIFICATION; DEFINITION; TREE AB Inflammatory and infectious lung diseases commonly involve bronchial airway structures and morphology, and these abnormalities are often analyzed non-invasively through high resolution computed tomography (CT) scans. Assessing airway wall surfaces and the lumen are of great importance for diagnosing pulmonary diseases. However, obtaining high accuracy from a complete 3-D airway tree structure can be quite challenging. The airway tree structure has spiculated shapes with multiple branches and bifurcation points as opposed to solid single organ or tumor segmentation tasks in other applications, hence, it is complex for manual segmentation as compared with other tasks. For computerized methods, a fundamental challenge in airway tree segmentation is the highly variable intensity levels in the lumen area, which often causes a segmentation method to leak into adjacent lung parenchyma through blurred airway walls or soft boundaries. Moreover, outer wall definition can be difficult due to similar intensities of the airway walls and nearby structures such as vessels. In this paper, we propose a computational framework to accurately quantify airways through (i) a novel hybrid approach for precise segmentation of the lumen, and (ii) two novel methods (a spatially constrained Markov random walk method (pseudo 3-D) and a relative fuzzy connectedness method (3-D)) to estimate the airway wall thickness. We evaluate the performance of our proposed methods in comparison with mostly used algorithms using human chest CT images. Our results demonstrate that, on publicly available data sets and using standard evaluation criteria, the proposed airway segmentation method is accurate and efficient as compared with the state-of-the-art methods, and the airway wall estimation algorithms identified the inner and outer airway surfaces more accurately than the most widely applied methods, namely full width at half maximum and phase congruency. (C) 2015 Elsevier B.V. All rights reserved. C1 [Xu, Ziyue; Foster, Brent; Mansoor, Awais; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging CIDI, Radiol & Imaging Sci Dept, Bethesda, MD 20892 USA. [Bagci, Ulas] Univ Cent Florida, Dept Comp Sci, Ctr Res Comp Vis CRCV, Orlando, FL 32816 USA. [Udupa, Jayaram K.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Bagci, U (reprint author), Univ Cent Florida, Dept Comp Sci, Ctr Res Comp Vis CRCV, Orlando, FL 32816 USA. EM ulasbagci@gmail.com OI Xu, Ziyue/0000-0002-5728-6869; Bagci, Ulas/0000-0001-7379-6829 FU CIDI; intramural research program of the National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Biomedical Imaging and Bioengineering (NIBIB); CRCV, UCF FX This research is supported by CIDI, the intramural research program of the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB). Dr. Bagci is supported in part by CRCV, UCF. NR 36 TC 2 Z9 2 U1 8 U2 24 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD AUG PY 2015 VL 24 IS 1 BP 1 EP 17 DI 10.1016/j.media.2015.05.003 PG 17 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CP9YV UT WOS:000360252700001 PM 26026778 ER PT J AU Li, S Ovcharenko, I AF Li, Shan Ovcharenko, Ivan TI Human Enhancers Are Fragile and Prone to Deactivating Mutations SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE enhancers; causal mutations; transcription factor binding sites; gene regulation ID GENOME-WIDE ASSOCIATION; TRANSCRIPTION FACTOR NETWORK; HUMAN GENE-EXPRESSION; CHIP-SEQ; APOLIPOPROTEIN-M; SEQUENCE; DNA; PSORIASIS; DATABASE; DISEASE AB To explore the underlying mechanisms whereby noncoding variants affect transcriptional regulation, we identified nucleotides capable of disrupting binding of transcription factors and deactivating enhancers if mutated (dubbed candidate killer mutations or KMs) in HepG2 enhancers. On average, approximately 11% of enhancer positions are prone to KMs. A comparable number of enhancer positions are capable of creating de novo binding sites via a single-nucleotide mutation (dubbed candidate restoration mutations or RSs). Both KM and RS positions are evolutionarily conserved and tend to form clusters within an enhancer. We observed that KMs have the most deleterious effect on enhancer activity. In contrast, RSs have a smaller effect in increasing enhancer activity. Additionally, the KMs are strongly associated with liver-related Genome Wide Association Study traits compared with other HepG2 enhancer regions. By applying our framework to lymphoblastoid cell lines, we found that KMs underlie differential binding of transcription factors and differential local chromatin accessibility. The gene expression quantitative trait loci associated with the tissue-specific genes are strongly enriched in KM positions. In summary, we conclude that the KMs have the greatest impact on the level of gene expression and are likely to be the causal variants of tissue-specific gene expression and disease predisposition. C1 [Li, Shan; Ovcharenko, Ivan] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Ovcharenko, I (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM ovcharen@nih.gov RI Li, Shan/E-5390-2010 FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. The authors are grateful to Di Huang, Dorothy L. Buchhagen, Gesine Cauer, Konnor La, and Parsa Hosseini for critical reading of the manuscript. NR 72 TC 3 Z9 3 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD AUG PY 2015 VL 32 IS 8 BP 2161 EP 2180 DI 10.1093/molbev/msv118 PG 20 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA CQ4PG UT WOS:000360586500020 PM 25976354 ER PT J AU Dunham, EC Banadyga, L Groseth, A Chiramel, AI Best, SM Ebihara, H Feldmann, H Hoenen, T AF Dunham, Eric C. Banadyga, Logan Groseth, Allison Chiramel, Abhilash I. Best, Sonja M. Ebihara, Hideki Feldmann, Heinz Hoenen, Thomas TI Assessing the contribution of interferon antagonism to the virulence of West African Ebola viruses SO NATURE COMMUNICATIONS LA English DT Article ID HEMORRHAGIC-FEVER VIRUSES; DOUBLE-STRANDED-RNA; VP35 PROTEIN; KARYOPHERIN ALPHA-1; INHIBITORY DOMAIN; NUCLEAR IMPORT; MARBURG-VIRUS; VP24; REPLICATION; TRANSCRIPTION AB The current Ebola virus (EBOV) outbreak in West Africa is unprecedented in terms of both its size and duration, and there has been speculation and concern regarding the potential for EBOV to increase in virulence as a result of its prolonged circulation in humans. Here we investigate the relative potency of the interferon (IFN) inhibitors encoded by EBOVs from West Africa, since an important EBOV virulence factor is inhibition of the antiviral IFN response. Based on this work we show that, in terms of IFN antagonism, the West African viruses display no discernible differences from the prototype Mayinga isolate, which corroborates epidemiological data suggesting these viruses show no increased virulence compared with those from previous outbreaks. This finding has important implications for public health decisions, since it does not provide experimental support for theoretical claims that EBOV might gain increased virulence due to the extensive human-to-human transmission in the on-going outbreak. C1 [Dunham, Eric C.; Banadyga, Logan; Groseth, Allison; Chiramel, Abhilash I.; Best, Sonja M.; Ebihara, Hideki; Feldmann, Heinz; Hoenen, Thomas] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. RP Hoenen, T (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM thomas.hoenen@nih.gov OI Hoenen, Thomas/0000-0002-5829-6305 FU Intramural Research Program of the NIH, NIAID FX We are grateful to Chris Basler (the Icahn School of Medicine at Mount Sinai) for providing the anti-VP35 antibody used in this study. This work was supported by the Intramural Research Program of the NIH, NIAID. NR 48 TC 7 Z9 7 U1 0 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 2015 VL 6 AR 8000 DI 10.1038/ncomms9000 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CQ1IQ UT WOS:000360351000010 PM 26242723 ER PT J AU Hao, XP Lucero, CM Turkbey, B Bernardo, ML Morcock, DR Deleage, C Trubey, CM Smedley, J Klatt, NR Giavedoni, LD Kristoff, J Xu, A Del Prete, GQ Keele, BF Rao, SS Alvord, WG Choyke, PL Lifson, JD Brenchley, JM Apetrei, C Pandrea, I Estes, JD AF Hao, Xing Pei Lucero, Carissa M. Turkbey, Baris Bernardo, Marcelino L. Morcock, David R. Deleage, Claire Trubey, Charles M. Smedley, Jeremy Klatt, Nichole R. Giavedoni, Luis D. Kristoff, Jan Xu, Amy Del Prete, Gregory Q. Keele, Brandon F. Rao, Srinivas S. Alvord, W. Gregory Choyke, Peter L. Lifson, Jeffrey D. Brenchley, Jason M. Apetrei, Cristian Pandrea, Ivona Estes, Jacob D. TI Experimental colitis in SIV-uninfected rhesus macaques recapitulates important features of pathogenic SIV infection SO NATURE COMMUNICATIONS LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; AFRICAN-GREEN MONKEYS; IMMUNODEFICIENCY VIRUS-INFECTION; GUT EPITHELIAL BARRIER; CHRONIC HIV-INFECTION; IMMUNE ACTIVATION; MICROBIAL TRANSLOCATION; ANTIRETROVIRAL THERAPY; SOOTY MANGABEYS; INTESTINAL INFLAMMATION AB Mucosal damage to the gastrointestinal (GI) tract with resulting microbial translocation is hypothesized to significantly contribute to the heightened and persistent chronic inflammation and immune activation characteristic to HIV infection. Here we employ a non-human primate model of chemically induced colitis in SIV-uninfected rhesus macaques that we developed using dextran sulfate sodium (DSS), to directly test this hypothesis. DSS treatment results in GI barrier damage with associated microbial translocation, inflammation and immune activation. The progression and severity of colitis are longitudinally monitored by a magnetic resonance imaging approach. DSS treatment of SIV-infected African green monkeys, a natural host species for SIV that does not manifest GI tract damage or chronic immune activation during infection, results in colitis with elevated levels of plasma SIV RNA, sCD14, LPS, CRP and mucosal CD4+ T-cell loss. Together these results support the hypothesis that GI tract damage leading to local and systemic microbial translocation, and associated immune activation, are important determinants of AIDS pathogenesis. C1 [Hao, Xing Pei] Leidos Biomed Res Inc, Pathol & Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Lucero, Carissa M.; Morcock, David R.; Deleage, Claire; Trubey, Charles M.; Del Prete, Gregory Q.; Keele, Brandon F.; Lifson, Jeffrey D.; Estes, Jacob D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Ft Detrick, MD 21702 USA. [Turkbey, Baris; Bernardo, Marcelino L.; Choyke, Peter L.] NCI, Mol Imaging Program, Bethesda, MD 20814 USA. [Smedley, Jeremy] Leidos Biomed Res Inc, Lab Anim Sci Program, Frederick Natl Lab Canc Res, Bethesda, MD 20814 USA. [Smedley, Jeremy] Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Klatt, Nichole R.] Univ Washington, WaNPRC, Dept Pharmaceut, Seattle, WA 98121 USA. [Giavedoni, Luis D.] Southwest Natl Primate Res Ctr, Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX 78227 USA. [Kristoff, Jan; Xu, Amy; Apetrei, Cristian; Pandrea, Ivona] Univ Pittsburgh, Ctr Vaccine Res, Pittsburgh, PA 15261 USA. [Kristoff, Jan] Univ Pittsburgh, Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Xu, Amy; Apetrei, Cristian] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA 15261 USA. [Rao, Srinivas S.] NIAID, Lab Anim Med, Vaccine Res Ctr, NIH, Bethesda, MD 20814 USA. [Alvord, W. Gregory] NCI, Stat Consulting, Data Management Serv Inc, Frederick, MD 21702 USA. [Brenchley, Jason M.] NIAID, Immunopathogenesis Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20814 USA. [Pandrea, Ivona] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USA. [Pandrea, Ivona] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15261 USA. RP Estes, JD (reprint author), Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, BG 535,POB B, Ft Detrick, MD 21702 USA. EM estesj@mail.nih.gov OI Smedley, Jeremy/0000-0003-3369-4662 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Division of Intramural Research/NIAID/NIH; PART grant [5T32AI065380-10]; [9R01HL117715-08] FX We gratefully acknowledge the expert support of the Pathology and Histotechnology Laboratory (PHL), ACVP Specimen Support Core, and animal care by the Laboratory Animal Science Program staff at the Frederick National Laboratory for Cancer Research, Frederick MD. This project has been funded with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and in part by the Division of Intramural Research/NIAID/NIH (J.M.B.), and 9R01HL117715-08 (I.P.). J.K. was supported by a PART grant No: 5T32AI065380-10. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 62 TC 14 Z9 14 U1 1 U2 5 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 2015 VL 6 AR 8020 DI 10.1038/ncomms9020 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CQ1IZ UT WOS:000360352000001 PM 26282376 ER PT J AU Lunetta, KL Day, FR Sulem, P Ruth, KS Tung, JY Hinds, DA Esko, T Elks, CE Altmaier, E He, CY Huffman, JE Mihailov, E Porcu, E Robino, A Rose, LM Schick, UM Stolk, L Teumer, A Thompson, DJ Traglia, M Wang, CA Yerges-Armstrong, LM Antoniou, AC Barbieri, C Coviello, AD Cucca, F Demerath, EW Dunning, AM Gandin, I Grove, ML Gudbjartsson, DF Hocking, LJ Hofman, A Huang, JY Jackson, RD Karasik, D Kriebel, J Lange, EM Lange, LA Langenberg, C Li, X Luan, JA Magi, R Morrison, AC Padmanabhan, S Pirie, A Polasek, O Porteous, D Reiner, AP Rivadeneira, F Rudan, I Sala, CF Schlessinger, D Scott, RA Stockl, D Visser, JA Volker, U Vozzi, D Wilson, JG Zygmunt, M Boerwinkle, E Buring, JE Crisponi, L Easton, DF Hayward, C Hu, FB Liu, SM Metspalu, A Pennell, CE Ridker, PM Strauch, K Streeten, EA Toniolo, D Uitterlinden, AG Ulivi, S Volzke, H Wareham, NJ Wellons, M Franceschini, N Chasman, DI Thorsteinsdottir, U Murray, A Stefansson, K Murabito, JM Ong, KK Perry, JRB Forouhi, NG Kerrison, ND Sharp, SJ Sims, M Barroso, I Deloukas, P McCarthy, MI Arriola, L Balkau, B Barricarte, A Boeing, H Franks, PW Gonzalez, C Grioni, S Kaaks, R Key, TJ Navarro, C Nilsson, PM Overvad, K Palli, D Panico, S Quiros, JR Rolandsson, O Sacerdote, C Sanchez, MJ Slimani, N Tjonneland, A Tumino, R van der A, DL van der Schouw, YT Riboli, E Smith, BH Campbell, A Deary, IJ McIntosh, AM AF Lunetta, Kathryn L. Day, Felix R. Sulem, Patrick Ruth, Katherine S. Tung, Joyce Y. Hinds, David A. Esko, Tonu Elks, Cathy E. Altmaier, Elisabeth He, Chunyan Huffman, Jennifer E. Mihailov, Evelin Porcu, Eleonora Robino, Antonietta Rose, Lynda M. Schick, Ursula M. Stolk, Lisette Teumer, Alexander Thompson, Deborah J. Traglia, Michela Wang, Carol A. Yerges-Armstrong, Laura M. Antoniou, Antonis C. Barbieri, Caterina Coviello, Andrea D. Cucca, Francesco Demerath, Ellen W. Dunning, Alison M. Gandin, Ilaria Grove, Megan L. Gudbjartsson, Daniel F. Hocking, Lynne J. Hofman, Albert Huang, Jinyan Jackson, Rebecca D. Karasik, David Kriebel, Jennifer Lange, Ethan M. Lange, Leslie A. Langenberg, Claudia Li, Xin Luan, Jian'an Maegi, Reedik Morrison, Alanna C. Padmanabhan, Sandosh Pirie, Ailith Polasek, Ozren Porteous, David Reiner, Alex P. Rivadeneira, Fernando Rudan, Igor Sala, Cinzia F. Schlessinger, David Scott, Robert A. Stoeckl, Doris Visser, Jenny A. Voelker, Uwe Vozzi, Diego Wilson, James G. Zygmunt, Marek Boerwinkle, Eric Buring, Julie E. Crisponi, Laura Easton, Douglas F. Hayward, Caroline Hu, Frank B. Liu, Simin Metspalu, Andres Pennell, Craig E. Ridker, Paul M. Strauch, Konstantin Streeten, Elizabeth A. Toniolo, Daniela Uitterlinden, Andre G. Ulivi, Sheila Voelzke, Henry Wareham, Nicholas J. Wellons, Melissa Franceschini, Nora Chasman, Daniel I. Thorsteinsdottir, Unnur Murray, Anna Stefansson, Kari Murabito, Joanne M. Ong, Ken K. Perry, John R. B. Forouhi, Nita G. Kerrison, Nicola D. Sharp, Stephen J. Sims, Matt Barroso, Ines Deloukas, Panos McCarthy, Mark I. Arriola, Larraitz Balkau, Beverley Barricarte, Aurelio Boeing, Heiner Franks, Paul W. Gonzalez, Carlos Grioni, Sara Kaaks, Rudolf Key, Timothy J. Navarro, Carmen Nilsson, Peter M. Overvad, Kim Palli, Domenico Panico, Salvatore Ramon Quiros, J. Rolandsson, Olov Sacerdote, Carlotta Sanchez, Maria-Jose Slimani, Nadia Tjonneland, Anne Tumino, Rosario van der A, Daphne L. van der Schouw, Yvonne T. Riboli, Elio Smith, Blair H. Campbell, Archie Deary, Ian J. McIntosh, Andrew M. CA EPIC-InterAct Consortium Generation Scotland TI Rare coding variants and X-linked loci associated with age at menarche SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; IDENTIFICATION; METAANALYSIS; MUTATIONS; CANCER; LAMB2 AB More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P = 2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait. C1 [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Lunetta, Kathryn L.; Murabito, Joanne M.] NHLBI, Framingham, MA 01702 USA. [Lunetta, Kathryn L.; Murabito, Joanne M.] Boston Univ, Framingham Heart Study, Framingham, MA 01702 USA. [Day, Felix R.; Elks, Cathy E.; Langenberg, Claudia; Luan, Jian'an; Scott, Robert A.; Wareham, Nicholas J.; Ong, Ken K.; Perry, John R. B.; Forouhi, Nita G.; Kerrison, Nicola D.; Sharp, Stephen J.; Sims, Matt; Rolandsson, Olov] Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Cambridge CB2 0QQ, England. [Sulem, Patrick; Gudbjartsson, Daniel F.; Thorsteinsdottir, Unnur; Stefansson, Kari] Amgen Inc, deCODE Genet, IS-101 Reykjavik, Iceland. [Ruth, Katherine S.; Murray, Anna] Univ Exeter, Sch Med, Genet Complex Traits, Exeter EX1 2LU, Devon, England. [Tung, Joyce Y.; Hinds, David A.] 23andMe Inc, Mountain View, CA 94043 USA. [Esko, Tonu; Mihailov, Evelin; Maegi, Reedik; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Esko, Tonu] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Esko, Tonu] Harvard Univ, Dept Genet, Sch Med, Boston, MA 02115 USA. [Esko, Tonu] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA. [Altmaier, Elisabeth; Kriebel, Jennifer] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Altmaier, Elisabeth; Strauch, Konstantin] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [He, Chunyan] Indiana Univ, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46202 USA. [He, Chunyan] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46202 USA. [Huffman, Jennifer E.; Hayward, Caroline] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Porcu, Eleonora; Cucca, Francesco; Crisponi, Laura] CNR, Inst Genet & Biomed Res, I-09042 Cagliari, Sardinia, Italy. [Porcu, Eleonora; Cucca, Francesco] Univ Sassari, Dept Biomed Sci, I-07100 Sassari, Italy. [Porcu, Eleonora] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Robino, Antonietta; Gandin, Ilaria; Vozzi, Diego; Ulivi, Sheila] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, I-34137 Trieste, Italy. [Rose, Lynda M.; Buring, Julie E.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Schick, Ursula M.; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Stolk, Lisette; Rivadeneira, Fernando; Visser, Jenny A.; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands. [Teumer, Alexander; Voelzke, Henry] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany. [Thompson, Deborah J.; Antoniou, Antonis C.; Pirie, Ailith; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Traglia, Michela; Barbieri, Caterina; Sala, Cinzia F.; Toniolo, Daniela] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy. [Wang, Carol A.; Pennell, Craig E.] Univ Western Australia, Sch Womens & Infants Hlth, Nedlands, WA 6009, Australia. [Yerges-Armstrong, Laura M.; Streeten, Elizabeth A.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutri, Program Personalized Med, Baltimore, MD 21201 USA. [Coviello, Andrea D.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Coviello, Andrea D.] Boston Univ, Sch Med, Dept Med, Endocrinol Sect, Boston, MA 02118 USA. [Demerath, Ellen W.] Univ Minnesotta, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Gandin, Ilaria] Univ Trieste, Dept Clin Med Sci Surg & Hlth, I-34149 Trieste, Italy. [Grove, Megan L.; Morrison, Alanna C.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Gudbjartsson, Daniel F.] Univ Iceland, Sch Engn & Nat Sci, IS-101 Reykjavik, Iceland. [Hocking, Lynne J.] Univ Aberdeen, Div Appl Med, Musculoskeletal Res Programme, Aberdeen AB25 2ZD, Scotland. [Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands. [Huang, Jinyan] Shanghai Jiao Tong Univ, Sch Med, State Key Lab Med Genom, Shanghai Inst Hematol,Rui Jin Hosp, Shanghai 200025, Peoples R China. [Jackson, Rebecca D.] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Karasik, David] Hebrew SeniorLife Inst Aging Res, Boston, MA 02131 USA. [Karasik, David; Buring, Julie E.; Ridker, Paul M.; Chasman, Daniel I.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kriebel, Jennifer] German Ctr Diabet Res, D-85764 Neuherberg, Germany. [Lange, Ethan M.; Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Lange, Ethan M.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Li, Xin; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Padmanabhan, Sandosh] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, British Heart Fdn,Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [Polasek, Ozren] Univ Split, Fac Med, Split, Croatia. [Porteous, David; Smith, Blair H.] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH4 2XU, Midlothian, Scotland. [Rudan, Igor] Univ Edinburgh, Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland. [Schlessinger, David] NIA, Intramural Res Program, Baltimore, MD 20892 USA. [Stoeckl, Doris] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17475 Greifswald, Germany. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Zygmunt, Marek] Univ Med Greifswald, Dept Obstet & Gynecol, D-17475 Greifswald, Germany. [Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Liu, Simin] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Liu, Simin] Brown Univ, Dept Med, Providence, RI 02912 USA. [Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia. [Strauch, Konstantin] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany. [Wellons, Melissa] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37203 USA. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Ong, Ken K.] Univ Cambridge, Dept Paediat, Cambridge CB2 0QQ, England. [Barroso, Ines; Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Barroso, Ines] Univ Cambridge, Metab Res Labs, Cambridge CB2 0QQ, England. [McCarthy, Mark I.] Univ Oxford, OCDEM, Oxford OX3 7LJ, England. [McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [McCarthy, Mark I.] Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Arriola, Larraitz] Publ Hlth Div Gipuzkoa, San Sebastian 20013, Spain. [Arriola, Larraitz] Basque Govt, Inst BIO Donostia, San Sebastian 20014, Spain. [Arriola, Larraitz; Barricarte, Aurelio; Navarro, Carmen; Sanchez, Maria-Jose] CIBERESP, Madrid 28029, Spain. [Balkau, Beverley] INSERM, U1018, CESP, F-94807 Villejuif, France. [Balkau, Beverley] Univ Paris 11, UMRS 1018, F-94805 Villejuif, France. [Barricarte, Aurelio] Navarre Publ Hlth Inst ISPN, Pamplona 31003, Spain. [Boeing, Heiner] German Inst Human Nutr Potsdam Rehbrucke, D-14558 Nuthetal, Germany. [Franks, Paul W.; Nilsson, Peter M.] Lund Univ, Dept Clin Sci, S-20502 Malmo, Sweden. [Franks, Paul W.; Rolandsson, Olov] Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden. [Gonzalez, Carlos] ICO, Barcelona 08916, Spain. [Grioni, Sara] Epidemiol & Prevent Unit, I-20133 Milan, Italy. [Kaaks, Rudolf] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Key, Timothy J.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford OX3 7LF, England. [Navarro, Carmen] Murcia Reg Hlth Council, Dept Epidemiol, Murcia 30008, Spain. [Navarro, Carmen] Univ Murcia, Unit Prevent Med & Publ Hlth, Sch Med, Espinardo 30100, Spain. [Overvad, Kim] Aarhus Univ, Dept Publ Hlth, Epidemiol Sect, DK-8000 Aarhus C, Denmark. [Overvad, Kim] Aalborg Univ Hosp, DK-9100 Aalborg, Denmark. [Palli, Domenico] Canc Res & Prevent Inst ISPO, I-50141 Florence, Italy. [Panico, Salvatore] Univ Naples Federico II, Dipartimento Med Clin & Chirurg, I-80131 Naples, Italy. [Ramon Quiros, J.] Publ Hlth Directorate, Oviedo 33006, Spain. [Sacerdote, Carlotta] Univ Turin, Citta Salute & Sci Hosp, Unit Canc Epidemiol, I-10126 Turin, Italy. [Sacerdote, Carlotta] Ctr Canc Prevent CPO, I-10126 Turin, Italy. [Sacerdote, Carlotta] Human Genet Fdn HuGeF, I-10126 Turin, Italy. [Sanchez, Maria-Jose] Andalusian Sch Publ Hlth, Granada 18080, Spain. [Sanchez, Maria-Jose] Inst Invest Biosanitaria Granada Ibs, Granada 18012, Spain. [Slimani, Nadia] Int Agcy Res Canc, F-69372 Lyon 08, France. [Tjonneland, Anne] Danish Canc Soc Res Ctr, DK-2100 Copenhagen, Denmark. [Tumino, Rosario] ASP, I-97100 Ragusa, Italy. [Tumino, Rosario] Ragusa Canc Registry, I-97100 Aire Onlus, Ragusa, Italy. [van der A, Daphne L.] Natl Inst Publ Hlth & Environm RIVM, NL-3720 BA Bilthoven, Netherlands. [van der Schouw, Yvonne T.] Univ Med Ctr Utrecht, NL-3508 GA Utrecht, Netherlands. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London W2 1PG, England. [Smith, Blair H.; Campbell, Archie; Deary, Ian J.; McIntosh, Andrew M.] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [McIntosh, Andrew M.] Univ Edinburgh, Div Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland. RP Ong, KK (reprint author), Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Box 285,Cambridge Biomed Campus, Cambridge CB2 0QQ, England. EM ken.ong@mrc-epid.cam.ac.uk; john.perry@mrc-epid.cam.ac.uk RI Polasek, Ozren/B-6002-2011; Rivadeneira, Fernando/O-5385-2015; Panico, Salvatore/K-6506-2016; Deloukas, Panos/B-2922-2013; Padmanabhan, Sandosh/S-3963-2016; Grioni, Sara/K-5320-2016; OI PALLI, Domenico/0000-0002-5558-2437; Dunning, Alison Margaret/0000-0001-6651-7166; Sacerdote, Carlotta/0000-0002-8008-5096; Karasik, David/0000-0002-8826-0530; Forouhi, Nita/0000-0002-5041-248X; vozzi, diego/0000-0002-2902-8184; Ewing, Ailith/0000-0002-2272-1277; McIntosh, Andrew/0000-0002-0198-4588; Polasek, Ozren/0000-0002-5765-1862; Rivadeneira, Fernando/0000-0001-9435-9441; Panico, Salvatore/0000-0002-5498-8312; Deloukas, Panos/0000-0001-9251-070X; Padmanabhan, Sandosh/0000-0003-3869-5808; Grioni, Sara/0000-0002-5891-8426; Day, Felix/0000-0003-3789-7651; Murray, Anna/0000-0002-2351-2522; Hocking, Lynne J/0000-0002-2414-2826; Magi, Reedik/0000-0002-2964-6011 FU Cancer Research UK [11174]; Chief Scientist Office [CZD/16/6/4]; Medical Research Council [MC_PC_U127561128, MC_U106179471, MC_U106179472, MC_UP_A100_1003, MC_UU_12015/1, MC_UU_12015/2, MC_UU_12015/5, MR/K026992/1]; NCATS NIH HHS [UL1 TR001108]; NCI NIH HHS [P30 CA015704, UM1 CA182913]; NIA NIH HHS [R01 AG029451, R21 AG032598] NR 29 TC 11 Z9 11 U1 2 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2015 VL 6 AR 7756 DI 10.1038/ncomms8756 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CQ1EK UT WOS:000360339900001 PM 26239645 ER PT J AU Nowinski, SM Solmonson, A Rundhaug, JE Rho, O Cho, J Lago, CU Riley, CL Lee, S Kohno, S Dao, CK Nikawa, T Bratton, SB Wright, CW Fischer, SM DiGiovanni, J Mills, EM AF Nowinski, Sara M. Solmonson, Ashley Rundhaug, Joyce E. Rho, Okkyung Cho, Jiyoon Lago, Cory U. Riley, Christopher L. Lee, Sunhee Kohno, Shohei Dao, Christine K. Nikawa, Takeshi Bratton, Shawn B. Wright, Casey W. Fischer, Susan M. DiGiovanni, John Mills, Edward M. TI Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis SO NATURE COMMUNICATIONS LA English DT Article ID GROWTH-FACTOR RECEPTOR; MOUSE SKIN CARCINOGENESIS; EPIDERMAL BASAL-CELLS; PROSTATE-CANCER CELLS; ATP CITRATE LYASE; LARGE GENE LISTS; GLUTAMINE-METABOLISM; AEROBIC GLYCOLYSIS; TRANSFORMED-CELLS; OXIDATIVE STRESS AB To support growth, tumour cells reprogramme their metabolism to simultaneously upregulate macromolecular biosynthesis while maintaining energy production. Uncoupling proteins (UCPs) oppose this phenotype by inducing futile mitochondrial respiration that is uncoupled from ATP synthesis, resulting in nutrient wasting. Here using a UCP3 transgene targeted to the basal epidermis, we show that forced mitochondrial uncoupling inhibits skin carcinogenesis by blocking Akt activation. Similarly, Akt activation is markedly inhibited in UCP3 overexpressing primary human keratinocytes. Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane. Overexpression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis. These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signalling. C1 [Nowinski, Sara M.; Rho, Okkyung; Cho, Jiyoon; Kohno, Shohei; Dao, Christine K.; Wright, Casey W.; DiGiovanni, John; Mills, Edward M.] Univ Texas Austin, Coll Pharm, Div Pharmacol & Toxicol, Austin, TX 78712 USA. [Nowinski, Sara M.; Solmonson, Ashley; Mills, Edward M.] Univ Texas Austin, Coll Pharm, Ctr Mol & Cellular Toxicol, Austin, TX 78712 USA. [Solmonson, Ashley; Riley, Christopher L.; Lee, Sunhee; Wright, Casey W.; DiGiovanni, John; Mills, Edward M.] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. [Rundhaug, Joyce E.; Bratton, Shawn B.; Fischer, Susan M.] Univ Texas MD Anderson Canc Ctr, Div Sci Pk Res, Smithville, TX 78957 USA. [Lago, Cory U.] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Nikawa, Takeshi] Univ Tokushima, Grad Sch, Inst Hlth Biosci, Dept Nutr Physiol, Tokushima 7708503, Japan. RP Mills, EM (reprint author), Univ Texas Austin, Coll Pharm, Div Pharmacol & Toxicol, Austin, TX 78712 USA. EM tedmills@austin.utexas.edu OI Solmonson, Ashley/0000-0001-8863-4558 FU NIH [CRED ES007784, DK089224, T32 DK 091317]; Texas Higher Education Coordinating Board; NIH/NIEHS [T32 ES0247]; PhRMA Foundation FX We thank K. Kiguchi for assistance with microscopy, and the MD Anderson Science Park, Smithville histology core for embedding, sectioning and staining services. We thank M. Keaton and E. Morin-Kensicki for assistance with metabolomics study design, sample and data processing and interpretation. We also thank the St David's Hospital nursery staff for their help with tissue collection. This work was supported by funding to E.M.M. from NIH CRED ES007784, NIH DK089224, and the Texas Higher Education Coordinating Board. S.M.N. and A.S. were also supported by NIH/NIEHS T32 ES0247, PI J.H. Richburg. Further support for S.M.N. was provided by the PhRMA Foundation and NIH T32 DK 091317, PI D. McClain. NR 62 TC 2 Z9 2 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2015 VL 6 AR 8137 DI 10.1038/ncomms9137 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CQ1KI UT WOS:000360356100001 PM 26310111 ER PT J AU Shukla, A Kong, D Sharma, M Magidson, V Loncarek, J AF Shukla, Anil Kong, Dong Sharma, Meena Magidson, Valentin Loncarek, Jadranka TI Plk1 relieves centriole block to reduplication by promoting daughter centriole maturation SO NATURE COMMUNICATIONS LA English DT Article ID CELL-CYCLE; GAMMA-TUBULIN; CENTROSOME DUPLICATION; MITOTIC CENTROSOMES; VERTEBRATE CELLS; PROTEIN; CPAP; RECRUITMENT; PROCENTRIOLE; REVEALS AB Centrosome overduplication promotes mitotic abnormalities, invasion and tumorigenesis. Cells regulate the number of centrosomes by limiting centriole duplication to once per cell cycle. The orthogonal orientation between a mother and a daughter centriole, established at the time of centriole duplication, is thought to block further duplication of the mother centriole. Loss of orthogonal orientation (disengagement) between two centrioles during anaphase is considered a licensing event for the next round of centriole duplication. Disengagement requires the activity of Polo-like kinase 1 (Plk1), but how Plk1 drives this process is not clear. Here we employ correlative live/electron microscopy and demonstrate that Plk1 induces maturation and distancing of the daughter centriole, allowing reduplication of the mother centriole even if the original daughter centriole is still orthogonal to it. We find that mother centrioles can undergo reduplication when original daughter centrioles are only similar to 80nm apart, which is the distance centrioles normally reach during prophase. C1 [Shukla, Anil; Kong, Dong; Sharma, Meena; Loncarek, Jadranka] NCI, Lab Prot Dynam & Signaling, NIH, CCR, Frederick, MD 21702 USA. [Magidson, Valentin] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Opt Microscopy & Anal Lab, Frederick, MD 21702 USA. RP Loncarek, J (reprint author), NCI, Lab Prot Dynam & Signaling, NIH, CCR, 1050 Boyles St, Frederick, MD 21702 USA. EM jadranka.loncarek@nih.gov RI Kong, Dong/O-4465-2016; OI Kong, Dong/0000-0002-7144-3808; Shukla, Anil/0000-0001-7797-7299 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank members of the Electron Microscopy Core at ATRF in Frederick for assistance with the TEM microscope, Dr Allan Weissman and Dr Kylie Walters for critical reading of the manuscript and Veronica Farmer for help with FACS analysis. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 39 TC 6 Z9 6 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2015 VL 6 AR 8077 DI 10.1038/ncomms9077 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CQ1JN UT WOS:000360353700003 PM 26293378 ER PT J AU Trcek, T Grosch, M York, A Shroff, H Lionnet, T Lehmann, R AF Trcek, Tatjana Grosch, Markus York, Andrew Shroff, Hari Lionnet, Timothee Lehmann, Ruth TI Drosophila germ granules are structured and contain homotypic mRNA clusters SO NATURE COMMUNICATIONS LA English DT Article ID TRANSLATIONAL CONTROL; OSKAR TRANSLATION; LIVE CELLS; PROTEIN; LOCALIZATION; NANOS; MELANOGASTER; EXPRESSION; PLASM; COLOCALIZATION AB Germ granules, specialized ribonucleoprotein particles, are a hallmark of all germ cells. In Drosophila, an estimated 200 mRNAs are enriched in the germ plasm, and some of these have important, often conserved roles in germ cell formation, specification, survival and migration. How mRNAs are spatially distributed within a germ granule and whether their position defines functional properties is unclear. Here we show, using single-molecule FISH and structured illumination microscopy, a super-resolution approach, that mRNAs are spatially organized within the granule whereas core germ plasm proteins are distributed evenly throughout the granule. Multiple copies of single mRNAs organize into 'homotypic clusters' that occupy defined positions within the center or periphery of the granule. This organization, which is maintained during embryogenesis and independent of the translational or degradation activity of mRNAs, reveals new regulatory mechanisms for germ plasm mRNAs that may be applicable to other mRNA granules. C1 [Trcek, Tatjana; Grosch, Markus; Lehmann, Ruth] NYU, Sch Med, Dept Cell Biol, HHMI,Skirball Inst Biomol Med, New York, NY 10016 USA. [York, Andrew; Shroff, Hari] Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD 20814 USA. [Lionnet, Timothee] Howard Hughes Med Inst, Transcript Imaging Consortium, Ashburn, VA 20147 USA. RP Lehmann, R (reprint author), NYU, Sch Med, Dept Cell Biol, HHMI,Skirball Inst Biomol Med, 540 First Ave, New York, NY 10016 USA. EM ruth.lehmann@med.nyu.edu RI Shroff, Hari/E-7247-2016; OI Shroff, Hari/0000-0003-3613-8215; Lionnet, Timothee/0000-0003-1508-0202; Lehmann, Ruth/0000-0002-8454-5651 FU Howard Hughes Medical Institute; Intramural Research Programs of the US National Institute of Biomedical Imaging and Bioengineering FX We thank Yang Deng of the NYULMC OCS Microscopy Core for his help with the wide field microscope. We thank Eli Rothenberg for his advice on overlap analysis and particle counting, and Felipe K. Teixeira and Maija Slaidina for comments on the manuscript. This work was funded by the Howard Hughes Medical Institute (also supporting R.L. and T.L.) and the Intramural Research Programs of the US National Institute of Biomedical Imaging and Bioengineering (also supporting A.G.Y. and H.S.). T.T. is an HHMI fellow of the Jane Coffin Childs Memorial Fund. NR 46 TC 13 Z9 13 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2015 VL 6 AR 7962 DI 10.1038/ncomms8962 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CQ1HC UT WOS:000360346900003 PM 26242323 ER PT J AU Wake, H Ortiz, FC Woo, DH Lee, PR Angulo, MC Fields, RD AF Wake, Hiroaki Ortiz, Fernando C. Woo, Dong Ho Lee, Philip R. Angulo, Maria Cecilia Fields, R. Douglas TI Nonsynaptic junctions on myelinating glia promote preferential myelination of electrically active axons SO NATURE COMMUNICATIONS LA English DT Article ID OLIGODENDROCYTE PRECURSOR CELLS; MOUSE SPINAL-CORD; WHITE-MATTER; EXTRASYNAPTIC TRANSMISSION; ACTION-POTENTIALS; RELEASE; DIFFERENTIATION; COMMUNICATION; MORPHOLOGY; GLUTAMATE AB The myelin sheath on vertebrate axons is critical for neural impulse transmission, but whether electrically active axons are preferentially myelinated by glial cells, and if so, whether axo-glial synapses are involved, are long-standing questions of significance to nervous system development, plasticity and disease. Here we show using an in vitro system that oligodendrocytes preferentially myelinate electrically active axons, but synapses from axons onto myelin-forming oligodendroglial cells are not required. Instead, vesicular release at nonsynaptic axo-glial junctions induces myelination. Axons releasing neurotransmitter from vesicles that accumulate in axon varicosities induces a local rise in cytoplasmic calcium in glial cell processes at these nonsynaptic functional junctions, and this signalling stimulates local translation of myelin basic protein to initiate myelination. C1 [Wake, Hiroaki; Woo, Dong Ho; Lee, Philip R.; Fields, R. Douglas] NICHHD, NIH, Sect Nervous Syst Dev & Plast, Bethesda, MD 20892 USA. [Ortiz, Fernando C.; Angulo, Maria Cecilia] INSERM, U1128, F-75006 Paris, France. [Ortiz, Fernando C.; Angulo, Maria Cecilia] Univ Paris 05, Sorbonne Paris Cite, F-75006 Paris, France. RP Fields, RD (reprint author), NICHHD, NIH, Sect Nervous Syst Dev & Plast, Bldg 35,Room 2A211,MSC 3713,35 Lincoln Dr, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov RI Angulo, Maria Cecilia/B-8236-2014 OI Angulo, Maria Cecilia/0000-0002-0758-0496 FU NICHD funds; Agence Nationale de la Recherche (ANR) [R14193KK]; Fondation pour l'aide a la recherche sur la Sclerose en Plaques (ARSEP); IDEX-Cite Paris Sorbonne; Fondation pour la Recherche Medicale (FRM) FX We thank Andrea Helo for her help on building the MATLAB custom routine used for leak subtraction. This work was supported by NICHD funds for intramural research. M.C.A. is part of the ENP-Ile-de-France network and was supported by grants from Agence Nationale de la Recherche (ANR, R14193KK), Fondation pour l'aide a la recherche sur la Sclerose en Plaques (ARSEP) and IDEX-Cite Paris Sorbonne. FCO is supported by a post-doc fellowship from Fondation pour la Recherche Medicale (FRM). NR 28 TC 26 Z9 27 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2015 VL 6 AR 7844 DI 10.1038/ncomms8844 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CQ1FR UT WOS:000360343200001 PM 26238238 ER PT J AU Wan, CK Li, P Spolski, R Oh, J Andraski, AB Du, N Yu, ZX Dillon, CP Green, DR Leonard, WJ AF Wan, Chi-Keung Li, Peng Spolski, Rosanne Oh, Jangsuk Andraski, Allison B. Du, Ning Yu, Zu-Xi Dillon, Christopher P. Green, Douglas R. Leonard, Warren J. TI IL-21-mediated non-canonical pathway for IL-1 beta production in conventional dendritic cells SO NATURE COMMUNICATIONS LA English DT Article ID CONVERTING-ENZYME; HOST-DEFENSE; STEADY-STATE; IN-VIVO; IL-21; INTERLEUKIN-21; INFLAMMASOME; ACTIVATION; PROTEINASE-3; INHIBITOR AB The canonical pathway for IL-1 beta production requires TLR-mediated NF-kappa B-dependent Il1b gene induction, followed by caspase-containing inflammasome-mediated processing of pro-IL-1 beta. Here we show that IL-21 unexpectedly induces IL-1 beta production in conventional dendritic cells (cDCs) via a STAT3-dependent but NF-kappa B-independent pathway. IL-21 does not induce Il1b expression in CD4(+) T cells, with differential histone marks present in these cells versus cDCs. IL-21-induced IL-1 beta processing in cDCs does not require caspase-1 or caspase-8 but depends on IL-21-mediated death and activation of serine protease(s). Moreover, STAT3-dependent IL-1 beta expression in cDCs at least partially explains the IL-21-mediated pathologic response occurring during infection with pneumonia virus of mice. These results demonstrate lineage-restricted IL-21-induced IL-1 beta via a non-canonical pathway and provide evidence for its importance in vivo. C1 [Wan, Chi-Keung; Li, Peng; Spolski, Rosanne; Oh, Jangsuk; Andraski, Allison B.; Du, Ning; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Wan, Chi-Keung; Li, Peng; Spolski, Rosanne; Oh, Jangsuk; Andraski, Allison B.; Du, Ning; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, Pathol Core, NIH, Bethesda, MD 20892 USA. [Dillon, Christopher P.; Green, Douglas R.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, 10 Ctr Dr,Bldg 10,Room 7B05, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute; NIH [R01AI44828] FX We thank Drs Jae Jin Chae, Dan Kastner, Giorgio Trinchieri, Richard Flavell and Vishva Dixit for providing mouse strains, and Dr Jian-Xin Lin, NHLBI, for critical comments. Dr Majid Kazemian for technical support. This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute (W.J.L.) and NIH grant R01AI44828 (D.R.G.). NR 38 TC 3 Z9 3 U1 1 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 2015 VL 6 AR 7988 DI 10.1038/ncomms8988 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CQ1HF UT WOS:000360347200006 PM 26269257 ER PT J AU Yoo, YS Park, YY Kim, JH Cho, H Kim, SH Lee, HS Kim, TH Kim, YS Lee, Y Kim, CJ Jung, JU Lee, JS Cho, H AF Yoo, Young-Suk Park, Yong-Yea Kim, Jae-Hoon Cho, Hyeseon Kim, Song-Hee Lee, Ho-Soo Kim, Tae-Hwan Kim, You Sun Lee, Youngsoo Kim, Chul-Joong Jung, Jae U. Lee, Jong-Soo Cho, Hyeseong TI The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling SO NATURE COMMUNICATIONS LA English DT Article ID NF-KAPPA-B; RIG-I; DOWN-REGULATION; IMMUNE-RESPONSE; MITOFUSIN 1; E3 LIGASES; DEGRADATION; ACTIVATION; PROTEINS; ADAPTER AB Mitochondria serve as platforms for innate immunity. The mitochondrial antiviral signalling (MAVS) protein forms aggregates that elicit robust type-I interferon induction on viral infection, but persistent MAVS signalling leads to host immunopathology; it remains unknown how these signalling aggregates are resolved. Here we identify the mitochondria-resident E3 ligase, MARCH5, as a negative regulator of MAVS aggregates. March(+/-) mice and MARCH5-deficient immune cells exhibit low viral replication and elevated type-I interferon responses to RNA viruses. MARCH5 binds MAVS only during viral stimulation when MAVS forms aggregates, and these interactions require the RING domain of MARCH5 and the CARD domain of MAVS. MARCH5, but not its RING mutant (MARCH5(H43W)), reduces the level of MAVS aggregates. MARCH5 transfers ubiquitin to Lys7 and Lys500 of MAVS and promotes its proteasome-mediated degradation. Our results indicate that MARCH5 modulates MAVS-mediated antiviral signalling, preventing excessive immune reactions. C1 [Yoo, Young-Suk; Park, Yong-Yea; Kim, Song-Hee; Lee, Ho-Soo; Kim, You Sun; Cho, Hyeseong] Ajou Univ, Grad Sch, Sch Med, Dept Biochem, Suwon 443380, South Korea. [Yoo, Young-Suk; Lee, Ho-Soo; Kim, You Sun; Lee, Youngsoo; Cho, Hyeseong] Ajou Univ, Grad Sch, Dept Biol Sci, Suwon 443380, South Korea. [Kim, Jae-Hoon; Kim, Tae-Hwan; Kim, Chul-Joong; Lee, Jong-Soo] Chungnam Natl Univ, Coll Vet Med, Plus Program BK21, Taejon 305764, South Korea. [Cho, Hyeseon] NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20852 USA. [Lee, Youngsoo; Cho, Hyeseong] Ajou Univ, Sch Med, Genom Instabil Res Ctr, Suwon 443380, South Korea. [Jung, Jae U.] Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90089 USA. RP Lee, JS (reprint author), Chungnam Natl Univ, Coll Vet Med, Plus Program BK21, Taejon 305764, South Korea. EM jongsool@cnu.ac.kr; hscho@ajou.ac.kr FU National Research Foundation of Korea - Korea government (MSIP) [2011-0017635, 2011-0030043]; Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea [112013032SB010] FX We thank Cho Hyeseon (NIH, Bethesda) for her critical reading and comments on our manuscript. This work was supported by the National Research Foundation of Korea grants funded by the Korea government (MSIP; No. 2011-0017635, 2011-0030043) and by the Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea (Grant No. 112013032SB010). NR 56 TC 9 Z9 9 U1 2 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 2015 VL 6 AR 7910 DI 10.1038/ncomms8910 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CQ1GN UT WOS:000360345400005 PM 26246171 ER PT J AU Pappas, A Shankaran, S McDonald, SA Vohr, BR Hintz, SR Ehrenkranz, RA Tyson, JE Yolton, K Das, A Bara, R Hammond, J Higgins, RD AF Pappas, Athina Shankaran, Seetha McDonald, Scott A. Vohr, Betty R. Hintz, Susan R. Ehrenkranz, Richard A. Tyson, Jon E. Yolton, Kimberly Das, Abhik Bara, Rebecca Hammond, Jane Higgins, Rosemary D. CA Eunice Kennedy Shriver NICHD Neona TI Cognitive Outcomes After Neonatal Encephalopathy SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB Cognitive impairment is an important issue found in survivors at 18 to 24 months in all major previous trials of hypothermia treatment of hypoxic ischemic encephalopathy (HIE). The authors of this study hypothesized that infants between 18 and 22 months with a Mental Developmental Index of less than 70 would continue to have cognitive impairment and development disabilities at school age. The study aimed to report special educational services and therapies, describe the range of cognitive outcomes of moderate or severe HIE in children, and evaluate the value of various predictors of school-age cognition. Data from the National Institute for Child Health and Development Neonatal Research Network multicenter trial of whole-body hypothermia, conducted between 2000 and 2003, were used in this secondary analysis. Participants who experienced moderate and severe encephalopathy within the first 6 hours of life were treated with either hypothermia or routine neonatal intensive care. Follow-up was at 18 to 22 months and 6 to 7 years and included neurologic examinations, the Bayley Scales of Infant Development, Wechsler intelligence scales, and Neuropsychological Assessment-Developmental NEuroPSYchological Assessment (NEPSY). Cerebral palsy severity was identified using the Gross Motor Function Classification System. Of 140 surviving children, 30 were lost to follow-up. Twenty-two percent of children were found to be untestable with the NEPSY because of severe cognitive and/or neurologic impairment. In children with cerebral palsy (CP), 96% (22/23) had an IQ of less than 70, and in children without CP, 9% had an IQ of less than 70, and 31% had an IQ score between 70 and 84. In children with Mental Development Index scores of less than 70, a wide range of gross motor outcomes was seen, with only 17% exhibiting fine motor skills. In children with an IQ of less than 70 at 6 to 7 years, only 23% had a normal gait, 6% to 16% of that group had normal complex motor functions, and about 10% had intact coordination and fine motor skills. Of the 110 children, 79 stayed in the same development range between 18 to 22 months and 6 to 7 years. Of the children followed up to 6 or 7 years, 7% to 9% had behavioral problems, compared with 5% to 7% among normally developing children, and 30% received special educational services. Children with neonatal encephalopathy were more likely to have special educational needs. The neuropathology of neonatal encephalopathy may be better understood with careful neurodevelopmental follow-up along with advanced neuroimaging, and this may provide new intervention opportunities. The study shows that while cognitive impairment is not specific to neonatal encephalopathy, it remains an important concern for survivors of neonatal encephalopathy. Whether motor impairment is present, school-age assessments and early intervention are recommended. C1 [Pappas, Athina; Shankaran, Seetha; Bara, Rebecca] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [McDonald, Scott A.] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Vohr, Betty R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Hintz, Susan R.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Ehrenkranz, Richard A.] Yale Univ, Dept Pediat, New Haven, CT 06520 USA. [Tyson, Jon E.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA. [Yolton, Kimberly] Univ Cincinnati, Dept Pediat, Cincinnati, OH USA. [Das, Abhik; Hammond, Jane] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Pappas, A (reprint author), Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. NR 0 TC 0 Z9 0 U1 3 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD AUG PY 2015 VL 70 IS 8 BP 487 EP 488 DI 10.1097/OGX.0000000000000232 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CP8KS UT WOS:000360143200005 ER PT J AU Pletnev, VZ Pletneva, NV Sarkisyan, KS Mishin, AS Lukyanov, KA Goryacheva, EA Ziganshin, RH Dauter, Z Pletnev, S AF Pletnev, Vladimir Z. Pletneva, Nadya V. Sarkisyan, Karen S. Mishin, Alexander S. Lukyanov, Konstantin A. Goryacheva, Ekaterina A. Ziganshin, Rustam H. Dauter, Zbigniew Pletnev, Sergei TI Structure of the green fluorescent protein NowGFP with an anionic tryptophan-based chromophore SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article DE fluorescent proteins; tryptophan-based chromophore; anionic tryptophan; crystal structure; spectral properties ID BIOLOGICAL RECOGNITION; AROMATIC RINGS; FRET AB A green-emitting fluorescent variant, NowGFP, with a tryptophan-based chromophore (Thr65-Trp66-Gly67) was recently developed from the cyan mCerulean by introducing 18 point mutations. NowGFP is characterized by bright green fluorescence at physiological and higher pH and by weak cyan fluorescence at low pH. Illumination with blue light induces irreversible photoconversion of NowGFP from a green-emitting to a cyan-emitting form. Here, the X-ray structures of intact NowGFP at pH 9.0 and pH 4.8 and of its photoconverted variant, NowGFP_conv, are reported at 1.35, 1.18 and 2.5 angstrom resolution, respectively. The structure of NowGFP at pH 9.0 suggests the anionic state of Trp66 of the chromophore to be the primary cause of its green fluorescence. At both examined pH values Trp66 predominantly adopted a cis conformation; only approximate to 20% of the trans conformation was observed at pH 4.8. It was shown that Lys61, which adopts two distinct pH-dependent conformations, is a key residue playing a central role in chromophore ionization. At high pH the side chain of Lys61 forms two hydrogen bonds, one to the indole N atom of Trp66 and the other to the carboxyl group of the catalytic Glu222, enabling an indirect noncovalent connection between them that in turn promotes Trp66 deprotonation. At low pH, the side chain of Lys61 is directed away from Trp66 and forms a hydrogen bond to Gln207. It has been shown that photoconversion of NowGFP is accompanied by decomposition of Lys61, with a predominant cleavage of its side chain at the CC bond. Lys61, Glu222, Thr203 and Ser205 form a local hydrogen-bond network connected to the indole ring of the chromophore Trp66; mutation of any of these residues dramatically affects the spectral properties of NowGFP. On the other hand, an Ala150Val replacement in the vicinity of the chromophore indole ring resulted in a new advanced variant with a 2.5-fold improved photostability. C1 [Pletnev, Vladimir Z.; Pletneva, Nadya V.; Sarkisyan, Karen S.; Mishin, Alexander S.; Lukyanov, Konstantin A.; Goryacheva, Ekaterina A.; Ziganshin, Rustam H.] Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. [Dauter, Zbigniew; Pletnev, Sergei] 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. RP Pletnev, VZ (reprint author), Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, GSP 7, Moscow, Russia. EM vzpletnev@gmail.com; pletnevs@mail.nih.gov RI Sarkisyan, Karen/M-6821-2015; Mishin, Alexander/L-9420-2014; Pletneva, Nadya/F-7839-2014; Pletnev, Vladimir/Q-6151-2016; Goryacheva, Ekaterina/Q-6277-2016; Ziganshin, Rustam/Q-7445-2016 OI Sarkisyan, Karen/0000-0002-5375-6341; Mishin, Alexander/0000-0002-4935-7030; Ziganshin, Rustam/0000-0002-7931-519X FU MCB RAS; Russian Foundation for Basic Research [14-04-00004, 13-04-01878-a]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This project has been supported by grants from the MCB RAS and the Russian Foundation for Basic Research (14-04-00004 and 13-04-01878-a). This research was partially carried out using the equipment provided by the IBCH core facility (CKP IBCH). Diffraction experiments were carried out on beamlines 22-ID and 22-BM of the Southeast Regional Collaborative Access Team (SER-CAT) located at the Advanced Photon Source, Argonne National Laboratory. Use of the APS was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. This project has been supported in part with Federal funds from the National Cancer Institute, National Institutes of Health (NIH) contract No. HHSN261200800001E and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 20 TC 4 Z9 4 U1 1 U2 12 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 1399-0047 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD AUG PY 2015 VL 71 BP 1699 EP 1707 DI 10.1107/S1399004715010159 PN 8 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA CO7QC UT WOS:000359354800011 PM 26249350 ER PT J AU Espeland, MA Probstfield, J Hire, D Redmon, JB Evans, GW Coday, M Lewis, CE Johnson, KC Wilmoth, S Bahnson, J Dulin, MF Green, JB Knowler, WC Kitabchi, A Murillo, AL Osei, K Rehman, SU Cushman, WC AF Espeland, Mark A. Probstfield, Jeffery Hire, Donald Redmon, J. Bruce Evans, Gregory W. Coday, Mace Lewis, Cora E. Johnson, Karen C. Wilmoth, Sharon Bahnson, Judy Dulin, Michael F. Green, Jennifer B. Knowler, William C. Kitabchi, Abbas Murillo, Anne L. Osei, Kwame Rehman, Shakaib U. Cushman, William C. CA Ahead Res Grp Accord Study Grp TI Systolic Blood Pressure Control Among Individuals With Type 2 Diabetes: A Comparative Effectiveness Analysis of Three Interventions SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; blood pressure control; blood pressure monitoring; comparative effectiveness; diabetes; hypertension; lifestyle intervention; obesity ID LIFE-STYLE INTERVENTION; WEIGHT-LOSS; HEALTH; TRIAL; PREVENTION; MANAGEMENT; MELLITUS; DISEASE AB BACKGROUND The relative effectiveness of 3 approaches to blood pressure control( i) an intensive lifestyle intervention (ILI) focused on weight loss, (ii) frequent goal-based monitoring of blood pressure with pharmacological management, and (iii) education and support-has not been established among overweight and obese adults with type 2 diabetes who are appropriate for each intervention. METHODS Participants from the Action for Health in Diabetes (Look AHEAD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) cohorts who met criteria for both clinical trials were identified. The proportions of these individuals with systolic blood pressure (SBP) < 140 mm Hg from annual standardized assessments over time were compared with generalized estimating equations. RESULTS Across 4 years among 480 Look AHEAD and 1,129 ACCORD participants with baseline SBPs between 130 and 159 mm Hg, ILI (OR = 1.46; 95% CI = [1.18-1.81]) and frequent goal-based monitoring with pharmacotherapy (OR = 1.51; 95% CI = [1.16-1.97]) yielded higher rates of blood pressure control compared to education and support. The intensive behavioral-based intervention may have been more effective among individuals with body mass index >30 kg/m(2), while frequent goal-based monitoring with medication management may be more effective among individuals with lower body mass index (interaction P = 0.047). CONCLUSIONS Among overweight and obese adults with type 2 diabetes, both ILI and frequent goal-based monitoring with pharmacological management can be successful strategies for blood pressure control. C1 [Espeland, Mark A.; Hire, Donald; Evans, Gregory W.; Wilmoth, Sharon; Bahnson, Judy] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27109 USA. [Probstfield, Jeffery; Murillo, Anne L.] Univ Washington, Seattle, WA 98195 USA. [Redmon, J. Bruce] Univ Minnesota, Minneapolis, MN USA. [Coday, Mace; Johnson, Karen C.; Kitabchi, Abbas] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Birmingham, AL USA. [Dulin, Michael F.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Green, Jennifer B.] Duke Univ, Med Ctr, Durham, NC USA. [Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Osei, Kwame] Ohio State Univ, Internal Med, Columbus, OH 43210 USA. [Rehman, Shakaib U.] Phoenix VA Hlth Care Syst, Phoenix, AZ USA. [Cushman, William C.] Vet Affairs Med Ctr, Memphis, TN USA. RP Espeland, MA (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27109 USA. EM mespelan@wakehealth.edu FU National Heart Lung and Blood Institute [N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184]; National Institutes of Health, National Institute of, Diabetes and Digestive and Kidney Diseases; National Institutes of Health, National Institute on Aging; National Institutes of Health, National Eye Institute; Center for Disease Control; IAA [Y1-HC-9035, Y1-HC-1010] FX This work was supported by National Heart Lung and Blood Institute contracts N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, and IAA #Y1-HC-9035 and IAA#Y1-HC-1010. Other components of the National Institutes of Health, including the National Institute of, Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute, contributed funding. The Center for Disease Control funded, substudies within ACCORD on cost-effectiveness and health-related quality of life. General Clinical Research Centers provide support at many sites. NR 21 TC 4 Z9 4 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 EI 1941-7225 J9 AM J HYPERTENS JI Am. J. Hypertens. PD AUG PY 2015 VL 28 IS 8 BP 995 EP 1009 DI 10.1093/ajh/hpu292 PG 15 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CO7OL UT WOS:000359349100007 PM 25666468 ER PT J AU Sharma, S Clark, S Abubakar, K Keszler, M AF Sharma, Saumya Clark, Shane Abubakar, Kabir Keszler, Martin TI Tidal Volume Requirement in Mechanically Ventilated Infants with Meconium Aspiration Syndrome SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE meconium aspiration syndrome; tidal volume; minute ventilation; mechanical ventilation ID TARGETED VENTILATION; PIGLET MODEL; LUNG INJURY AB Objective The aim of the study is to test the hypothesis that increased physiologic dead space and functional residual capacity seen in meconium aspiration syndrome (MAS) results in higher tidal volume (V-T) requirement to achieve adequate ventilation. Study Design Retrospective review of infants with MAS admitted to our hospital from 2000 to 2010 managed with conventional ventilation. Demographics, ventilator settings, V-T, respiratory rate (RR), and blood gas values were recorded. Minute ventilation (MV) was calculated as RR X V-T. Only V-T values with corresponding partial pressure of carbon dioxide (Paco(2)) between 35 and 60 mm Hg were included. Mean V-T/kg and MV/kg were calculated for each patient. Forty infants ventilated for lung disease other than MAS or pulmonary hypoplasia served as controls. Results Birth weights of the 28 MAS patients and 40 control infants were similar (3,330 +/- 500 g and 3,300 +/- 640 g). Two patients in each group required extracorporeal membrane oxygenation. Infants with MAS required 26% higher V-T and 42% higher MV compared with controls to maintain equal Paco2. Conclusion Infants with MAS require larger V-T and higher total MV to achieve similar alveolar ventilation, consistent with pathophysiology of MAS. Our findings provide the first reference data to guide selection of V-T in infants with MAS. C1 [Sharma, Saumya; Abubakar, Kabir] Georgetown Univ Hosp, Dept Pediat, Div Neonatol, Washington, DC 20007 USA. [Clark, Shane] NHGRI, Genom Med Div, NIH, Bethesda, MD 20892 USA. [Keszler, Martin] Brown Univ, Div Neonatol, Dept Pediat, Women & Infants Hosp, Providence, RI 02912 USA. RP Abubakar, K (reprint author), MedStar Georgetown Univ Hosp, Div Neonatol, M3400,3800 Reservoir Rd,NW, Washington, DC 20007 USA. EM abubakak@georgetown.edu OI Keszler, Martin/0000-0002-9964-664X NR 14 TC 1 Z9 1 U1 1 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 2015 VL 32 IS 10 BP 916 EP 919 DI 10.1055/s-0034-1396698 PG 4 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA CP4VQ UT WOS:000359881100003 PM 25738789 ER PT J AU Cheng, XT Zhou, B Lin, MY Cai, Q Sheng, ZH AF Cheng, Xiu-Tang Zhou, Bing Lin, Mei-Yao Cai, Qian Sheng, Zu-Hang TI Axonal autophagosomes use the ride-on service for retrograde transport toward the soma SO AUTOPHAGY LA English DT Editorial Material DE autophagy; amphisome; autophagosome; autophagic clearance; axon; dynein; late endosome; lysosome; retrograde transport; SNAPIN; syntaxin 17 AB Degradation of autophagic vacuoles (AVs) via lysosomes is an important homeostatic process in cells. Neurons are highly polarized cells with long axons, thus facing special challenges to transport AVs generated at distal processes toward the soma where mature acidic lysosomes are relatively enriched. We recently revealed a new motor-adaptor sharing mechanism driving autophagosome transport to the soma. Late endosome (LE)-loaded dynein-SNAPIN motor-adaptor complexes mediate the retrograde transport of autophagosomes upon their fusion with LEs in distal axons. This motor-adaptor sharing mechanism enables neurons to maintain effective autophagic clearance in the soma, thus reducing autophagic stress in axons. Therefore, our study reveals a new cellular mechanism underlying the removal of distal AVs engulfing aggregated misfolded proteins and dysfunctional organelles associated with several major neurodegenerative diseases. C1 [Cheng, Xiu-Tang; Zhou, Bing; Lin, Mei-Yao; Sheng, Zu-Hang] NINDS, Synapt Funct Sect, NIH, Bethesda, MD 20892 USA. [Cai, Qian] Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ USA. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov FU NINDS NIH HHS [ZIA NS002946, ZIA NS003029] NR 0 TC 4 Z9 4 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD AUG PY 2015 VL 11 IS 8 BP 1434 EP 1436 DI 10.1080/15548627.2015.1062203 PG 3 WC Cell Biology SC Cell Biology GA CP6DZ UT WOS:000359975900020 PM 26102591 ER PT J AU Andres, SA Appel, CD Westmoreland, JW Williams, JS Nguyen, Y Robertson, PD Resnick, MA Williams, RS AF Andres, S. A. Appel, C. D. Westmoreland, J. W. Williams, J. S. Nguyen, Y. Robertson, P. D. Resnick, M. A. Williams, R. S. TI Ctp1 Orchestrates DNA Binding and Bridging in DNA Repair. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Andres, S. A.; Appel, C. D.; Westmoreland, J. W.; Williams, J. S.; Nguyen, Y.; Robertson, P. D.; Resnick, M. A.; Williams, R. S.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA 8 BP S51 EP S51 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400085 ER PT J AU Conover, HN Lujan, SA Chapman, MJ Cornelio, DA Williams, JS Clark, AB Sharif, R Camilo, F Kunkel, TA Argueso, JL AF Conover, H. N. Lujan, S. A. Chapman, M. J. Cornelio, D. A. Williams, J. S. Clark, A. B. Sharif, R. Camilo, F. Kunkel, T. A. Argueso, J. L. TI Leading Strand-Specific Stimulation of Chromosomal Rearrangements by Ribonucleotides. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Conover, H. N.; Chapman, M. J.; Cornelio, D. A.; Sharif, R.; Camilo, F.; Argueso, J. L.] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. [Conover, H. N.; Argueso, J. L.] Colorado State Univ, Cell & Mol Biol Grad Program, Ft Collins, CO 80523 USA. [Lujan, S. A.; Williams, J. S.; Clark, A. B.; Kunkel, T. A.] NIEHS, Genome Integr & Struct Biol Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P1 BP S57 EP S57 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400108 ER PT J AU Daniels, SI Hu, W Chang, CC Tu, B Haider, I Li, G Rothman, N Smith, M Lan, Q Zhang, L AF Daniels, S., I Hu, W. Chang, C-C Tu, B. Haider, I Li, G. Rothman, N. Smith, M. Lan, Q. Zhang, L. TI Effects of Benzene Metabolites on Cellular Iron Status SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Daniels, S., I; Chang, C-C; Tu, B.; Haider, I; Smith, M.; Zhang, L.] Univ Calif Berkeley, Sch Publ Hlth, Environm Hlth Sci Div, Berkeley, CA 94720 USA. [Hu, W.; Rothman, N.; Lan, Q.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Li, G.] China CDC, Inst Occupat & Environm Hlth, Beijing, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P55 BP S71 EP S71 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400162 ER PT J AU Divi, KV Poirier, MC Olivero, OA AF Divi, K., V Poirier, M. C. Olivero, O. A. TI Use of a Derived Centrosome Primary Cilia Model to Evaluate the Aneugen Zidovudine (AZT) SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Divi, K., V; Poirier, M. C.; Olivero, O. A.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P62 BP S72 EP S72 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400169 ER PT J AU Freudenthal, BD Fedeles, BI Yau, E Singh, V Chang, SC Li, D Delaney, J Wilson, SH Essigmann, JM AF Freudenthal, B. D. Fedeles, B., I Yau, E. Singh, V Chang, S-C Li, D. Delaney, J. Wilson, S. H. Essigmann, J. M. TI The Intrinsic Mutagenic Properties of 5-chlorocytosine: A Mechanistic Connection between Chronic Inflammation and Cancer. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Freudenthal, B. D.] NIEHS, NIH, Durham, NC USA. [Fedeles, B., I; Yau, E.; Singh, V; Chang, S-C; Li, D.; Delaney, J.; Wilson, S. H.; Essigmann, J. M.] MIT, Cambridge, MA 02139 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA S72 BP S48 EP S48 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400071 ER PT J AU Gassman, NR Wilson, SH AF Gassman, N. R. Wilson, S. H. TI BPA Alters Cellular Microenvironment to Promote Cell Survival after Oxidative Stress SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Gassman, N. R.] Univ S Alabama, Mitchell Canc Inst, Mobile, AL 36688 USA. [Wilson, S. H.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P27 BP S64 EP S64 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400134 ER PT J AU Gray, KA Thompson, C AF Gray, K. A. Thompson, C. TI NIEHS Investment in Children's Environmental Health Studies: Opportunities for High-Dimensional Data Analyses and Exposure Characterization. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Gray, K. A.; Thompson, C.] NIEHS, Morrisville, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA S75 BP S49 EP S49 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400074 ER PT J AU Joubert, BR AF Joubert, B. R. CA PACE Consortium TI Epigenome-Wide Meta-Analysis of Methylation in Offspring Related to Maternal Smoking in Pregnancy in the Pregnancy and Child Epigenetics (PACE) Consortium. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Joubert, B. R.; PACE Consortium] NIEHS, NIH, Populat Hlth Branch, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 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 2015 VL 56 SU 1 MA S77 BP S49 EP S49 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400075 ER PT J AU Kunkel, TA AF Kunkel, T. A. TI Genome Wide Studies of Nuclear DNA Replication Fidelity SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Kunkel, T. A.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA S10 BP S33 EP S33 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400010 ER PT J AU Lormand, J Fouquerel, E Freudenthal, B Sobol, RW Myong, S Opresko, PL AF Lormand, J. Fouquerel, E. Freudenthal, B. Sobol, R. W. Myong, S. Opresko, P. L. TI Investigating How Oxidative DNA Damage Influences Telomere Maintenance. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Lormand, J.; Fouquerel, E.; Opresko, P. L.] Univ Pittsburgh, Hillman Canc Ctr, Dept EOH, Pittsburgh, PA USA. [Freudenthal, B.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Sobol, R. W.] Univ S Alabama, Mitchell Canc Inst, Mobile, AL 36688 USA. [Myong, S.] Univ Illinois, Dept Bioengn, Urbana, IL 61801 USA. [Opresko, P. L.] Carnegie Mellon Univ, Ctr Nucle Acids Sci & Technol, Pittsburgh, PA 15213 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA 1 BP S50 EP S50 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400078 ER PT J AU Rider, CV Auerbach, SS Ferguson, SS Tokar, EJ Hsieh, JH Shockley, KR Germolec, DR Mutlu, E Masten, SA Waidyanatha, S AF Rider, C., V Auerbach, S. S. Ferguson, S. S. Tokar, E. J. Hsieh, J. H. Shockley, K. R. Germolec, D. R. Mutlu, E. Masten, S. A. Waidyanatha, S. TI From Deepwater Horizon to High-Throughput Screening: Polycyclic Aromatic Compound Testing at the National Toxicology Program SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Rider, C., V; Auerbach, S. S.; Ferguson, S. S.; Tokar, E. J.; Hsieh, J. H.; Shockley, K. R.; Germolec, D. R.; Mutlu, E.; Masten, S. A.; Waidyanatha, S.] NIEHS, NTP, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 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 2015 VL 56 SU 1 MA S23 BP S37 EP S37 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400023 ER PT J AU Sandler, DP Kwok, RK AF Sandler, D. P. Kwok, R. K. TI Health Effects in Oil Spill Clean-Up Workers Participating in the Gulf Long-Term Follow-Up Study (GuLF STUDY) SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Sandler, D. P.; Kwok, R. K.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 1 Z9 1 U1 1 U2 7 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 2015 VL 56 SU 1 MA S21 BP S36 EP S36 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400021 ER PT J AU Schaaper, RM Singh, D Itsko, M AF Schaaper, R. M. Singh, D. Itsko, M. TI Antimutagenic Role and Structure-Function of an Unusual E. coli dGTPase. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Schaaper, R. M.; Singh, D.; Itsko, M.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA 24 BP S55 EP S55 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400101 ER PT J AU Seifried, HE AF Seifried, H. E. TI Is an Ounce of Prevention Really Worth a Pound of Cure? SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Seifried, H. E.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA S14 BP S34 EP S34 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400014 ER PT J AU Smith-Roe, SL Swartz, CD Hobbs, CA Blystone, CR Garantziotis, S Witt, KL AF Smith-Roe, S. L. Swartz, C. D. Hobbs, C. A. Blystone, C. R. Garantziotis, S. Witt, K. L. TI Black Cohosh Extract, a Popular Herbal Product, is Genotoxic In Vivo and In Vitro SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Smith-Roe, S. L.; Blystone, C. R.; Witt, K. L.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Swartz, C. D.; Hobbs, C. A.] ILS Inc, Genet & Mol Toxicol Div, Res Triangle Pk, NC USA. [Garantziotis, S.] NIEHS, Clin Res Program, Res Triangle Pk, NC 27709 USA. RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 2 U2 7 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 2015 VL 56 SU 1 MA P64 BP S73 EP S73 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400171 ER PT J AU Swartz, CD Hobbs, CA Recio, L Auerbach, SS Smith-Roe, SL Witt, KL AF Swartz, C. D. Hobbs, C. A. Recio, L. Auerbach, S. S. Smith-Roe, S. L. Witt, K. L. TI Lack of Genotoxic Potential of Elk River Chemical Contaminants As Assessed by In Vivo Micronucleus and Bacterial Mutagenicity Assays SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Swartz, C. D.; Hobbs, C. A.; Recio, L.] Integrated Lab Syst, Res Triangle Pk, NC USA. [Auerbach, S. S.; Smith-Roe, S. L.; Witt, K. L.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P86 BP S78 EP S78 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400193 ER PT J AU Tumbale, PP Williams, JS Schellenberg, MJ Kunkel, TA Williams, RS AF Tumbale, P. P. Williams, J. S. Schellenberg, M. J. Kunkel, T. A. Williams, R. S. TI Aprataxin Resolves Adenylated RNA-DNA Junctions to Maintain Genome Integrity. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Tumbale, P. P.; Williams, J. S.; Schellenberg, M. J.; Kunkel, T. A.; Williams, R. S.] NIEHS, Genome Integr & Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA 26 BP S56 EP S56 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400103 ER PT J AU Van Houten, B Kong, M Liu, L Min, JH Bernstein, K Wyrick, J Watkins, S Gassman, N Wilson, S AF Van Houten, B. Kong, M. Liu, L. Min, J-H Bernstein, K. Wyrick, J. Watkins, S. Gassman, N. Wilson, S. TI Watching Eukaryotic Nucleotide Excision Repair: One Molecule at a Time SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Van Houten, B.; Kong, M.; Liu, L.] Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Min, J-H] Univ Illinois, Dept Chem, Chicago, IL 60680 USA. [Bernstein, K.] Univ Pittsburgh, Dept Mol Genet, Pittsburgh, PA USA. [Wyrick, J.] Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. [Watkins, S.] Univ Pittsburgh, Ctr Biol Imaging, Pittsburgh, PA USA. [Gassman, N.; Wilson, S.] NIEHS, Lab Struct Biol, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA S8 BP S33 EP S33 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400009 ER PT J AU Witt, KL Hsieh, JH Xia, M Huang, R Auerbach, SS Paules, RS Shockley, KR Merrick, BA Sedykh, A Tice, RR Smith-Roe, SL AF Witt, K. L. Hsieh, J. H. Xia, M. Huang, R. Auerbach, S. S. Paules, R. S. Shockley, K. R. Merrick, B. A. Sedykh, A. Tice, R. R. Smith-Roe, S. L. TI High-Throughput Screening for Rapid Identification of Potential Genotoxicants in Large Compound Libraries: Comparison of the Tox21 Approach to Classic Genotoxicity Assays. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Witt, K. L.; Hsieh, J. H.; Auerbach, S. S.; Paules, R. S.; Merrick, B. A.; Tice, R. R.; Smith-Roe, S. L.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Xia, M.; Huang, R.] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Shockley, K. R.] NIEHS, Biostat & Computat Biol Branch, Res Triangle Pk, NC 27709 USA. [Sedykh, A.] MultiCASE, Beachwood, OH USA. NR 0 TC 0 Z9 0 U1 1 U2 4 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 2015 VL 56 SU 1 MA 16 BP S53 EP S53 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400093 ER PT J AU Fan, RZ Wang, YF Boehnke, M Chen, W Li, Y Ren, HB Lobach, I Xiong, MM AF Fan, Ruzong Wang, Yifan Boehnke, Michael Chen, Wei Li, Yun Ren, Haobo Lobach, Iryna Xiong, Momiao TI Gene Level Meta-Analysis of Quantitative Traits by Functional Linear Models SO GENETICS LA English DT Article DE meta-analysis; rare variants; common variants; association mapping; quantitative trait loci; complex traits; functional data analysis ID GENOME-WIDE ASSOCIATION; RARE VARIANTS; LOCI; DISEASES; MAP AB Meta-analysis of genetic data must account for differences among studies including study designs, markers genotyped, and covariates. The effects of genetic variants may differ from population to population, i.e., heterogeneity. Thus, meta-analysis of combining data of multiple studies is difficult. Novel statistical methods for meta-analysis are needed. In this article, functional linear models are developed for meta-analyses that connect genetic data to quantitative traits, adjusting for covariates. The models can be used to analyze rare variants, common variants, or a combination of the two. Both likelihood-ratio test (LRT) and F-distributed statistics are introduced to test association between quantitative traits and multiple variants in one genetic region. Extensive simulations are performed to evaluate empirical type I error rates and power performance of the proposed tests. The proposed LRT and F-distributed statistics control the type I error very well and have higher power than the existing methods of the meta-analysis sequence kernel association test (MetaSKAT). We analyze four blood lipid levels in data from a meta-analysis of eight European studies. The proposed methods detect more significant associations than MetaSKAT and the P-values of the proposed LRT and F-distributed statistics are usually much smaller than those of MetaSKAT. The functional linear models and related test statistics can be useful in whole-genome and whole-exome association studies. C1 [Fan, Ruzong; Wang, Yifan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Chen, Wei] Univ Pittsburgh, Med Ctr, Div Pulm Med Allergy & Immunol, Pittsburgh, PA 15224 USA. [Li, Yun] Univ N Carolina, Dept Genet, Dept Biostat, Chapel Hill, NC 27599 USA. [Ren, Haobo] Regeneron Pharmaceut, Basking Ridge, NJ 07920 USA. [Lobach, Iryna] Univ Calif San Francisco, Div Biostat, Dept Epidemiol & Biostat, San Francisco, CA 94185 USA. [Xiong, Momiao] Univ Texas Houston, Ctr Human Genet, Houston, TX 77225 USA. RP Fan, RZ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B07J,MSC 7510, Bethesda, MD 20892 USA. EM fanr@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH); Wei Chen's NIH [R01EY024226, R01HG007358]; University of Pittsburgh [R01EY024226]; NIH [R01HG006292, R01HG006703] FX Two anonymous reviewers and the editors, Chiara Sabatti and Gary Churchill, provided very good and insightful comments for us to improve the manuscript. We greatly thank the European cohort investigators for letting us analyze the data and use them as examples. Heather M. Stringham and Tanya M. Teslovich kindly sent us the data of the European cohorts and patiently answered many questions about the cohorts, which we greatly appreciated. We thank Seunggeun Lee for sending us the simulation program of SKAT and sequence data generated by Yun Li using the program COSI. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (http://biowulf.nih.gov). The methods proposed in this article are implemented by using the procedure of functional data analysis (fda) in the statistical package R. The R codes for data analysis and simulations are available at http://www.nichd.nih.gov/about/org/diphr/bbb/software/fan/Pages/default. aspx. This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH) (Ruzong Fan and Yifan Wang); by Wei Chen's NIH grants R01EY024226 and R01HG007358 and the University of Pittsburgh (Ruzong Fan is an unpaid collaborator on the grant R01EY024226); and by NIH grants R01HG006292 and R01HG006703 (to Yun Li). NR 39 TC 11 Z9 11 U1 0 U2 2 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD AUG PY 2015 VL 200 IS 4 BP 1089 EP + DI 10.1534/genetics.115.178343 PG 27 WC Genetics & Heredity SC Genetics & Heredity GA CP5JI UT WOS:000359917000010 PM 26058849 ER PT J AU Gartstein, MA Putnick, D Kwak, K Hahn, CS Bornstein, MH AF Gartstein, Maria A. Putnick, Diane Kwak, Keumjoo Hahn, Chun-Shin Bornstein, Marc H. TI Stability of temperament in South Korean infants from 6 to 12 to 18 months: Moderation by age, gender, and birth order SO INFANT BEHAVIOR & DEVELOPMENT LA English DT Article ID NONSHARED ENVIRONMENT; FAMILY C1 [Gartstein, Maria A.] Washington State Univ, Pullman, WA 99164 USA. [Putnick, Diane; Hahn, Chun-Shin; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Kwak, Keumjoo] Seoul Natl Univ, Seoul 151, South Korea. RP Gartstein, MA (reprint author), Washington State Univ, Pullman, WA 99164 USA. EM gartstma@wsu.edu; Marc_H_Bornstein@nih.gov OI Putnick, Diane/0000-0002-6323-749X FU Intramural Research Program of the NIH, NICHD FX This research was supported by the Intramural Research Program of the NIH, NICHD. NR 19 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-6383 EI 1879-0453 J9 INFANT BEHAV DEV JI Infant Behav. Dev. PD AUG PY 2015 VL 40 BP 103 EP 107 DI 10.1016/j.infbeh.2015.05.002 PG 5 WC Psychology, Developmental SC Psychology GA CP4YU UT WOS:000359889300011 PM 26101164 ER PT J AU Bornstein, MH Arterberry, ME Mash, C Manian, N AF Bornstein, Marc H. Arterberry, Martha E. Mash, Clay Manian, Nanmathi TI Discrimination of facial expression by 5-month-old infants of nondepressed and clinically depressed mothers (vol 34, pg 100, 2011) SO INFANT BEHAVIOR & DEVELOPMENT LA English DT Correction C1 [Bornstein, Marc H.; Mash, Clay; Manian, Nanmathi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, NIH, Publ Hlth Serv, Bethesda, MD 20892 USA. [Arterberry, Martha E.] Colby Coll, Waterville, ME 04901 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Bornstein@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-6383 EI 1879-0453 J9 INFANT BEHAV DEV JI Infant Behav. Dev. PD AUG PY 2015 VL 40 BP 270 EP 270 DI 10.1016/j.infbeh.2015.06.001 PG 1 WC Psychology, Developmental SC Psychology GA CP4YU UT WOS:000359889300026 ER PT J AU Deseive, S Chen, MY Korosoglou, G Leipsic, J Martuscelli, E Carrascosa, P Mirsadraee, S White, C Hadamitzky, M Martinoff, S Menges, AL Bischoff, B Massberg, S Hausleiter, J AF Deseive, Simon Chen, Marcus Y. Korosoglou, Grigorios Leipsic, Jonathon Martuscelli, Eugenio Carrascosa, Patricia Mirsadraee, Saeed White, Charles Hadamitzky, Martin Martinoff, Stefan Menges, Anna-Leonie Bischoff, Bernhard Massberg, Steffen Hausleiter, Joerg TI Prospective Randomized Trial on Radiation Dose Estimates of CT Angiography Applying Iterative Image Reconstruction The PROTECTION V Study SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE computed tomography angiography; coronary; iterative image reconstruction; radiation dose ID FILTERED BACK-PROJECTION; COMPUTED-TOMOGRAPHY ANGIOGRAPHY; PITCH SPIRAL ACQUISITION; CORONARY-ANGIOGRAPHY; DIAGNOSTIC-ACCURACY; QUALITY; EXPOSURE; REDUCTION AB OBJECTIVES The purpose of this study was to assess the potential of iterative image reconstruction (IR) of images for radiation dose reduction in coronary computed tomography angiography (CIA). Therefore, IR in combination with 30% tube current reduction was compared with standard scanning with filtered back projection (FBP) reconstruction. BACKGROUND Lately, new IR techniques with advanced raw data processing have been introduced by different computed tomography vendors, thus allowing for either image noise reduction at unchanged radiation dose levels or radiation dose reductions at comparable image noise levels. METHODS In this prospective, multicenter, multivendor noninferiority trial, we randomized 400 consecutive patients to 1 of 2 groups: a control group using standard FBP image reconstruction and standard tube current or an interventional group using IR technique and 30% tube current reduction. The primary endpoint was to demonstrate noninferiority in image quality (IQ) in the IR group. IQ was assessed on a 4-point scale (1, nondiagnostic IQ; 4, excellent IQ). Secondary endpoints included total radiation dose estimates and the rate of downstream testing during 30-day follow-up. RESULTS Median IQ in the IR group was noninferior compared with the conventional FBP group (IR, 3.5 [interquartile range: 3.0 to 4.0]; FBP, 3.4 [interquartile range: 2.8 to 4.0], p for noninferiority <0.016). The radiation exposure was significantly lower in the IR group (median dose-length-product 157 [interquartile range: 114 to 239] mGy.cm vs. 222 [interquartile range: 141 to 319] mGy.cm for IR vs. FBP, respectively, p < 0.0001). The rate of downstream testing did not differ significantly (7.7% vs. 7.9% for IR vs. FBP, respectively, p = 0.94). CONCLUSIONS Coronary CTA image quality is maintained with the combined use of a 30% reduced tube current and IR algorithms when compared with conventional FBP image reconstruction techniques and standard tube current. (C) 2015 by the American College of Cardiology Foundation. C1 [Deseive, Simon; Menges, Anna-Leonie; Massberg, Steffen; Hausleiter, Joerg] Univ Munich, Med Klin & Poliklin 1, D-81377 Munich, Germany. [Deseive, Simon; Hadamitzky, Martin; Martinoff, Stefan; Menges, Anna-Leonie; Massberg, Steffen; Hausleiter, Joerg] Tech Univ Munich, Deutsch Herzzentrum Munchen, Klin, Inst Radiol & Nukl Med, D-80290 Munich, Germany. [Chen, Marcus Y.] NIH, Bethesda, MD 20892 USA. [Korosoglou, Grigorios] Univ Klinikum Heidelberg, Klin Innere Med 3, Heidelberg, Germany. [Leipsic, Jonathon] Univ British Columbia, Dept Radiol, St Pauls Hosp, Vancouver, BC, Canada. [Martuscelli, Eugenio] Univ Roma Tor Vergata, Dept Internal Med, Rome, Italy. [Martuscelli, Eugenio] Clin Paideia, Rome, Italy. [Carrascosa, Patricia] Dept Tomog Computada & Invest Diagnost Maipu, Buenos Aires, DF, Argentina. [Mirsadraee, Saeed] Univ Edinburgh, Dept Radiol, Edinburgh, Midlothian, Scotland. [White, Charles] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Bischoff, Bernhard] Univ Munich, Inst Klin Radiol, D-81377 Munich, Germany. RP Hausleiter, J (reprint author), Univ Munich, Klinikum Grosshadern, Med Klin & Poliklin 1, Marchioninistr 15, D-81377 Munich, Germany. EM joerg.hausleiter@med.uni-muenchen.de FU Siemens Medical Systems; Abbott Vascular; GE Healthcare FX Dr. Hausleiter has received research grants and speaker honoraria from Siemens Medical Systems and Abbott Vascular unrelated to the current study. Dr. Leipsic is on the Speakers Bureau for GE Healthcare. Dr. Carrascosa is on the Speakers Bureau for GE Healthcare and Philips Medical Systems; and has received research grants from GE Healthcare unrelated to the current study. Dr. Chen has a research agreement with Toshiba Medical Systems. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 27 TC 12 Z9 12 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X EI 1876-7591 J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD AUG PY 2015 VL 8 IS 8 BP 888 EP 896 DI 10.1016/j.jcmg.2015.02.024 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CP5BD UT WOS:000359895400003 PM 26189118 ER PT J AU He, C Yu, CR Sun, L Mandi, RM Larkin, J Egwuagu, CE AF He, Chang Yu, Cheng-Rong Sun, Lin Mandi, Rashid M. Larkin, Joseph, III Egwuagu, Charles E. TI Topical administration of a suppressor of cytokine signaling-1 (SOCS1) mimetic peptide inhibits ocular inflammation and mitigates ocular pathology during mouse uveitis SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Uveitis; Experimental autoimmune uveitis (EAU); Suppressor of cytokine signaling; Ocular inflammation; SOCS1; SOCS1 mimetic; Biologics ID EXPERIMENTAL AUTOIMMUNE UVEITIS; T-CELLS; DISEASE; INDUCTION; IMMUNITY; MICE; MECHANISMS; EXPRESSION; PREVENTS; PROTEINS AB Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases and pathology derives from sustained production of pro-inflammatory cytokines in the optical axis. Although topical or systemic steroids are effective therapies, their adverse effects preclude prolonged usage and are impetus for seeking alternative immunosuppressive agents, particularly for patients with refractory uveitis. In this study, we synthesized a 16 amino acid membrane-penetrating lipophilic suppressor of cytokine signaling 1 peptide (SOCS1-KIR) that inhibits JAK/STAT signaling pathways and show that it suppresses and ameliorates experimental autoimmune uveitis (EAU), the mouse model of human uveitis. Fundus images, histological and optical coherence tomography analysis of eyes showed significant suppression of clinical disease, with average clinical score of 0.5 compared to 2.0 observed in control mice treated with scrambled peptide. We further show that SOCS1-KIR conferred protection from ocular pathology by inhibiting the expansion of pathogenic Th17 cells and inhibiting trafficking of inflammatory cells into the neuroretina during EAU. Dark-adapted scotopic and photopic electroretinograms further reveal that SOCS1-KIR prevented decrement of retinal function, underscoring potential neuroprotective effects of SOCS1-KIR in uveitis. Importantly, SOCS1-KIR is non-toxic, suggesting that topical administration of SOCS1-Mimetics can be exploited as a non-invasive treatment for uveitis and for limiting cytokine-mediated pathology in other ocular inflammatory diseases including scleritis. Published by Elsevier Ltd. C1 [He, Chang; Yu, Cheng-Rong; Sun, Lin; Mandi, Rashid M.; Egwuagu, Charles E.] NEI, Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. [Larkin, Joseph, III] Univ Florida, Dept Microbiol & Cell Sci, Gainesville, FL 32611 USA. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, NIH, Bldg 10,Room 10N109A,10 Ctr Dr, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov RI Sun, Lin/I-3146-2016 FU Intramural Research Program of National Eye Institute (NEI); National Institutes of Health (NIH) [EY000350-15, EY000280-23] FX We thank Dr. Haohua Qian and Yichao Li (Visual function core, National Eye Institute, National Institutes of Health) for OCT and ERG technical assistance. Research was supported by the Intramural Research Program of the National Eye Institute (NEI) and National Institutes of Health (NIH): Projects numbers are listed (EY000350-15 and EY000280-23). NR 30 TC 2 Z9 2 U1 1 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 EI 1095-9157 J9 J AUTOIMMUN JI J. Autoimmun. PD AUG PY 2015 VL 62 BP 31 EP 38 DI 10.1016/j.jaut.2015.05.011 PG 8 WC Immunology SC Immunology GA CP4TN UT WOS:000359875600004 PM 26094775 ER PT J AU Aman, M Rettiganti, M Nagaraja, HN Hollway, JA McCracken, J McDougle, CJ Tierney, E Scahill, L Arnold, LE Hellings, J Posey, DJ Swiezy, NB Ghuman, J Grados, M Shah, B Vitiello, B AF Aman, Michael Rettiganti, Mallikarjuna Nagaraja, Haikady N. Hollway, Jill A. McCracken, James McDougle, Christopher J. Tierney, Elaine Scahill, Lawrence Arnold, L. Eugene Hellings, Jessica Posey, David J. Swiezy, Naomi B. Ghuman, Jaswinder Grados, Marco Shah, Bhavik Vitiello, Benedetto TI Tolerability, Safety, and Benefits of Risperidone in Children and Adolescents with Autism: 21-Month Follow-up After 8-Week Placebo-Controlled Trial SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID PERVASIVE DEVELOPMENTAL DISORDERS; ABERRANT BEHAVIOR CHECKLIST; LONG-TERM SAFETY; OPEN-LABEL; PEDIATRIC PSYCHOPHARMACOLOGY; ANTIPSYCHOTIC MEDICATIONS; SPECTRUM DISORDERS; INDUCED ENURESIS; WEIGHT-GAIN; SCALE AB Objective: Risperidone has demonstrated efficacy for acute (8 week) and intermediate length (6 month) management of severe irritability and aggression in children and adolescents with autism. Less is known about the long-term effects of risperidone exposure in this population. We examined the tolerability, safety, and therapeutic benefit of risperidone exposure over a 1-2 year follow-up period. Methods: In a naturalistic study, 84 children and adolescents 5-17 years of age (from an original sample of 101) were assessed an average of 21.4 months after initial entry into a placebo-controlled 8 week trial of risperidone for children and adolescents with autism and severe irritability. They were assessed at baseline and at follow-up on safety and tolerability measures (blood, urinalysis, electrocardiogram [ECG], medical history, vital signs, neurological symptoms, other adverse events), developmental measures (adaptive behavior, intelligence quotient [IQ]), and standardized rating instruments. Treatment over the follow-up period, after completion of protocol participation, was uncontrolled. Statistical analyses assessed outcome over time with or without prolonged risperidone therapy. Results: Two-thirds of the 84 subjects continued to receive risperidone (mean 2.47mg/day, S.D. 1.29mg). At follow-up, risperidone was associated with more enuresis, more excessive appetite, and more weight gain, but not more adverse neurological effects. No clinically significant events were noted on blood counts, chemistries, urinalysis, ECG, or interim medical history. Regardless of drug condition at follow-up, there was considerable improvement in maladaptive behavior compared with baseline, including core symptoms associated with autism. Height and weight gains were elevated with risperidone. Social skills on Vineland Adaptive Behavior Scale (VABS) improved with risperidone. Parent-rated Aberrant Behavior Checklist (ABC) Irritability subscale scores were reduced in those taking risperidone at follow-up. Several other measures of maladaptive behavior (some related to socialization) also showed improved functioning in association with risperidone on the ABC or on the Modified Real Life Rating Scale. Conclusions: Increased appetite, weight gain, and enuresis are risks associated with long-term risperidone. Our data suggest that these risks were balanced by longer-term behavioral and social benefits for many children over 1.8 years of ongoing treatment. C1 [Aman, Michael; Hollway, Jill A.; Arnold, L. Eugene; Hellings, Jessica] Ohio State Univ, Nisonger Ctr, Columbus, OH 43210 USA. [Rettiganti, Mallikarjuna] Univ Arkansas Med Sci, Dept Pediat, Biostat Program, Little Rock, AR 72205 USA. [Nagaraja, Haikady N.] Ohio State Univ, Coll Publ Hlth, Biostat, Columbus, OH 43210 USA. [McCracken, James; Shah, Bhavik] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA. [McDougle, Christopher J.; Posey, David J.; Swiezy, Naomi B.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Tierney, Elaine; Ghuman, Jaswinder; Grados, Marco] Kennedy Krieger Inst, Baltimore, MD USA. [Scahill, Lawrence] Marcus Autism Ctr, Atlanta, GA, Rep of Georgia. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. RP Aman, M (reprint author), Ohio State Univ, Nisonger Ctr UCEDD, 581 Dodd Dr, Columbus, OH 43210 USA. EM aman.1@osu.edu FU National Institute of Mental Health (NIMH), National Institutes of Health (NIH) [N01MH80011, N01MH70010, N01MH70001, N01MH70009]; NIH/National Center for Research Resources (NIH/NCRR) General Clinical Research Centers grants at Indiana University [M01 RR00750]; NIH/National Center for Research Resources (NIH/NCRR) General Clinical Research Centers grants at Johns Hopkins University [M01RR00052]; NIH/National Center for Research Resources (NIH/NCRR) General Clinical Research Centers grants at Ohio State University [M01 RR00034]; NIH/National Center for Research Resources (NIH/NCRR) General Clinical Research Centers grants at Yale University [M01 RR06022]; Korczak Foundation; NIMH [MH01805] FX This project was supported by funds from the National Institute of Mental Health (NIMH), National Institutes of Health (NIH), under contracts N01MH80011 (PI: Michael G. Aman), N01MH70010 (PI: James T. McCracken), N01MH70001 (PI: Christopher J. McDougle), and N01MH70009 (PI: Lawrence Scahill). This research was also supported by the NIH/National Center for Research Resources (NIH/NCRR) General Clinical Research Centers grants at Indiana University, M01 RR00750; Johns Hopkins University, M01RR00052; Ohio State University, M01 RR00034; and Yale University, M01 RR06022, Korczak Foundation (Dr. Scahill), and by grant MH01805 from NIMH (Dr. McCracken). NR 47 TC 6 Z9 7 U1 2 U2 16 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 1 PY 2015 VL 25 IS 6 BP 482 EP 493 DI 10.1089/cap.2015.0005 PG 12 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA CP1AJ UT WOS:000359607900005 PM 26262903 ER PT J AU Leon-Sarmiento, FE Peckham, E Leon-Ariza, DS Bara-Jimenez, W Hallett, M AF Leon-Sarmiento, Fidias E. Peckham, Elizabeth Leon-Ariza, Daniel S. Bara-Jimenez, William Hallett, Mark TI Auditory and Lower Limb Tactile Prepulse Inhibition in Primary Restless Legs Syndrome: Clues to Its Pathophysiology SO JOURNAL OF CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Restless legs syndrome; Prepulse inhibition; Startle reflex; Blink reflex ID ACOUSTIC STARTLE RESPONSE; BLINK REFLEX EXCITABILITY; RETICULAR-FORMATION; HUNTINGTONS-DISEASE; SLEEP; HUMANS; STIMULATION; MODULATION; MOVEMENTS; STIMULUS AB The resting sensory discomfort transiently relieved upon movement of the affected area in restless legs syndrome suggests that sensorimotor integration mechanisms, specifically gating, may be altered in the disease. The authors sought to determine the effects of prepulse auditory and tactile stimulation applied to lower limbs on the blink reflex of patients with restless legs syndrome and healthy subjects. Seventeen patients with restless legs syndrome and 17 age- and sex-matched healthy controls were investigated. Auditory stimuli and tactile lower limb stimulation were applied as prepulses. The R2 response of the blink reflex induced by electrical stimulation applied to the right supraorbital nerve was selected as the test stimulus. Time intervals between prepulses and response-eliciting stimuli were 40, 70, 90, 110, and 200 milliseconds. There were no differences in either the auditory or tactile prepulse conditions between patients and controls and no differences between these measures within subject groups. We concluded that the tactile lower limb and the auditory prepulse effects on the brainstem interneurons mediating the blink reflex share common neural pathways. Because forebrain interneurons mediate these prepulse effects, they are likely not involved in the disordered sensorimotor interaction of restless legs syndrome. C1 [Leon-Sarmiento, Fidias E.; Peckham, Elizabeth; Bara-Jimenez, William; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Leon-Sarmiento, Fidias E.] Univ Penn, Sch Med, Ctr Smell & Taste, Philadelphia, PA 19104 USA. [Leon-Sarmiento, Fidias E.] Unicolciencias Univ Nacl, Mediciencias Res Grp, Bogota, Colombia. [Leon-Ariza, Daniel S.] Univ Santander UDES, Fac Hlth, Bucaramanga, Colombia. RP Leon-Sarmiento, FE (reprint author), Univ Penn, Sch Med, Ctr Smell & Taste, 5 Ravdin Pavil,3400 Spruce St, Philadelphia, PA 19104 USA. EM feleones@gmail.com FU NINDS Intramural program; Department of Defense of the United States [USAMRAAW81XWH-09-1-0467] FX This study was supported by the NINDS Intramural program. F. E. Leon-Sarmiento was also supported by a grant from the Department of Defense of the United States (USAMRAAW81XWH-09-1-0467). The authors would like to thank Dr. Neil Jeffries for his help with the statistical analysis. NR 57 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0736-0258 EI 1537-1603 J9 J CLIN NEUROPHYSIOL JI J. Clin. Neurophysiol. PD AUG PY 2015 VL 32 IS 4 BP 369 EP 374 DI 10.1097/WNP.0000000000000196 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CP4FK UT WOS:000359837200015 PM 26241246 ER PT J AU Samsel, L Mccoy, JP AF Samsel, Leigh Mccoy, J. Philip, Jr. TI Imaging flow cytometry for the study of erythroid cell biology and pathology SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Imaging flow cytometry; Erythrocyte; Red blood cell; Sickle cell; Malaria ID RED-BLOOD-CELLS; DISEASE; HEMOGLOBIN; MATURATION; ERYTHROBLASTS; ENUCLEATION; POPULATION; MURINE; SYSTEM AB Erythroid cell maturation and diseases affecting erythrocytes are frequently accompanied by morphologic and immunophenotypic changes to these cells. In the past, these changes have been assessed primarily through the use of manual microscopy, which substantially limits the statistical rigor, throughput, and objectivity of these studies. Imaging flow cytometry provides a technology to examine both the morphology of cells as well as to quantify the staining intensity and signal distribution of numerous fluorescent markers on a cell-by-cell basis with high throughput in a statistically robust manner, and thus is ideally suited to studying erythroid cell biology. To date imaging flow cytometry has been used to study erythrocytes in three areas: 1) erythroid cell maturation, 2) sickle cell disease, and 3) infectious diseases such as malaria. In the maturation studies, imaging flow cytometry can closely recapitulate known stages of maturation and has led to the identification of a new population of erythroid cell precursors. In sickle cell disease, imaging flow cytometry provides a robust method to quantify sickled erythrocytes and to identify cellular aggregates linked to morbidities, and in malaria, imaging flow cytometry has been used to screen for new chemotherapeutic agents. These studies have demonstrated the value of imaging flow cytometry for investigations of erythrocyte biology and pathology. Published by Elsevier B.V. C1 [Samsel, Leigh; Mccoy, J. Philip, Jr.] NHLBI, Bethesda, MD 20892 USA. RP Mccoy, JP (reprint author), 10 Ctr Dr Room 8C104, Bethesda, MD 20852 USA. FU National Heart, Lung, and Blood Institute FX This work was supported by the Intramural Research Program, National Heart, Lung, and Blood Institute. NR 25 TC 3 Z9 4 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD AUG PY 2015 VL 423 SI SI BP 52 EP 59 DI 10.1016/j.jim.2015.03.019 PG 8 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA CP5ZP UT WOS:000359964400008 PM 25858229 ER PT J AU Zhao, WP Fogg, DK Kaplan, MJ AF Zhao, Wenpu Fogg, Darin K. Kaplan, Mariana J. TI A novel image-based quantitative method for the characterization of NETosis SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Neutrophil extracellular traps; Flow cytometry; Microscopy; Cell death ID NEUTROPHIL EXTRACELLULAR TRAPS; PEPTIDYLARGININE DEIMINASE INHIBITION; FLOW-CYTOMETRY; ELASTASE; LUPUS AB NETosis is a newly recognized mechanism of programmed neutrophil death. It is characterized by a stepwise progression of chromatin decondensation, membrane rupture, and release of bactericidal DNA-based structures called neutrophil extracellular traps (NETs). Conventional 'suicidal' NETosis has been described in pathogenic models of systemic autoimmune disorders. Recent in vivo studies suggest that a process of 'vital' NETosis also exists, in which chromatin is condensed and membrane integrity is preserved. Techniques to assess 'suicidal' or 'vital' NET formation in a specific, quantitative, rapid and semiautomated way have been lacking, hindering the characterization of this process. Here we have developed a new method to simultaneously assess both 'suicidal' and 'vital' NETosis, using high-speed multi-spectral imaging coupled to morphometric image analysis, to quantify spontaneous NET formation observed ex-vivo or stimulus-induced NET formation triggered in vitro. The use of imaging flow cytomety allows automated, quantitative and rapid analysis of subcellular morphology and texture, and introduces the potential for further investigation using NETosis as a biomarker in pre-clinical and clinical studies. Published by Elsevier B.V. C1 [Zhao, Wenpu; Kaplan, Mariana J.] NIAMSD, Syst Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Fogg, Darin K.] EMD Millipore Corp, Billerica, MA 01821 USA. RP Kaplan, MJ (reprint author), NIAMSD, Syst Autoimmun Branch, Intramural Res Program, NIH, 10 Ctr Dr 6D47C, Bethesda, MD 20892 USA. EM mariana.kaplan@nih.gov FU NIAMS/NIH FX This study was supported by the Intramural Research Program at NIAMS/NIH. We thank Jason S. Knight for helpful discussions. Darin K. Fogg is employed by EMD Millipore Corporation. The other authors have no conflicts of interest to disclose. NR 25 TC 16 Z9 16 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD AUG PY 2015 VL 423 SI SI BP 104 EP 110 DI 10.1016/j.jim.2015.04.027 PG 7 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA CP5ZP UT WOS:000359964400015 PM 26003624 ER PT J AU Holmstrom, KM Pan, X Liu, JC Menazza, S Liu, J Nguyen, TT Pan, HH Parks, RJ Anderson, S Noguchi, A Springer, D Murphy, E Finkel, T AF Holmstroem, Kira M. Pan, Xin Liu, Julia C. Menazza, Sara Liu, Jie Nguyen, Tiffany T. Pan, Haihui Parks, Randi J. Anderson, Stasia Noguchi, Audrey Springer, Danielle Murphy, Elizabeth Finkel, Toren TI Assessment of cardiac function in mice lacking the mitochondrial calcium uniporter SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Mitochondria; Calcium; Bioenergetics; Cardiac function ID HEART; METABOLISM; CA2+ AB Mitochondrial calcium is thought to play an important role in the regulation of cardiac bioenergetics and function. The entry of calcium into the mitochondrial matrix requires that the divalent cation pass through the inner mitochondrial membrane via a specialized pore known as the mitochondrial calcium uniporter (MCU). Here, we use mice deficient of MCU expression to rigorously assess the role of mitochondrial calcium in cardiac function. Mitochondria isolated from MCU-/- mice have reduced matrix calcium levels, impaired calcium uptake and a defect in calcium-stimulated respiration. Nonetheless, we find that the absence of MCU expression does not affect basal cardiac function at either 12 or 20-months of age. Moreover, the physiological response of MCU-/- mice to isoproterenol challenge or transverse aortic constriction appears similar to control mice. Thus, while mitochondria derived from MCU-/- mice have markedly impaired mitochondrial calcium handling, the hearts of these animals surprisingly appear to function relatively normally under basal conditions and during stress. Published by Elsevier Ltd. C1 [Holmstroem, Kira M.; Pan, Xin; Liu, Julia C.; Liu, Jie; Pan, Haihui; Finkel, Toren] NHLBI, Ctr Mol Med, Bethesda, MD 20892 USA. [Pan, Xin] Natl Ctr Biomed Anal, Cell Biol Lab, Beijing 100850, Peoples R China. [Menazza, Sara; Nguyen, Tiffany T.; Parks, Randi J.; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Anderson, Stasia] NHLBI, Anim MRI Core, NIH, Bethesda, MD 20892 USA. [Noguchi, Audrey; Springer, Danielle] NHLBI, Murine Phenotyping Core, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NIH, 10 Ctr Dr,Bldg 10 CRC 5-3330, Bethesda, MD 20892 USA. EM finkelt@nih.gov OI Holmstrom, Kira/0000-0001-6434-7909 FU Leducq Foundation; NIH FX We thank Hong San for assistance with the TAC surgery, Zuxi Yu for help with pathology and Ilsa I Rovira for help for the manuscript. This work was supported by a grant from the Leducq Foundation and with NIH Intramural Funds. NR 15 TC 13 Z9 14 U1 2 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD AUG PY 2015 VL 85 BP 178 EP 182 DI 10.1016/j.yjmcc.2015.05.022 PG 5 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA CP4UO UT WOS:000359878300020 PM 26057074 ER PT J AU Ramsden, CE Zamora, D Makriyannis, A Wood, JT Mann, JD Faurot, KR MacIntosh, BA Majchrzak-Hong, SF Gross, JR Courville, AB Davis, JM Hibbeln, JR AF Ramsden, Christopher E. Zamora, Daisy Makriyannis, Alexandros Wood, JodiAnne T. Mann, J. Douglas Faurot, Keturah R. MacIntosh, Beth A. Majchrzak-Hong, Sharon F. Gross, Jacklyn R. Courville, Amber B. Davis, John M. Hibbeln, Joseph R. TI Diet-Induced Changes in n-3-and n-6-Derived Endocannabinoids and Reductions in Headache Pain and Psychological Distress SO JOURNAL OF PAIN LA English DT Article DE Endocannabinoids; psychological distress; headache; 2-docosahexaenoylglycerol; docosahexaenoylethanolamine; 2-arachidonoylglycerol ID FATTY-ACID-COMPOSITION; DOCOSAHEXAENOIC ACID; RANDOMIZED-TRIAL; ADIPOSE-TISSUE; LINOLEIC-ACID; IN-VIVO; ANANDAMIDE; N-3; RELIABILITY; METABOLOME AB Omega-3 and omega-6 fatty acids are biosynthetic precursors of endocannabinoids with antinociceptive, anxiolytic, and neurogenic properties. We recently reported that targeted dietary manipulation-increasing omega-3 fatty acids while reducing omega-6 linoleic acid (the H3-16 intervention) reduced headache pain and psychological distress among chronic headache patients. It is not yet known whether these clinical improvements were due to changes in endocannabinoids and related mediators derived from omega-3 and omega-6 fatty acids. We therefore used data from this trial (N = 55) to investigate 1) whether the H3-L6 intervention altered omega-3- and omega-6-derived endocannabinoids in plasma and 2) whether diet-induced changes in these bioactive lipids were associated with clinical improvements. The H3-L6 intervention significantly increased the omega-3 docosahexaenoic acid derivatives 2-docosahexaenoylglycerol (+65%, P < .001) and docosahexaenoylethanolamine (+99%, P < .001) and reduced the omega-6 arachidonic acid derivative 2-arachidonoylglycerol (-25%, P = .001). Diet-induced changes in these endocannabinoid derivatives of omega-3 docosahexaenoic acid, but not omega-6 arachidonic acid, correlated with reductions in physical pain and psychological distress. These findings demonstrate that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids in humans and suggest that 2-docosahexaenoylglycerol and docosahexaenoylethanolamine could have physical and/or psychological pain modulating properties. Trial registration: ClinicalTrials.gov (NCT01157208) Perspective: This article demonstrates that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids and that these changes are related to reductions in headache pain and psychological distress. These findings suggest that dietary interventions could provide an effective, complementary approach for managing chronic pain and related conditions. Published by Elsevier Inc. on behalf of the American Pain Society C1 [Ramsden, Christopher E.; Majchrzak-Hong, Sharon F.; Hibbeln, Joseph R.] NIAAA, Sect Nutr Neurosci, NIH, Bethesda, MD USA. [Ramsden, Christopher E.; Zamora, Daisy; Faurot, Keturah R.] Univ N Carolina, Dept Phys Med & Rehabil, Chapel Hill, NC USA. [Mann, J. Douglas] Univ N Carolina, Dept Neurol, Program Integrat Med, Chapel Hill, NC USA. [Makriyannis, Alexandros; Wood, JodiAnne T.] Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA. [Makriyannis, Alexandros; Wood, JodiAnne T.] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Makriyannis, Alexandros; Wood, JodiAnne T.] Northeastern Univ, Dept Pharmaceut Sci, Boston, MA 02115 USA. [MacIntosh, Beth A.] Univ N Carolina, North Carolina Translat Clin Sci Inst, Nutr Res & Metab Core, Chapel Hill, NC USA. [Gross, Jacklyn R.] NIH, Anesthesia Sect, Dept Perioperat Med, Ctr Clin, Bethesda, MD 20892 USA. [Courville, Amber B.] NIH, Dept Nutr, Ctr Clin, Bethesda, MD 20892 USA. [Davis, John M.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. RP Ramsden, CE (reprint author), Bldg 31,Room 1854C,31 Ctr Dr, Bethesda, MD 20892 USA. EM chris.ramsden@nih.gov FU Mayday Fund; UNC (NCCAM, NIH) [T32-AT003378]; North Carolina Clinical and Translational Sciences Institute (NCRR, NIH) [UL1RR025747]; UNC Nutrition Obesity Research Center, CHAI Core (NIDDK, NIH) [DK056350]; National Institute on Drug Abuse [DA07215, DA09158]; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX Supported by the Mayday Fund (primary funding source); the UNC Research Fellowship in Complementary and Alternative Medicine (grant T32-AT003378, NCCAM, NIH); the North Carolina Clinical and Translational Sciences Institute (grant UL1RR025747, NCRR, NIH); the UNC Nutrition Obesity Research Center, CHAI Core (grant DK056350, NIDDK, NIH); the National Institute on Drug Abuse (DA07215 and DA09158); and the Intramural Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 41 TC 8 Z9 8 U1 1 U2 7 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD AUG PY 2015 VL 16 IS 8 BP 707 EP 716 DI 10.1016/j.jpain.2015.04.007 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CP5AK UT WOS:000359893500004 PM 25958314 ER PT J AU Nahin, RL AF Nahin, Richard L. TI Estimates of Pain Prevalence and Severity in Adults: United States, 2012 SO JOURNAL OF PAIN LA English DT Article DE Cross-sectional study; pain frequency; pain severity; language preference; minority groups ID NUTRITION EXAMINATION SURVEY; GENERAL-POPULATION; NATIONAL-HEALTH; PHYSICAL-ACTIVITY; BACK-PAIN; FOLLOW-UP; COMMUNITY; HISPANICS; SAMPLE; LIFE AB Using a simple approach for coding pain severity, the present study describes self-reported pain in U.S. adults. Data are included for 8,781 adults who completed the Functioning and Disability Supplement of the 2012 National Health Interview Survey. An internationally piloted pain severity coding system was used to group participants into 5 discrete ordered pain categories based on their pain persistence (days with pain in the last 3 months) and bothersomeness (little, a lot, somewhere in between): pain free and categories 1 (low) to 4 (high). It is estimated that 126.1 million adults reported some pain in the previous 3 months, with 25.3 million adults (11.2%) suffering from daily (chronic) pain and 23.4 million (10.3%) reporting a lot of pain. Based on the persistence and bothersomeness of their pain, 14.4 million adults (6.4%) were classified as having the highest level of pain, category 4, with an additional 25.4 million adults (11.3%) experiencing category 3 pain. Individuals with category 3 or 4 pain were likely to have worse health status, to use more health care, and to suffer from more disability than those with less severe pain. Associations were seen between pain severity and selected demographic variables including race, ethnicity, preferred language, sex, and age. Perspective: U.S. estimates of pain prevalence are presented using a simple approach for assigning pain severity developed by the Washington Group on Disability Statistics. Concurrent validity is assessed. Although this approach is promising, additional work is required to determine the usefulness of the Washington Group pain categories for pain research or clinical practice. Published by Elsevier Inc. on behalf of the American Pain Society C1 NIH, Natl Ctr Complementary & Integrat Hlth, Bethesda, MD 20892 USA. RP Nahin, RL (reprint author), NIH, Natl Ctr Complementary & Integrat Hlth, 6707 Democracy Blvd,Suite 401, Bethesda, MD 20892 USA. EM nahinr@mail.nih.gov OI Nahin, Richard/0000-0002-3682-4816 FU Intramural NIH HHS [Z99 AT999999] NR 44 TC 44 Z9 44 U1 3 U2 20 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD AUG PY 2015 VL 16 IS 8 BP 769 EP 780 DI 10.1016/j.jpain.2015.05.002 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CP5AK UT WOS:000359893500010 PM 26028573 ER PT J AU Mitsuhiro, MH Berezovsky, A Belfort, R Ellwein, LB Salomao, SR AF Mitsuhiro, Marcia H. Berezovsky, Adriana Belfort, Rubens, Jr. Ellwein, Leon B. Salomao, Solange R. TI Uptake, Barriers and Outcomes in the Follow-up of Patients Referred for Free-of-Cost Cataract Surgery in the Sao Paulo Eye Study SO OPHTHALMIC EPIDEMIOLOGY LA English DT Article DE Barriers; cataract; cataract surgery; outcomes; uptake ID SELF-REPORTED BARRIERS; SURGICAL COVERAGE; VISUAL IMPAIRMENT; POPULATION; PREVALENCE; BLINDNESS; NIGERIA; BRAZIL; SERVICES; INDIA AB Purpose: To determine uptake, barriers and outcomes in the follow-up of patients referred for free-of-charge, expedited cataract surgery in the Sao Paulo Eye Study (SPES). Methods: SPES was a population-based study of urban, low-middle income residents aged >= 50 years. Presenting visual acuity (PVA), best-corrected visual acuity, refraction, and slit-lamp examination were performed in 3677 participants. For subjects with cataract as a principal cause of best-corrected visual acuity <= 20/40, surgery was offered free of charge. Two years after the baseline study, surgery uptake, barriers to surgery, and visual outcomes were analyzed. Results: Among 210 (5.71%) participants who had a cataract surgery indication at baseline, 164 (78.1%) were successfully contacted and 55 (33.5%) reported being operated on for cataract, with 51 agreeing to be re-examined. In a multiple logistic regression model, age, sex, schooling, previous cataract surgery, and PVA at baseline were not significantly associated with surgery uptake. Co-existing health conditions (20.4%), fear of surgery (12.2%) and fear of losing eyesight (11.6%) were the most frequent barriers to cataract surgery adherence. Among the 69 eyes operated on in the interval between baseline and follow-up, PVA >= 20/63 was observed in 50 (72.6%, 95% confidence interval, CI, 62.2-82.3%), PVA <20/63-20/200 in 11 (15.8%, 95% CI 8.9-22.9%) and PVA <20/200 in 8 (11.6%, 95% CI 5.3-17.9%). Conclusions: Quality of surgery is an increasing determinant of uptake rates. Although free-of-charge and expedited cataract surgery was offered, surgical outcomes might have influenced the low uptake. Aside from cataract surgery campaigns, improvement of surgeon skills, accurate biometry, treatment of ocular comorbidities, postoperative follow-up and eye-care education are needed. C1 [Mitsuhiro, Marcia H.; Berezovsky, Adriana; Belfort, Rubens, Jr.; Salomao, Solange R.] Univ Fed Sao Paulo, Escola Paulista Med, Dept Oftalmol, BR-04023062 Sao Paulo, SP, Brazil. [Ellwein, Leon B.] NEI, Bethesda, MD 20892 USA. RP Salomao, SR (reprint author), Univ Fed Sao Paulo, Escola Paulista Med, Dept Oftalmol, Rua Botucatu 821, BR-04023062 Sao Paulo, SP, Brazil. EM ssalomao@unifesp.br RI Salomao, Solange/G-9500-2012; Berezovsky, Adriana/F-2341-2013 OI Salomao, Solange/0000-0002-3436-5599; FU Coordenadoria de Apoio a Pessoal de Nivel Superior (CAPES, Brasilia, Brasil); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brasilia, Brasil); World Health Organization (WHO), Geneva, Switzerland (under the National Institutes of Health, Bethesda, Maryland) [NEI-EY-2103] FX Financial support was received from: Coordenadoria de Apoio a Pessoal de Nivel Superior (CAPES, Brasilia, Brasil) post-doctoral scholarship to MHM; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brasilia, Brasil) research scholarships to AB, RB and SRS; and World Health Organization (WHO), Geneva, Switzerland (under the National Institutes of Health, Bethesda, Maryland contract no. NEI-EY-2103). NR 30 TC 4 Z9 4 U1 1 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0928-6586 EI 1744-5086 J9 OPHTHAL EPIDEMIOL JI Ophthalmic Epidemiol. PD AUG PY 2015 VL 22 IS 4 SI SI BP 253 EP 259 DI 10.3109/09286586.2014.966849 PG 7 WC Ophthalmology SC Ophthalmology GA CP4VH UT WOS:000359880200004 PM 25310584 ER PT J AU Esposito, G Valenzi, S Islam, T Bornstein, MH AF Esposito, Gianluca Valenzi, Stefano Islam, Tanvir Bornstein, Marc H. TI Three physiological responses in fathers and non-fathers' to vocalizations of typically developing infants and infants with Autism Spectrum Disorder SO RESEARCH IN DEVELOPMENTAL DISABILITIES LA English DT Article DE ASD cry; Atypical cry; Communication; Atypical development ID YOUNG-CHILDREN; DISTRESS; EXPRESSION; CRY; DELAY; RISK AB Children with ASD, even before receiving a formal diagnosis, express atypical patterns of distress vocalizations (namely, episodes of crying). Their cries have higher fundamental frequencies, shorter inter-bout pauses, and fewer utterances. Cries of children with ASD are also perceived differently from other cries, and these perceptual differences may alter parent-infant interaction. This study assessed multiple physiological responses in fathers and non-fathers to atypical distress vocalizations (cries of children with ASD), acoustically matched typical distress vocalizations (cries of typically developing children), and positive vocalizations (laughter of typically developing children). The experimental procedures were designed to measure how components of the autonomic nervous system respond to typical and atypical infant vocalizations. Three convergent methodologies (Galvanic Skin Response-GSR; cardiac dynamics via Inter-Beat Interval-IBI; right hand temperature change-RHTC) were performed on two groups with contrasting caregiving experience: fathers of typically developing children (n = 10) and non-fathers (n = 10). Inferential statistical analysis compared the two groups (fathers, non-fathers) and three stimulus types (ASD cry, typical cry, laughter) for the three measures (GSR, IBI, RHTC). Both fathers and non-fathers showed greater negative responses (increased GSR) to ASD cries compared to typical cries and laughter. Fathers showed higher IBI and greater temperature increases (RHTC) than non-fathers while listening to typical and atypical cries. Fathers and non-fathers showed more emotional arousal mediated by sympathetic activation while listening to cries of children with ASD. Fathers were calmer and acted more promptly than non-fathers while listening to typical cries, perhaps because the fathers had more experience in caring for crying infants. These findings point to similarities and differences in fathers' and non-fathers' physiological responsiveness to cries of children with ASD and might guide specific intervention programs for parents of children at risk of ASD. (C) 2015 Elsevier Ltd.. All rights reserved. C1 [Esposito, Gianluca] Univ Trent, Affiliat Behav & Physiol Lab, Dept Psychol & Cognit Sci, I-38068 Rovereto, TN, Italy. [Esposito, Gianluca] Nanyang Technol Univ, Div Psychol, Early Cognit Lab, Singapore 639798, Singapore. [Valenzi, Stefano; Islam, Tanvir] RIKEN Brain Sci Inst, Lab Adv Brain Signal Proc, Saitama, Japan. [Islam, Tanvir] RIKEN Brain Sci Inst, Lab Dev Gene Regulat, Saitama, Japan. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Esposito, G (reprint author), Univ Trent, Affiliat Behav & Physiol Lab, Dept Psychol & Cognit Sci, I-38068 Rovereto, TN, Italy. EM gianluca.esposito@unitn.it FU Japan Society for the Promotion of Science [JSPS PE09064, 24730563, 2402747]; FPR Program (RIKEN Brain Science Institute); NIH-NICHD (USA) FX All participants in this study are gratefully acknowledged. This research was supported by the ST fellowship from Japan Society for the Promotion of Science (JSPS PE09064), Grant-in-aid for Scientific Research from Japan Society for the Promotion of Science (Projects # 24730563 and #2402747), the FPR Program (RIKEN Brain Science Institute), and the Intramural Research Program of the NIH-NICHD (USA). NR 44 TC 0 Z9 0 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-4222 J9 RES DEV DISABIL JI Res. Dev. Disabil. PD AUG-SEP PY 2015 VL 43-44 BP 43 EP 50 DI 10.1016/j.ridd.2015.06.007 PG 8 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA CP4TS UT WOS:000359876100005 PM 26151442 ER PT J AU Carty, CL Keene, KL Cheng, YC Meschia, JF Chen, WM Nalls, M Bis, JC Kittner, SJ Rich, SS Tajuddin, S Zonderman, AB Evans, MK Langefeld, CD Gottesman, R Mosley, TH Shahar, E Woo, D Yaffe, K Liu, YM Sale, MM Dichgans, M Malik, R Longstreth, WT Mitchell, BD Psaty, BM Kooperberg, C Reiner, A Worrall, BB Fornage, M AF Carty, Cara L. Keene, Keith L. Cheng, Yu-Ching Meschia, James F. Chen, Wei-Min Nalls, Mike Bis, Joshua C. Kittner, Steven J. Rich, Stephen S. Tajuddin, Salman Zonderman, Alan B. Evans, Michele K. Langefeld, Carl D. Gottesman, Rebecca Mosley, Thomas H. Shahar, Eyal Woo, Daniel Yaffe, Kristine Liu, Yongmei Sale, Michele M. Dichgans, Martin Malik, Rainer Longstreth, W. T., Jr. Mitchell, Braxton D. Psaty, Bruce M. Kooperberg, Charles Reiner, Alexander Worrall, Bradford B. Fornage, Myriam CA COMPASS Consortia METASTROKE Consortia TI Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans SO STROKE LA English DT Article DE African Americans; genetic association studies; genome-wide association study; meta-analysis; stroke ID ISCHEMIC-STROKE; ATHEROSCLEROTIC STROKE; HEART-ASSOCIATION; COMMON VARIANTS; SUBTYPES; DISEASE; DESIGN; BLACKS; UPDATE; HEALTH AB Background and Purpose-The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. Methods-Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. Results-The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9x10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS. Conclusions-We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations. C1 [Carty, Cara L.; Kooperberg, Charles; Reiner, Alexander] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Keene, Keith L.] E Carolina Univ, Ctr Hlth Dispar, Greenville, NC USA. [Cheng, Yu-Ching; Kittner, Steven J.] Baltimore Vet Adm Med Ctr, Baltimore, MD USA. [Cheng, Yu-Ching; Kittner, Steven J.; Mitchell, Braxton D.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Meschia, James F.] Mayo Clin Florida, Jacksonville, FL USA. [Chen, Wei-Min; Rich, Stephen S.; Sale, Michele M.; Worrall, Bradford B.] Univ Virginia, Publ Hlth Sci, Charlottesville, VA USA. [Nalls, Mike; Tajuddin, Salman; Zonderman, Alan B.; Evans, Michele K.] NIA, NIH, Bethesda, MD 20892 USA. [Bis, Joshua C.; Longstreth, W. T., Jr.; Psaty, Bruce M.; Reiner, Alexander] Univ Washington, Seattle, WA 98195 USA. [Langefeld, Carl D.; Liu, Yongmei] Wake Forest Univ, Winston Salem, NC 27109 USA. [Gottesman, Rebecca] Johns Hopkins Univ, Sch Med, Div Cerebrovasc Neurol, Baltimore, MD USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Neurol, Jackson, MS USA. [Shahar, Eyal] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. [Woo, Daniel] Univ Cincinnati, Dept Neurol & Rehabil Med, Cincinnati, OH 45221 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Dichgans, Martin; Malik, Rainer] Univ Munich, Inst Stroke & Dementia Res, Munich Cluster Syst Neurol Synergy, Klinikum Univ Munchen, Munich, Germany. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Unit, Seattle, WA USA. [Fornage, Myriam] Univ Texas Houston, Ctr Human Genet, Houston, TX USA. RP Carty, CL (reprint author), George Washington Univ, Ctr Translat Sci, Childrens Natl Med Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. EM ccarty@cnmc.org OI Zonderman, Alan B/0000-0002-6523-4778; Mitchell, Braxton/0000-0003-4920-4744; Tajuddin, Salman M./0000-0002-7919-8528 FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health (NIH) [HHSN268200625226C]; NIH and NIH Roadmap for Medical Research [UL1RR025005]; National Institute of Neurological Disorders and Stroke [U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393]; National Institute on Aging [R01AG023629]; National Center for Advancing Translational Sciences [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Research Center [DK063491]; NIH Genes, Environment and Health Initiative Grant, as part of the GENEVA consortium [U01 HG004436]; Mid-Atlantic Nutrition and Obesity Research Center [P30-DK072488]; Office of Research and Development, Medical Research Service; Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans' Affairs; Department of Veterans' Affairs career development award [1IK2BX001823]; Intramural Research Program of the NIH, National Institute of Aging; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; Intramural Research Program of the National Institute of Aging (PI Singleton) [Z01 AG000954-06]; National Institute of Neurological Disorders and Stroke (PI Meschia) [R01 NS42733, R01NS39987]; NIH Office of Research on Women's Health [R01-NS45012, U01-NS069208-01]; Division of Adult and Community Health, Centers for Disease Control; National Human Genome Research Institute, as part of the Genomics and Randomized Trials Network [U01-HG005160]; National Heart, Lung, and Blood Institute, NIH; 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]; [R01-NS34447] FX Atherosclerosis Risk in Communities Study was supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health (NIH) contract HHSN268200625226C. Infrastructure was partly supported by Grant no. UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. Cardiovascular Health Study (CHS) was supported by National Heart, Lung, and Blood Institute contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with contributions from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from the National Institute on Aging. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data were supported, in part, by the National Center for Advancing Translational Sciences, grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Genetics of Early Onset Stroke was supported by the NIH Genes, Environment and Health Initiative Grant U01 HG004436, as part of the GENEVA consortium, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30-DK072488); the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans' Affairs. Study recruitment and datasets assembly were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and grants from the National Institute of Neurological Disorders and Stroke and the NIH Office of Research on Women's Health (R01-NS45012, U01-NS069208-01). Dr Cheng was supported by the Department of Veterans' Affairs career development award (1IK2BX001823). Healthy Aging in Neighborhoods of Diversity across the Life Span was supported by the Intramural Research Program of the NIH, National Institute of Aging and the National Center on Minority Health and Health Disparities (project no. Z01-AG000513 and human subjects protocol no. 2009-149). Ischemic Stroke Genetics Study (ISGS) and Siblings with Ischemic Stroke Study (SWISS) were supported by the National Institute of Neurological Disorders and Stroke grants (R01 NS42733; PI Meschia) and (R01NS39987; PI Meschia), respectively with additional support, in part, from the Intramural Research Program of the National Institute of Aging (Z01 AG000954-06; PI Singleton). Both studies used samples and clinical data from the NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository, human subjects protocol no. 2003-081 and 2004-147. Vitamin Intervention for Stroke Prevention (VISP) was funded by the National Institute of Neurological Disorders and Stroke (R01-NS34447).; Genome-wide association study data for a subset of VISP participants supported by the National Human Genome Research Institute (U01-HG005160), as part of the Genomics and Randomized Trials Network (PI: Drs Sale and Worrall). Women's Health Initiative was supported by the National Heart, Lung, and Blood Institute, NIH, and 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. Funders had no role in study design, data collection and analysis, decision to publish, or article preparation. NR 35 TC 8 Z9 8 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD AUG PY 2015 VL 46 IS 8 BP 2063 EP 2068 DI 10.1161/STROKEAHA.115.009044 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CP6CP UT WOS:000359972200021 PM 26089329 ER PT J AU Sandsmark, DK Messe, SR Zhang, XM Roy, J Nessel, L Hamm, LL He, J Horwitz, EJ Jaar, BG Kallem, RR Kusek, JW Mohler, ER Porter, A Seliger, SL Sozio, SM Townsend, RR Feldman, HI Kasner, SE AF Sandsmark, Danielle K. Messe, Steven R. Zhang, Xiaoming Roy, Jason Nessel, Lisa Hamm, Lotuce Lee He, Jiang Horwitz, Edward J. Jaar, Bernard G. Kallem, Radhakrishna R. Kusek, John W. Mohler, Emile R., III Porter, Anna Seliger, Stephen L. Sozio, Stephen M. Townsend, Raymond R. Feldman, Harold I. Kasner, Scott E. CA CRIC Study Investigators TI Proteinuria, but Not eGFR, Predicts Stroke Risk in Chronic Kidney Disease Chronic Renal Insufficiency Cohort Study SO STROKE LA English DT Article DE albuminuria; kidney diseases; risk factors; proteinuria; stroke ID GLOMERULAR-FILTRATION-RATE; INCIDENT STROKE; CARDIOVASCULAR MORTALITY; ATRIAL-FIBRILLATION; CYSTATIN C; ALL-CAUSE; MICROALBUMINURIA; ALBUMINURIA; ASSOCIATION; METAANALYSIS AB Background and Purpose-Chronic kidney disease is associated with an increased risk of cardiovascular events. However, the impact of chronic kidney disease on cerebrovascular disease is less well understood. We hypothesized that renal function severity would be predictive of stroke risk, independent of other vascular risk factors. Methods-The study population included 3939 subjects enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study, a prospective observational cohort. Stroke events were reported by participants and adjudicated by 2 vascular neurologists. Cox proportional hazard models were used to compare measures of baseline renal function with stroke events. Multivariable analysis was performed to adjust for key covariates. Results-In 3939 subjects, 143 new stroke events (0.62 events per 100 person-years) occurred over a mean follow-up of 6.4 years. Stroke risk was increased in subjects who had worse baseline measurements of renal function (estimated glomerular filtration rate and total proteinuria or albuminuria). When adjusted for variables known to influence stroke risk, total proteinuria or albuminuria, but not estimated glomerular filtration rate, were associated with an increased risk of stroke. Treatment with blockers of the renin-angiotensin system did not decrease stroke risk in individuals with albuminuria. Conclusions-Proteinuria and albuminuria are better predictors of stroke risk in patients with chronic kidney disease than estimated glomerular filtration rate. The impact of therapies targeting proteinuria/albuminuria in individuals with chronic kidney disease on stroke prevention warrants further investigation. C1 [Sandsmark, Danielle K.; Messe, Steven R.; Kasner, Scott E.] Hosp Univ Penn, Dept Neurol, Dept Med, Philadelphia, PA 19104 USA. [Kallem, Radhakrishna R.; Townsend, Raymond R.] Hosp Univ Penn, Renal Electrolyte & Hypertens Div, Dept Med, Philadelphia, PA 19104 USA. [Mohler, Emile R., III] Hosp Univ Penn, Div Vasc Med, Dept Med, Philadelphia, PA 19104 USA. [Zhang, Xiaoming; Roy, Jason; Nessel, Lisa; Feldman, Harold I.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Hamm, Lotuce Lee] Tulane Univ, Dept Med, New Orleans, LA 70118 USA. [He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Horwitz, Edward J.] Metrohealth, Dept Med, Cleveland, OH USA. [Jaar, Bernard G.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Kusek, John W.] NIDDK, Div Kidney Urol & Hematol Dis, Bethesda, MD USA. [Porter, Anna] Univ Illinois, Dept Nephrol, Chicago, IL USA. [Seliger, Stephen L.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Sozio, Stephen M.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. RP Sandsmark, DK (reprint author), Univ Penn, Perelman Sch Med, Dept Neurol, 3400 Spruce St,3W Gates Bldg, Philadelphia, PA 19104 USA. EM danielle.sandsmark@uphs.upenn.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award [NIH/NCATS UL1TR000003]; Johns Hopkins University [UL1 TR-000424]; University of Maryland [GCRC M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland; National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) [UL1TR000439] FX The funding for the CRIC Study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by: the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/NCATS UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR). NR 40 TC 15 Z9 15 U1 2 U2 3 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 2015 VL 46 IS 8 BP 2075 EP 2080 DI 10.1161/STROKEAHA.115.009861 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CP6CP UT WOS:000359972200023 PM 26130097 ER PT J AU Al Hazzouri, AZ Vittinghoff, E Sidney, S Reis, JP Jacobs, DR Yaffe, K AF Al Hazzouri, Adina Zeki Vittinghoff, Eric Sidney, Stephen Reis, Jared P. Jacobs, David R., Jr. Yaffe, Kristine TI Intima-Media Thickness and Cognitive Function in Stroke-Free Middle-Aged Adults Findings From the Coronary Artery Risk Development in Young Adults Study SO STROKE LA English DT Article DE carotid intima-media thickness; cognition; epidemiology; risk factors; stroke ID PULSE-WAVE VELOCITY; CAROTID ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; ISCHEMIC-STROKE; BLOOD-PRESSURE; DEMENTIA; ASSOCIATION; PERFORMANCE; HEALTH; IMPAIRMENT AB Background and Purpose-The relationship between carotid artery intima-media thickness (IMT) and cognitive function in midlife remains relatively unexplored. We examined the association between IMT and cognitive function in a middle-aged epidemiological cohort of 2618 stroke-free participants. Methods-At the year 20 visit (our study baseline), participants from the Coronary Artery Risk Development in Young Adults study had IMT measured by ultrasound at the common carotid artery. Five years later, participants completed a cognitive battery consisting of the Rey Auditory-Verbal Learning Test of verbal memory, the Digit Symbol Substitution Test of processing speed, and the Stroop test of executive function. We transformed cognitive scores into standardized z scores, with negative values indicating worse performance. Results-Mean age at baseline was 45.3 years (SD, 3.6). Greater IMT (per 1 SD difference of 0.12 mm) was significantly associated with worse performance on all cognitive tests (z scores) in unadjusted linear regression models (verbal memory, -0.16; 95% confidence interval [CI], -0.20 to -0.13; processing speed, -0.23; 95% CI, -0.27 to -0.19; and executive function, -0.17; 95% CI, -0.20 to -0.13). In models adjusted for sociodemographics and vascular risk factors that lie earlier in the causal pathway, greater IMT remained negatively associated with processing speed (-0.06; 95% CI, -0.09 to -0.02; P, 0.003) and borderline associated with executive function (-0.03; 95% CI, -0.07 to 0.00; P, 0.07) but not with verbal memory. Conclusions-We observed an association between greater IMT and worse processing speed-a key component of cognitive functioning-at middle age above and beyond traditional vascular risk factors. Efforts targeted at preventing early stages of atherosclerosis may modify the course of cognitive aging. C1 [Al Hazzouri, Adina Zeki] Univ Miami, Div Epidemiol & Populat Hlth Sci, Dept Publ Hlth Sci, Miami, FL 33136 USA. [Vittinghoff, Eric; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Sidney, Stephen] Kaiser Permanente, Div Res, Oakland, CA USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Al Hazzouri, AZ (reprint author), Univ Miami, Div Epidemiol & Populat Hlth Sci, Dept Publ Hlth Sci, Miami, FL 33136 USA. EM axz122@miami.edu FU National Institutes of Health, National Institute on Aging [K01AG047273]; National Institutes of Health/National Institute on Aging (NIA) [k24AG031155]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; Intramural Research Program of the NIA; NIA [AG0005]; NHLBI [AG0005] FX Dr Zeki Al Hazzouri was supported by a grant from the National Institutes of Health, National Institute on Aging (K01AG047273). Dr Yaffe was supported by a grant from the National Institutes of Health/National Institute on Aging (NIA; k24AG031155). 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 NIA, and an intra-agency agreement between NIA and NHLBI (AG0005). This article has been reviewed by CARDIA for scientific content. NR 37 TC 2 Z9 2 U1 0 U2 7 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 2015 VL 46 IS 8 BP 2190 EP 2196 DI 10.1161/STROKEAHA.115.008994 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CP6CP UT WOS:000359972200041 ER PT J AU Boden-Albala, B Carman, H Southwick, L Parikh, NS Roberts, E Waddy, S Edwards, D AF Boden-Albala, Bernadette Carman, Heather Southwick, Lauren Parikh, Nina S. Roberts, Eric Waddy, Salina Edwards, Dorothy TI Examining Barriers and Practices to Recruitment and Retention in Stroke Clinical Trials SO STROKE LA English DT Article DE clinical trial; ethnic groups; health policy; National Institutes of Health (US); stroke ID UNDERREPRESENTED POPULATIONS; AFRICAN-AMERICAN; PARTICIPATION; DISEASE; RECOMMENDATIONS; INVESTIGATORS; MINORITIES; PHYSICIANS; UPDATE; WOMEN AB Background and Purpose-The National Institutes of Health policy calls for the inclusion of under-represented groups, such as women and minorities, in clinical research. Poor minority recruitment and retention in stroke clinical trials remain a significant challenge limiting safety and efficacy in a general population. Previous research examines participant barriers to clinical trial involvement, but little is known about the investigator perspective. This study addresses this gap and examines researcher-reported barriers and best practices of minority involvement in stroke clinical trials. Methods-Quantitative and qualitative methods, including surveys, focus groups, and key informant interviews were used. Results-In a survey of 93 prominent stroke researchers, 43 (51.2%; 70% response rate) respondents reported proactively setting recruitment goals for minority inclusion, 29 respondents (36.3%) reported requiring cultural competency staff training, and 44 respondents (51.2%) reported using community consultation about trial design. Focus groups and key informant interviews highlighted structural and institutional challenges to recruitment of minorities, including mistrust of the research/medical enterprise, poor communication, and lack of understanding of clinical trials. Researcher-identified best practices included using standardized project management procedures and protocols (eg, realistic budgeting to support challenges in recruitment, such as travel/parking reimbursement for participants), research staff cultural competency and communication training, and developing and fostering community partnerships that guide the research process. Conclusions-This study's formative evaluation contributes a new dimension to the literature as it highlights researcher-reported barriers and best practices for enhancing participation of minority populations into stroke clinical trials. C1 [Boden-Albala, Bernadette; Carman, Heather; Southwick, Lauren; Parikh, Nina S.; Roberts, Eric] NYU, Coll Global Publ Hlth, New York, NY 10003 USA. [Boden-Albala, Bernadette] NYU, Langone Med Ctr, Dept Neurol, New York, NY 10003 USA. [Boden-Albala, Bernadette] NYU, Dept Epidemiol, Coll Dent, New York, NY 10003 USA. [Waddy, Salina] NINDS, NIH, Rockville, MD USA. [Edwards, Dorothy] Univ Wisconsin, Dept Kinesiol, Madison, WI 53706 USA. RP Boden-Albala, B (reprint author), NYU, Coll Global Publ Hlth, 550 1St Ave, New York, NY 10003 USA. EM bb109@nyu.edu OI Boden-Albala, Bernadette/0000-0002-3752-329X FU National Institutes of Health [MD006961] FX This work was supported by the National Institutes of Health (U24#MD006961). NR 22 TC 3 Z9 3 U1 3 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD AUG PY 2015 VL 46 IS 8 BP 2232 EP 2237 DI 10.1161/STROKEAHA.114.008564 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CP6CP UT WOS:000359972200047 PM 26185186 ER PT J AU Huang, GX Arany, PR Mooney, DJ AF Huang, George X. Arany, Praveen R. Mooney, David J. TI Modeling and Validation of Multilayer Poly(Lactide-Co-Glycolide) Scaffolds for In Vitro Directed Differentiation of Juxtaposed Cartilage and Bone SO TISSUE ENGINEERING PART A LA English DT Article ID MESENCHYMAL STEM-CELLS; GROWTH-FACTORS; OSTEOBLASTIC DIFFERENTIATION; ARTICULAR CONDYLE; TISSUE; MATRICES; MARROW AB Polymeric scaffolds, which release growth factors in a temporally controlled manner, have successfully directed the differentiation of stem cells into monolithic tissues of a single lineage. However, engineering precise boundaries in multilineage functional tissues, such as the juxtaposed cartilaginous and osseous tissue present in articulated joints, often remains a challenge. This work demonstrates a precise materials system for in vitro reconstruction of the three-dimensional architecture of these types of human tissues. Multilayer poly(lactide-co-glycolide) (PLG) scaffolds were used to produce spatiotemporal gradients to direct the differentiation of an initially uniform population of mesenchymal stem cells (MSCs) into juxtaposed cartilage and bone. Specifically, growth factors (chondrogenic transforming growth factor-3 and osteogenic bone morphogenetic protein-4) and their neutralizing antibodies were incorporated within distinct layers of the PLG scaffolds to create spatially segregated morphogen fields within the scaffold volume. The multilayer PLG scaffold designs were optimized by mathematical modeling, and generation of spatially segregated morphogen gradients was validated by assessing activity of luciferase reporter cell lines responsive to each growth factor. Scaffolds seeded with MSCs demonstrated production of juxtaposed cartilage and bone, as evaluated by biochemical staining and western blotting for tissue-specific matrix proteins. This work demonstrates a significant advance for the engineering of implantable constructs comprising tissues of multiple lineages, with potential applications in orthopedic regenerative medicine. C1 [Huang, George X.; Arany, Praveen R.; Mooney, David J.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Huang, George X.; Arany, Praveen R.; Mooney, David J.] Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA. [Arany, Praveen R.] Harvard Univ, Sch Dent Med, Cambridge, MA 02138 USA. [Arany, Praveen R.] NIH, Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Mooney, DJ (reprint author), Harvard Univ, Sch Engn & Appl Sci, Pierce Hall Room 325,29 Oxford St, Cambridge, MA 02138 USA. EM mooneyd@seas.harvard.edu FU NIH [R01 DE013033] FX The authors thank Will Yuen for his assistance with mathematical modeling, Jaeyun Kim for help with fabricating nanoparticles, Daniel Rifkin, NYUMC, for providing TGF-beta (p3TP-luc) and BMP (C2C12BRE) luciferase reporter cell lines, and James Weaver for his assistance with SEM-EDS analysis. This work was funded by the NIH (R01 DE013033). NR 27 TC 3 Z9 3 U1 1 U2 10 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD AUG 1 PY 2015 VL 21 IS 15-16 BP 2228 EP 2240 DI 10.1089/ten.tea.2015.0089 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA CP3WF UT WOS:000359812700009 PM 25923238 ER PT J AU Fichtner-Feigl, S Kesselring, R Strober, W AF Fichtner-Feigl, Stefan Kesselring, Rebecca Strober, Warren TI Chronic inflammation and the development of malignancy in the GI tract SO TRENDS IN IMMUNOLOGY LA English DT Review ID INDUCED CYTIDINE DEAMINASE; ACUTE APOPTOTIC RESPONSE; INDUCED COLON TUMORS; COLORECTAL-CANCER; INTESTINAL NEOPLASIA; ULCERATIVE-COLITIS; SIGNALING PATHWAY; BOWEL-DISEASE; MOUSE MODEL; DNA-DAMAGE AB The role of immunologic factors in the development of gastrointestinal (GI) neoplasia, made evident from the high degree of association of chronic intestinal or gastric inflammation with the development of cancer, has attracted much attention because it promises new ways of treating disease. Here we develop the idea that immunologic factors influence the appearance of GI cancer on two levels: (i) a basic and initiating level during which the epithelial cell is induced to undergo pre-cancerous molecular changes that render it prone to further cancer progression; and (ii) a secondary level that builds on this vulnerability and drives the cell into frank malignancy. This secondary level is uniquely dependent on a single epithelial cell signaling pathway centered on STAT3, and it is this pathway upon which stimulation of mucosal cytokine production and microbiota effects converge. C1 [Fichtner-Feigl, Stefan; Kesselring, Rebecca] Univ Med Ctr Regensburg, Dept Surg, D-93053 Regensburg, Germany. [Fichtner-Feigl, Stefan] Regensburg Ctr Intervent Immunol, D-93053 Regensburg, Germany. [Strober, Warren] Natl Inst Allergy & Infect, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. RP Strober, W (reprint author), Natl Inst Allergy & Infect, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. EM WSTROBER@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000354-26] NR 65 TC 6 Z9 6 U1 3 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 EI 1471-4981 J9 TRENDS IMMUNOL JI Trends Immunol. PD AUG PY 2015 VL 36 IS 8 BP 451 EP 459 DI 10.1016/j.it.2015.06.007 PG 9 WC Immunology SC Immunology GA CP4WI UT WOS:000359882900004 PM 26194796 ER PT J AU Tsang, JS AF Tsang, John S. TI Utilizing population variation, vaccination, and systems biology to study human immunology SO TRENDS IN IMMUNOLOGY LA English DT Review ID HUMAN IMMUNE-SYSTEM; SINGLE-CELL TRANSCRIPTOMICS; SET ENRICHMENT ANALYSIS; YELLOW-FEVER VACCINE; INFLUENZA VACCINATION; GENE-EXPRESSION; GENOME-WIDE; MISSING HERITABILITY; LUPUS-ERYTHEMATOSUS; SEASONAL INFLUENZA AB The move toward precision medicine has highlighted the importance of understanding biological variability within and across individuals in the human population. In particular, given the prevalent involvement of the immune system in diverse pathologies, an important question is how much and what information about the state of the immune system is required to enable accurate prediction of future health and response to medical interventions. Towards addressing this question, recent studies using vaccination as a model perturbation and systems-biology approaches are beginning to provide a glimpse of how natural population variation together with multiplexed, high-throughput measurement and computational analysis can be used to uncover predictors of immune response quality in humans. Here I discuss recent developments in this emerging field, with emphasis on baseline correlates of vaccination responses, sources of immune-state variability, as well as relevant features of study design, data generation, and computational analysis. C1 [Tsang, John S.] NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, Bethesda, MD 20892 USA. [Tsang, John S.] NIH, TransNIH Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. RP Tsang, JS (reprint author), NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM john.tsang@nih.gov FU NIAID FX I thank Pamela Schwartzberg, Ronald Germain, members of my laboratory, colleagues at the Trans-NIH Center for Human Immunology (CHI) and the Human Immunology Project Consortium (HIPC) for insightful discussions on many of the topics covered in this review; Yuri Kotliarov for simulation and artwork in Figure 1, Susan Moir on discussions on B cell subsets, Hana Golding for suggesting papers on antibody titer response dynamics, Mario Roederer for discussions about their work on the genetic analysis of immune traits, and Ronald Germain, Andrea Radtke, Pamela Schwartzberg, and Rachel Sparks for comments on the manuscript. This work is funded by the NIAID Intramural Program. NR 131 TC 8 Z9 8 U1 6 U2 18 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 EI 1471-4981 J9 TRENDS IMMUNOL JI Trends Immunol. PD AUG PY 2015 VL 36 IS 8 BP 479 EP 493 DI 10.1016/j.it.2015.06.005 PG 15 WC Immunology SC Immunology GA CP4WI UT WOS:000359882900007 PM 26187853 ER PT J AU Bemben, MA Shipman, SL Nicoll, RA Roche, KW AF Bemben, Michael A. Shipman, Seth L. Nicoll, Roger A. Roche, Katherine W. TI The cellular and molecular landscape of neuroligins SO TRENDS IN NEUROSCIENCES LA English DT Review ID INHIBITORY SYNAPSE DEVELOPMENT; EXCITATORY SYNAPSES; ADHESION MOLECULES; NEUREXIN COMPLEX; GLUTAMATERGIC SYNAPSES; HIPPOCAMPAL-NEURONS; BETA-NEUREXINS; AUTISM; PROTEIN; MUTATION AB A fundamental physical interaction exists across the synapse. It is mediated by synaptic adhesion molecules, and is among the earliest and most indispensable of molecular events occurring during synaptogenesis. The regulation of adhesion molecules and their interactions with other synaptic proteins likely affect not only on synapse formation but also on ongoing synaptic function. We review research on one major family of postsynaptic adhesion molecules, neuroligins, which bind to their presynaptic partner neurexin across the synaptic cleft. We move from a structural overview to the broad cellular and synaptic context of neuroligins, intermolecular interactions, and molecular modifications that occur within a synapse. Finally, we examine evidence concerning the physiological functions of neuroligin in a cell and highlight areas requiring further investigation. C1 [Bemben, Michael A.; Roche, Katherine W.] NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. [Bemben, Michael A.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Shipman, Seth L.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Shipman, Seth L.] Harvard Univ, Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Nicoll, Roger A.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Nicoll, Roger A.] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA. RP Nicoll, RA (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. EM roger.nicoll@ucsf.edu; rochek@mail.nih.gov OI Roche, Katherine/0000-0001-7282-6539 NR 88 TC 10 Z9 10 U1 5 U2 25 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD AUG PY 2015 VL 38 IS 8 BP 496 EP 505 DI 10.1016/j.tins.2015.06.004 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CP4TW UT WOS:000359876500007 PM 26209464 ER PT J AU Wilson, AL Boelaert, M Kleinschmidt, I Pinder, M Scott, TW Tusting, LS Lindsay, SW AF Wilson, Anne L. Boelaert, Marleen Kleinschmidt, Immo Pinder, Margaret Scott, Thomas W. Tusting, Lucy S. Lindsay, Steve W. TI Evidence-based vector control? Improving the quality of vector control trials SO TRENDS IN PARASITOLOGY LA English DT Review DE vector-borne disease; vector control; Phase III trials; research design/standards ID LASTING INSECTICIDAL NETS; CLUSTER-RANDOMIZED-TRIALS; TREATED BED NETS; PLASMODIUM-FALCIPARUM INFECTIONS; DAR-ES-SALAAM; MALARIA CONTROL; AEDES-AEGYPTI; VISCERAL LEISHMANIASIS; CUTANEOUS LEISHMANIASIS; IMPREGNATED BEDNETS AB Vector-borne diseases (VBDs) such as malaria, dengue, and leishmaniasis cause a high level of morbidity and mortality. Although vector control tools can play a major role in controlling and eliminating these diseases, in many cases the evidence base for assessing the efficacy of vector control interventions is limited or not available. Studies assessing the efficacy of vector control interventions are often poorly conducted, which limits the return on investment of research funding. Here we outline the principal design features of Phase Ill vector control field studies, highlight major failings and strengths of published studies, and provide guidance on improving the design and conduct of vector control studies. We hope that this critical assessment will increase the impetus for more carefully considered and rigorous design of vector control studies. C1 [Wilson, Anne L.; Pinder, Margaret; Lindsay, Steve W.] Univ Durham, Sch Biol & Biomed Sci, Durham DH1 3LE, England. [Boelaert, Marleen] Inst Trop Med, Dept Publ Hlth, B-2000 Antwerp, Belgium. [Kleinschmidt, Immo] Univ London London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London WC1E 7HT, England. [Pinder, Margaret] MRC Unit, Banjul, Gambia. [Scott, Thomas W.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tusting, Lucy S.] Univ London London Sch Hyg & Trop Med, Dept Dis Control, London WC1E 7HT, England. RP Lindsay, SW (reprint author), Univ Durham, Sch Biol & Biomed Sci, South Rd, Durham DH1 3LE, England. EM s.w.lindsay@durham.ac.uk OI Tusting, Lucy/0000-0002-6897-8625 FU Bill & Melinda Gates Foundation [OPP1053338]; Research and Policy for Infectious Disease Dynamics (RAPIDD) programme of the Science and Technology Directorate, US Department of Homeland Security, Fogarty International Center (US National Institutes of Health) FX This work was supported by a grant from the Bill & Melinda Gates Foundation (OPP1053338: S.W.L., A.L.W.) and the Research and Policy for Infectious Disease Dynamics (RAPIDD) programme of the Science and Technology Directorate, US Department of Homeland Security, Fogarty International Center (US National Institutes of Health; T.W.S., S.W.L.). NR 93 TC 8 Z9 8 U1 4 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 EI 1471-5007 J9 TRENDS PARASITOL JI Trends Parasitol. PD AUG PY 2015 VL 31 IS 8 BP 380 EP 390 DI 10.1016/j.pt.2015.04.015 PG 11 WC Parasitology SC Parasitology GA CP4TY UT WOS:000359876700010 PM 25999026 ER PT J AU Shinagare, AB Vikram, R Jaffe, C Akin, O Kirby, J Huang, E Freymann, J Sainani, NI Sadow, CA Bathala, TK Rubin, DL Oto, A Heller, MT Surabhi, VR Katabathina, V Silverman, SG AF Shinagare, Atul B. Vikram, Raghu Jaffe, Carl Akin, Oguz Kirby, Justin Huang, Erich Freymann, John Sainani, Nisha I. Sadow, Cheryl A. Bathala, Tharakeswara K. Rubin, Daniel L. Oto, Aytekin Heller, Matthew T. Surabhi, Venkateswar R. Katabathina, Venkat Silverman, Stuart G. TI Radiogenomics of clear cell renal cell carcinoma: preliminary findings of The Cancer Genome Atlas-Renal Cell Carcinoma (TCGA-RCC) Imaging Research Group SO ABDOMINAL IMAGING LA English DT Article DE Clear cell renal cell carcinoma; CT; MRI; Mutational status; Radiogenomics ID TUMOR-SUPPRESSOR GENE; MUTATIONS; HETEROGENEITY; INFORMATICS; ANNOTATION; IMPACT; PBRM1 AB To investigate associations between imaging features and mutational status of clear cell renal cell carcinoma (ccRCC). This multi-institutional, multi-reader study included 103 patients (77 men; median age 59 years, range 34-79) with ccRCC examined with CT in 81 patients, MRI in 19, and both CT and MRI in three; images were downloaded from The Cancer Imaging Archive, an NCI-funded project for genome-mapping and analyses. Imaging features [size (mm), margin (well-defined or ill-defined), composition (solid or cystic), necrosis (for solid tumors: 0%, 1%-33%, 34%-66% or > 66%), growth pattern (endophytic, < 50% exophytic, or a parts per thousand yen50% exophytic), and calcification (present, absent, or indeterminate)] were reviewed independently by three readers blinded to mutational data. The association of imaging features with mutational status (VHL, BAP1, PBRM1, SETD2, KDM5C, and MUC4) was assessed. Median tumor size was 49 mm (range 14-162 mm), 73 (71%) tumors had well-defined margins, 98 (95%) tumors were solid, 95 (92%) showed presence of necrosis, 46 (45%) had a parts per thousand yen50% exophytic component, and 18 (19.8%) had calcification. VHL (n = 52) and PBRM1 (n = 24) were the most common mutations. BAP1 mutation was associated with ill-defined margin and presence of calcification (p = 0.02 and 0.002, respectively, Pearson's chi (2) test); MUC4 mutation was associated with an exophytic growth pattern (p = 0.002, Mann-Whitney U test). BAP1 mutation was associated with ill-defined tumor margins and presence of calcification; MUC4 mutation was associated with exophytic growth. Given the known prognostic implications of BAP1 and MUC4 mutations, these results support using radiogenomics to aid in prognostication and management. C1 [Shinagare, Atul B.; Sainani, Nisha I.; Sadow, Cheryl A.; Silverman, Stuart G.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Vikram, Raghu; Bathala, Tharakeswara K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Jaffe, Carl] Boston Med Ctr, Boston, MA USA. [Akin, Oguz] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kirby, Justin; Huang, Erich; Freymann, John] Natl Canc Inst, Bethesda, MD USA. [Rubin, Daniel L.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Oto, Aytekin] Univ Chicago, Chicago, IL 60637 USA. [Heller, Matthew T.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Surabhi, Venkateswar R.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Katabathina, Venkat] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. RP Shinagare, AB (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM ashinagare@partners.org OI Akin, Oguz/0000-0002-2041-6199 FU Cancer Imaging Program, Division of Cancer Treatment and Diagnosis (DCTD)/National Cancer Institute (NCI)/National Institutes of Health (NIH); National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Image data used in this research were obtained from The Cancer Imaging Archive (http://cancerimagingarchive.net/) sponsored by the Cancer Imaging Program, Division of Cancer Treatment and Diagnosis (DCTD)/National Cancer Institute (NCI)/National Institutes of Health (NIH). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We thank Alessandro Furlan, MD for participating as a study reader. We thank Ms. Brenda Fevrier-Sullivan from NCI for administrative support. NR 34 TC 10 Z9 10 U1 3 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 EI 1432-0509 J9 ABDOM IMAGING JI Abdom. Imaging PD AUG PY 2015 VL 40 IS 6 BP 1684 EP 1692 DI 10.1007/s00261-015-0386-z PG 9 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA CO8QM UT WOS:000359435300036 PM 25753955 ER PT J AU Brown, AM Elbuluk, O Mertan, F Sankineni, S Margolis, DJ Wood, BJ Pinto, PA Choyke, PL Turkbey, B AF Brown, Anna M. Elbuluk, Osama Mertan, Francesca Sankineni, Sandeep Margolis, Daniel J. Wood, Bradford J. Pinto, Peter A. Choyke, Peter L. Turkbey, Baris TI Recent advances in image-guided targeted prostate biopsy SO ABDOMINAL IMAGING LA English DT Article DE Prostate cancer; Biopsy; Targeted; MRI; TRUS ID TRANSRECTAL ULTRASOUND BIOPSY; CANCER-DETECTION; FUSION BIOPSY; NEEDLE-BIOPSY; MRI; ANTIGEN; TIME; MEN; GUIDANCE; REGISTRATION AB Prostate cancer is a common malignancy in the United States that results in over 30,000 deaths per year. The current state of prostate cancer diagnosis, based on PSA screening and sextant biopsy, has been criticized for both overdiagnosis of low-grade tumors and underdiagnosis of clinically significant prostate cancers (Gleason score a parts per thousand yen7). Recently, image guidance has been added to perform targeted biopsies of lesions detected on multi-parametric magnetic resonance imaging (mpMRI) scans. These methods have improved the ability to detect clinically significant cancer, while reducing the diagnosis of low-grade tumors. Several approaches have been explored to improve the accuracy of image-guided targeted prostate biopsy, including in-bore MRI-guided, cognitive fusion, and MRI/transrectal ultrasound fusion-guided biopsy. This review will examine recent advances in these image-guided targeted prostate biopsy techniques. C1 [Brown, Anna M.; Elbuluk, Osama; Mertan, Francesca; Sankineni, Sandeep; Choyke, Peter L.; Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Brown, Anna M.] Duke Univ, Sch Med, Durham, NC USA. [Elbuluk, Osama; Margolis, Daniel J.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Mertan, Francesca] Grove City Coll, Grove City, PA USA. [Wood, Bradford J.; Pinto, Peter A.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. [Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, NIH, 10 Ctr Dr,Room B3B85, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov FU NIH; Pfizer Inc; Doris Duke Charitable Foundation; Newport Foundation; American Association for Dental Research; Howard Hughes Medical Institute; Colgate-Palmolive Company FX 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 Pfizer Inc, The Doris Duke Charitable Foundation, The Newport Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. NR 66 TC 8 Z9 8 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 EI 1432-0509 J9 ABDOM IMAGING JI Abdom. Imaging PD AUG PY 2015 VL 40 IS 6 BP 1788 EP 1799 DI 10.1007/s00261-015-0353-8 PG 12 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA CO8QM UT WOS:000359435300048 PM 25596716 ER PT J AU Zhou, D Hansen, D Shabalin, IG Gustchina, A Vieira, DF de Brito, MV Araujo, APU Oliva, MLV Wlodawer, A AF Zhou, Dongwen Hansen, Daiane Shabalin, Ivan G. Gustchina, Alla Vieira, Debora F. de Brito, Marlon V. Araujo, Ana Paula U. Oliva, Maria Luiza V. Wlodawer, Alexander TI Structure of BbKI, a disulfide-free plasma kallikrein inhibitor SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS LA English DT Article DE -trefoil; Kunitz inhibitor; kallikrein; crystal structure ID KUNITZ PROTEINASE-INHIBITORS; FIBROBLAST GROWTH-FACTORS; BAUHINIA-BAUHINIOIDES; TRYPSIN-INHIBITOR; CRYSTAL-STRUCTURE; ENTEROLOBIUM-CONTORTISILIQUUM; SEEDS; EXPRESSION; CRYSTALLIZATION; INTEGRATION AB A serine protease inhibitor from Bauhinia bauhinioides (BbKI) belongs to the Kunitz family of plant inhibitors, which are common in plant seeds. BbKI does not contain any disulfides, unlike most other members of this family. It is a potent inhibitor of plasma kallikrein, in addition to other serine proteases, and thus exhibits antithrombotic activity. A high-resolution crystal structure of recombinantly expressed BbKI was determined (at 1.4 angstrom resolution) and was compared with the structures of other members of the family. Modeling of a complex of BbKI with plasma kallikrein indicates that changes in the local structure of the reactive loop that includes the specificity-determining Arg64 are necessary in order to explain the tight binding. An R64A mutant of BbKI was found to be a weaker inhibitor of plasma kallikrein, but was much more potent against plasmin, suggesting that this mutant may be useful for preventing the breakup of fibrin and maintaining clot stability, thus preventing excessive bleeding. C1 [Zhou, Dongwen; Gustchina, Alla; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Hansen, Daiane; Oliva, Maria Luiza V.] Univ Fed Sao Paulo, Escola Paulista Med, BR-04044020 Sao Paulo, SP, Brazil. [Shabalin, Ivan G.] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. [Vieira, Debora F.; de Brito, Marlon V.; Araujo, Ana Paula U.] Univ Sao Paulo, Inst Phys Sao Carlos, BR-13560970 Sao Paulo, SP, Brazil. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM wlodawer@nih.gov RI Araujo, Ana Paula/I-6664-2012; Shabalin, Ivan/H-1902-2016; Sao Carlos Institute of Physics, IFSC/USP/M-2664-2016 OI Shabalin, Ivan/0000-0003-3955-9242; FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; CAPES; CNPq; FAPESP [2009/53766-5] FX We acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team (SER-CAT) located at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and in part by CAPES, CNPq and FAPESP 2009/53766-5. NR 43 TC 2 Z9 2 U1 2 U2 6 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 2015 VL 71 BP 1055 EP 1062 DI 10.1107/S2053230X15011127 PN 8 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA CO7PK UT WOS:000359352700023 PM 26249699 ER PT J AU Stolzenberg-Solomon, RZ Newton, CC Silverman, DT Pollak, M Nogueira, LM Weinstein, SJ Albanes, D Mannisto, S Jacobs, EJ AF Stolzenberg-Solomon, Rachael Z. Newton, Christina C. Silverman, Debra T. Pollak, Michael Nogueira, Leticia M. Weinstein, Stephanie J. Albanes, Demetrius Mannisto, Satu Jacobs, Eric J. TI Circulating Leptin and Risk of Pancreatic Cancer: A Pooled Analysis From 3 Cohorts SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE adiposity; insulin resistance; leptin; pancreatic cancer ID GLYCATION END-PRODUCTS; PROSPECTIVE EPIC COHORT; HIGH-FAT DIET; INSULIN-RESISTANCE; SOLUBLE RECEPTOR; SCREENING TRIAL; CELL FUNCTION; SERUM LEPTIN; MALE SMOKERS; WEIGHT-LOSS AB Adiposity is associated with pancreatic cancer; however, the underlying mechanism(s) is uncertain. Leptin is an adipokine involved inmetabolic regulation, and obese individuals have higher concentrations. We conducted a pooled, nested case-control study of cohort participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and the Cancer Prevention Study II Nutrition Cohort to investigate whether prediagnostic serum leptin was associated with pancreatic cancer. A total of 731 pancreatic adenocarcinoma cases that occurred between 1986 and 2010 were included (maximum follow-up, 23 years). Incidence density-selected controls (n = 909) were matched to cases by cohort, age, sex, race, and blood draw date. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Sex-specific quintiles were based on the distribution of the controls. Overall, serum leptin was not associated with pancreatic cancer (quintile 5 vs. quintile 1: odds ratio = 1.13, 95% confidence interval: 0.75, 1.71; P-trend = 0.38). There was a significant interaction by follow-up time (P = 0.003), such that elevated risk was apparent only during follow-up of more than 10 years after blood draw (quintile 5 vs. quintile 1: odds ratio = 2.55, 95% confidence interval: 1.23, 5.27; P-trend = 0.004). Our results support an association between increasing leptin concentration and pancreatic cancer; however, long follow-up is necessary to observe the relationship. Subclinical disease may explain the lack of association during early follow-up. C1 [Stolzenberg-Solomon, Rachael Z.; Silverman, Debra T.; Nogueira, Leticia M.; Weinstein, Stephanie J.; Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Newton, Christina C.; Jacobs, Eric J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Chron Dis, Helsinki, Finland. [Pollak, Michael] McGill Univ, Dept Oncol, Montreal, PQ, Canada. RP Stolzenberg-Solomon, RZ (reprint author), 9609 Med Ctr Dr,Room 6E420, Rockville, MD 20850 USA. EM rs221z@nih.gov OI Mannisto, Satu/0000-0002-8668-3046 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute; Extramural Research Program of the Division of Cancer Control and Population Sciences, National Cancer Institute; American Cancer Society; US Public Health Service from National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C] FX This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, the Extramural Research Program of the Division of Cancer Control and Population Sciences, National Cancer Institute, and the American Cancer Society. Additionally, this research was supported by US Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services. NR 46 TC 6 Z9 8 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2015 VL 182 IS 3 BP 187 EP 197 DI 10.1093/aje/kwv041 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CO7BC UT WOS:000359311500001 PM 26085045 ER PT J AU McMahon, FJ AF McMahon, Francis J. TI Clinically Useful Genetic Markers of Antidepressant Response: How Do We Get There From Here? SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; PHARMACOGENOMICS; DEPRESSION C1 [McMahon, Francis J.] NIMH, Human Genet Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [McMahon, Francis J.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. RP McMahon, FJ (reprint author), NIMH, Human Genet Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM mcmahonf@mail.nih.gov OI McMahon, Francis/0000-0002-9469-305X FU NIMH FX Supported by the NIMH Intramural Research Program NR 12 TC 1 Z9 1 U1 0 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2015 VL 172 IS 8 BP 697 EP 699 DI 10.1176/appi.ajp.2015.15050644 PG 3 WC Psychiatry SC Psychiatry GA CO6NZ UT WOS:000359274700001 PM 26234589 ER PT J AU Shaw, P AF Shaw, Philip TI Gene and Environment Interactions in the Brain: A Pathway to ADHD? SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID SEROTONIN TRANSPORTER GENE; LIFE EVENTS; POLYMORPHISM; METAANALYSIS; DEPRESSION; 5-HTTLPR; VARIANT C1 [Shaw, Philip] NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Shaw, Philip] NIMH, Bethesda, MD 20892 USA. RP Shaw, P (reprint author), NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov NR 16 TC 0 Z9 0 U1 2 U2 12 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2015 VL 172 IS 8 BP 702 EP 703 DI 10.1176/appi.ajp.2015.15050619 PG 2 WC Psychiatry SC Psychiatry GA CO6NZ UT WOS:000359274700003 PM 26234591 ER PT J AU Kowalczyk, WJ Phillips, KA Jobes, ML Kennedy, AP Ghitza, UE Agage, DA Schmittner, JP Epstein, DH Preston, KL AF Kowalczyk, William J. Phillips, Karran A. Jobes, Michelle L. Kennedy, Ashley P. Ghitza, Udi E. Agage, Daniel A. Schmittner, John P. Epstein, David H. Preston, Kenzie L. TI Clonidine Maintenance Prolongs Opioid Abstinence and Decouples Stress From Craving in Daily Life: A Randomized Controlled Trial With Ecological Momentary Assessment SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID COCAINE-DEPENDENT INDIVIDUALS; DOSE NICOTINE PATCH; INDUCED REINSTATEMENT; TRANSLATIONAL RESEARCH; OPIATE WITHDRAWAL; SMOKING LAPSES; DRUG RELAPSE; REAL-TIME; SEEKING; HEROIN AB Objective:The authors tested whether clonidine blocks stress-induced seeking of heroin and cocaine. The study was also intended to confirm translational findings from a rat model of drug relapse by using ecological momentary assessment of patients' stress to test hypotheses about clonidine's behavioral mechanism of action. Method: The authors conducted a randomized double-blind placebo-controlled clinical trial with 208 opioid-dependent patients at an outpatient buprenorphine clinic. The 118 participants (57%) who maintained abstinence during weeks 5-6 were continued on buprenorphine and randomly assigned to receive clonidine (N=61) or placebo (N=57) for 14 weeks. Urine was tested thrice weekly. Lapse was defined as any opioid-positive or missed urine test, and relapse as two or more consecutive lapses. Time to lapse and relapse were examined with Cox regressions; longest period of abstinence was examined with a t test and ecological momentary assessment data were examined with generalized linear mixed models. Results: In an intent-to-treat analysis, clonidine produced the longest duration (in consecutive days) of abstinence from opioids during the intervention phase (34.8 days [SD=3.7] compared with 25.5 days [SD=2.7); Cohen's d=0.38). There was no group difference in time to relapse, but the clonidine group took longer to lapse (hazard ratio=0.67, 95% Cl=0.45-1.00). Ecological momentary assessment showed that daily-life stress was partly decoupled from opioid craving in the clonidine group, supporting the authors' hypothesized mechanism for clonidine's benefits. Conclusions: Clonidine, a readily available medication, is useful in opioid dependence not just for reduction of withdrawal signs, but also as an adjunctive maintenance treatment that increases duration of abstinence. Even in the absence of physical withdrawal, it decouples stress from craving in everyday life. C1 [Preston, Kenzie L.] NIDA, Clin Pharmacol & Therapeut Res Branch, Baltimore, MD 21224 USA. NIMH, Clin Trials Operat & Biostat Branch, Rockville, MD 20857 USA. NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. Spectrum Hlth Syst, Adv Heart Failure Program, Grand Rapids, MI USA. RP Preston, KL (reprint author), NIDA, Clin Pharmacol & Therapeut Res Branch, Baltimore, MD 21224 USA. EM kprestoh@intra.nida.nih.gov OI Kowalczyk, William/0000-0001-8026-285X NR 40 TC 12 Z9 12 U1 0 U2 6 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2015 VL 172 IS 8 BP 760 EP 767 DI 10.1176/appi.ajp.2014.14081014 PG 8 WC Psychiatry SC Psychiatry GA CO6NZ UT WOS:000359274700016 PM 25783757 ER PT J AU Coulibaly, YI Dembele, B Diallo, AA Konate, S Dolo, H Coulibaly, SY Doumbia, SS Soumaoro, L Coulibaly, ME Bockarie, MJ Molyneux, D Nutman, TB Klion, AD Toure, YT Traore, SF AF Coulibaly, Yaya I. Dembele, Benoit Diallo, Abdallah Amadou Konate, Siaka Dolo, Houseini Coulibaly, Siaka Yamoussa Doumbia, Salif Seriba Soumaoro, Lamine Coulibaly, Michel Emmanuel Bockarie, Moses J. Molyneux, David Nutman, Thomas B. Klion, Amy D. Toure, Yeya T. Traore, Sekou F. TI The Impact of Six Annual Rounds of Mass Drug Administration on Wuchereria bancrofti Infections in Humans and in Mosquitoes in Mali SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID LYMPHATIC FILARIASIS ELIMINATION; ANOPHELES-TRANSMITTED FILARIASIS; GLOBAL PROGRAM; TRANSMISSION; DIETHYLCARBAMAZINE; FACILITATION; ALBENDAZOLE; LIMITATION; DYNAMICS; VECTORS AB Wuchereria bancrofti prevalence and transmission were assessed in six endemic villages in Sikasso, Mali prior to and yearly during mass drug administration (MDA) with albendazole and ivermectin from 2002 to 2007. Microfilaremia was determined by calibrated thick smear of night blood in adult volunteers and circulating filarial antigen was measured using immunochromatographic card test in children < 5 years of age. Mosquitoes were collected by human landing catch from July to December. None of the 686 subjects tested were microfilaremic 12 months after the sixth MDA round. More importantly, circulating antigen was not detected in any of the 120 children tested, as compared with 53% (103/194) before the institution of MDA. The number of infective bites/human/year decreased from 4.8 in 2002 to 0.04 in 2007, and only one mosquito containing a single infective larva was observed 12 months after the final MDA round. Whether this dramatic reduction in transmission will be sustained following cessation of MDA remains to be seen. C1 [Coulibaly, Yaya I.; Dembele, Benoit; Diallo, Abdallah Amadou; Konate, Siaka; Dolo, Houseini; Coulibaly, Siaka Yamoussa; Doumbia, Salif Seriba; Soumaoro, Lamine; Coulibaly, Michel Emmanuel; Traore, Sekou F.] Int Ctr Excellence Res ICER Mali, Filariasis Res & Training Unit, Bamako, Mali. Univ Liverpool, Liverpool Liverpool Sch Trop Med, Ctr Neglected Trop Dis, Liverpool L69 3BX, Merseyside, England. [Nutman, Thomas B.] NIH, Parasit Dis Lab, Helminth Immunol Sect, Bethesda, MD 20892 USA. [Klion, Amy D.] NIH, Parasit Dis Lab, Eosinophil Pathol Sect, Bethesda, MD 20892 USA. [Toure, Yeya T.] World Hlth Org, Vectors Environm & Soc Res, Geneva, Switzerland. RP Coulibaly, YI (reprint author), FMPOS, BP 1805, Bamako, Mali. EM yicoulibaly@icermali.org; dbenedictus@hotmail.com; adaxe@icermali.org; kiforo2002@yahoo.fr; hdolo@icermali.org; yamoussa@icermali.org; Salifdoumbia@icermali.org; soumla@icermilli.org; michou@icermali.org; Moses.Bockarie@Istmed.ac.uk; David.Molyneux@LSTMed.ac.uk; tnutman@niaid.nih.gov; aklion@niaid.nih.gov; tourey@who.int; cheick@icermali.org FU WHO/UNDP/World Bank Special Program for Tropical Diseases [A00583]; Lymphatic Filariasis Support Centre of the Liverpool School of Tropical Medicine, UK from the UK Department for International Development; Division of Intramural Research, NIAID, NIH FX This study was funded by the WHO/UNDP/World Bank Special Program for Tropical Diseases grant (ID A00583) to SFK and the Lymphatic Filariasis Support Centre of the Liverpool School of Tropical Medicine, UK through a grant from the UK Department for International Development. This study was funded in part by the Division of Intramural Research, NIAID, NIH. NR 19 TC 4 Z9 4 U1 0 U2 3 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD AUG PY 2015 VL 93 IS 2 BP 356 EP 360 DI 10.4269/ajtmh.14-0516 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CO7GK UT WOS:000359327400030 PM 26033027 ER PT J AU Radke, AK Gewirtz, JC Carroll, ME AF Radke, Anna K. Gewirtz, Jonathan C. Carroll, Marilyn E. TI Effects of age, but not sex, on elevated startle during withdrawal from acute morphine in adolescent and adult rats SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE adolescent; adult; morphine; rat; startle; withdrawal ID CONDITIONED PLACE PREFERENCE; OPIATE WITHDRAWAL; ACUTE ETHANOL; FEMALE RATS; PHYSICAL-DEPENDENCE; SACCHARIN INTAKE; LOW LOS; NICOTINE; COCAINE; ANXIETY AB Investigations into animal models of drug withdrawal have largely found that emotional signs of withdrawal (e.g. anxiety, anhedonia, and aversion) in adolescents are experienced earlier and less severely than in their adult counterparts. The majority of these reports have examined withdrawal from ethanol or nicotine. To expand our knowledge about the emotional withdrawal state in adolescent rats, we used potentiation of the acoustic startle reflex after an acute dose of morphine (10mg/kg, subcutaneously) as a measure of opiate withdrawal. Startle was measured at four time points after morphine injection (2, 3, 4, and 5h) in 28-day-old and 90-day-old male and female rats. The results of this experiment revealed that peak potentiation of the startle reflex occurred at 3h in the adolescent rats and at 5h in the adult rats, and that the magnitude of withdrawal was larger in the adults. No sex differences were observed. Overall, these results affirm that, similar to withdrawal from ethanol and nicotine, opiate withdrawal signs are less severe in adolescent than in adult rats. C1 [Radke, Anna K.; Carroll, Marilyn E.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Gewirtz, Jonathan C.] Univ Minnesota, Dept Neurosci, Minneapolis, MN USA. [Gewirtz, Jonathan C.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. RP Radke, AK (reprint author), NIAAA, Natl Inst Hlth, 5625 Fishers Lane, Rockville, MD 20852 USA. EM anna.radke@nih.gov FU NIH [R01 DA003240-28]; University of Minnesota FX We thank Sofiya Hupalo and Jacob Leslie for technical assistance. This work was funded by NIH grants R01 DA003240-28 (M.E.C.) and the University of Minnesota (J.C.G.). NR 41 TC 3 Z9 3 U1 1 U2 4 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 2015 VL 26 IS 5 BP 485 EP 488 DI 10.1097/FBP.0000000000000151 PG 4 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA CP0XO UT WOS:000359600300009 PM 26154436 ER PT J AU Giffen, CA Carroll, LE Adams, JT Brennan, SP Coady, SA Wagner, EL AF Giffen, Carol A. Carroll, Leslie E. Adams, John T. Brennan, Sean P. Coady, Sean A. Wagner, Elizabeth L. TI Providing Contemporary Access to Historical Biospecimen Collections: Development of the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) SO BIOPRESERVATION AND BIOBANKING LA English DT Article AB The National Heart, Lung, and Blood Institute (NHLBI), within the United States' National Institutes of Health (NIH), established a Biorepository in 1976 that initially archived biospecimens from population-based blood product safety surveys. It was later expanded to biospecimens from clinical and epidemiological studies in heart, lung, and blood disorders. The NHLBI also established a Data Repository in 2000 to store and distribute study data from NHLBI-sponsored research. The NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) was established in 2008 to develop the infrastructure needed to link the contents of these two related NHLBI Repositories, facilitate access to repository resources, and streamline request processes. Three key program subcomponents were developed simultaneously: 1) the linkage of biospecimen electronic inventory records with their clinical or characterization data; 2) the development and implementation of a website with both public-facing information and private processing workspaces; and 3) the development of processes to maximize efficiency via a web-based system while maintaining workflow control, document tracking, and secure processes. The BioLINCC website was launched on October 1, 2009 with eight biospecimen collections and data from 72 research studies. By the end of the fourth online year, 38 biospecimen collections were linked and posted, and data from 108 research studies had been made available for request. The number of registered users by the end of the fourth online year approached 2600, and continues to show a trend towards an increasing rate of new users per year. BioLINCC has fulfilled 381 requests comprising 851 data collections, as well as 600 teaching dataset requests and 75 data renewal agreements. 154 biospecimen requests comprising 147,388 biospecimens were fulfilled or actively in process. We conclude that the BioLINCC program has been successful in its goal to increase the visibility and utilization of NHLBI biospecimen and data repository resources. C1 [Giffen, Carol A.; Carroll, Leslie E.; Adams, John T.; Brennan, Sean P.] Informat Management Serv Inc, Calverton, MD 20705 USA. [Coady, Sean A.] NHLBI, Epidemiol Branch, Prevent & Populat Sci Program, Div Cardiovasc Dis, Bethesda, MD 20892 USA. [Wagner, Elizabeth L.] NHLBI, Translat Blood Sci & Resources Branch, Div Blood Dis & Resources, Bethesda, MD 20892 USA. RP Giffen, CA (reprint author), Informat Management Serv Inc, 3901 Calverton Blvd,Suite 200, Calverton, MD 20705 USA. EM giffenc@imsweb.com FU BioLINCC under NIH/NHLBI [HHSN268201400014C]; NHLBI Biorepository under NIH/NHLBI [HHSN268201400035C] FX BioLINCC is funded under NIH/NHLBI contract HHSN268201400014C. The NHLBI Biorepository is funded under NIH/NHLBI contract HHSN268201400035C. NR 3 TC 7 Z9 7 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1947-5535 EI 1947-5543 J9 BIOPRESERV BIOBANK JI Biopreserv. Biobank. PD AUG 1 PY 2015 VL 13 IS 4 BP 271 EP 279 DI 10.1089/bio.2014.0050 PG 9 WC Cell Biology; Chemistry, Applied; Medical Laboratory Technology SC Cell Biology; Chemistry; Medical Laboratory Technology GA CP0TX UT WOS:000359589800007 PM 26186276 ER PT J AU Akinyemiju, T Moore, JX Altekruse, SF AF Akinyemiju, Tomi Moore, Justin Xavier Altekruse, Sean F. TI Breast cancer survival in African-American women by hormone receptor subtypes SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Hormone receptor subtype; Triple negative; African Americans; Survival AB Breast cancer accounts for over 200,000 annual cases among women in the United States, and is the second leading cause of cancer-related deaths. However, few studies have investigated the association between breast cancer subtype and survival among African-American women. We analyzed cancer-related deaths among African-American women using data obtained from the SEER database linked to the 2000 U.S. census data. We examined distribution of baseline socio-demographic and clinical characteristics by breast cancer subtypes and used Cox proportional hazard models to determine associations between breast cancer subtypes and cancer-related mortality, adjusting for age, socio-economic status, stage at diagnosis, and treatment. Among 19,836 female breast cancer cases, 54.4 % were diagnosed with the HER2-/HR+ subtype, with the majority of those cases occurring among women ages 55 and older. However, after adjusting for age, stage, and treatment type (surgery, radiation, or no radiation and/or cancer-directed surgery), TNBC (HR 2.34; 95 % CI 1.95-2.81) and HER2+/HR- (HR 1.39, 95 % CI 1.08-1.79) cases had significantly higher hazards of cancer-related deaths compared with HER2+/HR+ cases. Adjusting for socio-economic status did not significantly alter these associations. African-American women with TNBC were more likely to have a cancer-related death than African-American women with other breast cancer subtypes. This association remained after adjustments for age, stage, treatment, and socio-economic status. Further studies are needed to identify subtype-specific risk and prognostic factors aimed at better informing prevention efforts for all women. C1 [Akinyemiju, Tomi; Moore, Justin Xavier] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. [Moore, Justin Xavier] Univ Alabama Birmingham, Dept Emergency Med, Sch Med, Birmingham, AL 35294 USA. [Altekruse, Sean F.] NCI, Canc Stat Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Akinyemiju, T (reprint author), Univ Alabama Birmingham, Dept Epidemiol, 1720 2nd Ave S RPHB Rm 210, Birmingham, AL 35294 USA. EM tomiakin@uab.edu OI Moore, Justin/0000-0002-5496-752X NR 0 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD AUG PY 2015 VL 153 IS 1 BP 211 EP 218 DI 10.1007/s10549-015-3528-7 PG 8 WC Oncology SC Oncology GA CP3JL UT WOS:000359775100021 PM 26250393 ER PT J AU Coghill, AE Engels, EA AF Coghill, Anna E. Engels, Eric A. TI Are Cancer Outcomes Worse in the Presence of HIV Infection? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID TUMOR IMMUNOGENICITY; COLORECTAL-CANCER; UNITED-STATES; T-CELLS; IMMUNOSURVEILLANCE; LYMPHOCYTES; SURVIVAL; MELANOMA C1 [Coghill, Anna E.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. RP Coghill, AE (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20892 USA. EM anna.coghill@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 19 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2015 VL 24 IS 8 BP 1165 EP 1166 DI 10.1158/1055-9965.EPI-15-0454 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CO7DY UT WOS:000359320500003 PM 26240170 ER PT J AU Sisti, JS Hankinson, SE Caporaso, NE Gu, FY Tamimi, RM Rosner, B Xu, X Ziegler, R Eliassen, AH AF Sisti, Julia S. Hankinson, Susan E. Caporaso, Neil E. Gu, Fangyi Tamimi, Rulla M. Rosner, Bernard Xu, Xia Ziegler, Regina Eliassen, A. Heather TI Caffeine, Coffee, and Tea Intake and Urinary Estrogens and Estrogen Metabolites in Premenopausal Women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER RISK; CHROMATOGRAPHY-MASS SPECTROMETRY; 2-TO 3-YEAR PERIOD; ESTRADIOL METABOLITES; STEROID-HORMONES; CONSUMPTION; PLASMA; CELLS; REPRODUCIBILITY; PROLIFERATION AB Background: Prior studies have found weak inverse associations between breast cancer and caffeine and coffee intake, possibly mediated through their effects on sex hormones. Methods: High-performance liquid chromatography/tandem mass spectrometry was used to quantify levels of 15 individual estrogens and estrogen metabolites (EM) among 587 premenopausal women in the Nurses' Health Study II with mid-luteal phase urine samples and caffeine, coffee, and/or tea intakes from self-reported food frequency questionnaires. Multivariate linear mixed models were used to estimate geometric means of individual EM, pathways, and ratios by intake categories, and P values for tests of linear trend. Results: Compared with women in the lowest quartile of caffeine consumption, those in the top quartile had higher urinary concentrations of 16 alpha-hydroxyestrone (28% difference; P-trend = 0.01) and 16-epiestriol (13% difference; P-trend = 0.04), and a decreased parent estrogens/2-, 4-, 16-pathway ratio (P-trend = 0.03). Coffee intake was associated with higher 2-catechols, including 2-hydroxyestradiol (57% difference, >= 4 cups/day vs. <= 6 cups/week; P-trend = 0.001) and 2-hydroxyestrone (52% difference; P-trend = 0.001), and several ratio measures. Decaffeinated coffee was not associated with 2-pathway metabolism, but women in the highest (vs. lowest) category of intake (>= 2 cups/day vs. <= 1-3 cups/month) had significantly lower levels of two 16-pathway metabolites, estriol (25% difference; P-trend = 0.01) and 17-epiestriol (48% difference; P-trend = 0.0004). Tea intake was positively associated with 17-epiestriol (52% difference; P-trend = 0.01). Conclusion: Caffeine and coffee intake were both associated with profiles of estrogen metabolism in premenopausal women. Impact: Consumption of caffeine and coffee may alter patterns of premenopausal estrogen metabolism. (C) 2015 AACR. C1 [Sisti, Julia S.; Hankinson, Susan E.; Tamimi, Rulla M.; Eliassen, A. Heather] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hankinson, Susan E.; Tamimi, Rulla M.; Rosner, Bernard; Eliassen, A. Heather] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Hankinson, Susan E.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. [Caporaso, Neil E.; Gu, Fangyi; Ziegler, Regina] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Xu, Xia] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD USA. RP Sisti, JS (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM jss235@mail.harvard.edu FU National Cancer Institute [UM1 CA176726, CA67262, CA50385, HHSN261200800001E]; Division of Cancer Epidemiology and Genetics of the National Cancer Institute; [R25 CA098566]; [T32 CA900137] FX This study was supported by Infrastructure Grant UM1 CA176726 and Research Grants CA67262 (to S.E. Hankinson) and CA50385 from the National Cancer Institute and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, and with federal funds of the National Cancer Institute awarded under Contract HHSN261200800001E to SAIC-Frederick. J.S. Sisti was funded by R25 CA098566 and T32 CA900137. NR 44 TC 3 Z9 3 U1 1 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2015 VL 24 IS 8 BP 1174 EP 1183 DI 10.1158/1055-9965.EPI-15-0246 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CO7DY UT WOS:000359320500005 PM 26063478 ER PT J AU Tanner, JA Novalen, M Jatlow, P Huestis, MA Murphy, SE Kaprio, J Kankaanpaa, A Galanti, L Stefan, C George, TP Benowitz, NL Lerman, C Tyndale, RF AF Tanner, Julie-Anne Novalen, Maria Jatlow, Peter Huestis, Marilyn A. Murphy, Sharon E. Kaprio, Jaakko Kankaanpaa, Aino Galanti, Laurence Stefan, Cristiana George, Tony P. Benowitz, Neal L. Lerman, Caryn Tyndale, Rachel F. TI Nicotine Metabolite Ratio (3-Hydroxycotinine/Cotinine) in Plasma and Urine by Different Analytical Methods and Laboratories: Implications for Clinical Implementation SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID TREATMENT-SEEKING SMOKERS; HUMAN LIVER-MICROSOMES; SMOKING-CESSATION; TRANSDERMAL NICOTINE; AD-LIBITUM; CYP2A6; COTININE; PHARMACOKINETICS; ASSOCIATION; VARIABILITY AB Background: The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3'-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers. Methods: Plasma (n = 35) and urine (n = 35) samples were sent to eight different laboratories, which used similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland-Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods. Results: Measures of plasma NMR were in strong agreement between methods according to Bland-Altman analysis (ratios, 0.82-1.16) and were highly correlated (all Pearson r > 0.96, P < 0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62-1.71) and less strongly correlated (Pearson r values of 0.66-0.98, P < 0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than that in urine, as was observed for NMR. Conclusions: Plasma is a very reliable biologic source for the determination of NMR, robust to differences in these analytical protocols or assessment site. Impact: Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies. (C)2015 AACR. C1 [Tanner, Julie-Anne; Novalen, Maria; George, Tony P.; Tyndale, Rachel F.] CAMH, Campbell FamilyMental Hlth Res Inst, Toronto, ON, Canada. [Tanner, Julie-Anne; Novalen, Maria; Tyndale, Rachel F.] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada. [Jatlow, Peter] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA. [Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD USA. [Murphy, Sharon E.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN USA. [Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Kaprio, Jaakko; Kankaanpaa, Aino] Natl Inst Hlth & Welf THL, Helsinki, Finland. [Kaprio, Jaakko] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Galanti, Laurence] Mt Godinne Univ Hosp, Dept Clin Biol, Yvoir, Belgium. [Stefan, Cristiana] Ctr Addict & Mental Hlth, Clin Lab & Diagnost Serv, Toronto, ON, Canada. [George, Tony P.] Univ Toronto, Dept Psychiat, Div Brain & Therapeut, Toronto, ON M5S 1A8, Canada. [George, Tony P.; Tyndale, Rachel F.] CAMH, Schizophrenia Div, Toronto, ON, Canada. [Benowitz, Neal L.] Univ Calif San Francisco, Dept Med, Div Clin Pharmacol & Expt Therapeut, San Francisco, CA USA. [Benowitz, Neal L.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, Div Clin Pharmacol & Expt Therapeut, San Francisco, CA 94143 USA. [Lerman, Caryn] Univ Penn, Dept Psychiat, Ctr Interdisciplinary Res Nicotine Addict, Philadelphia, PA 19104 USA. RP Tyndale, RF (reprint author), Univ Toronto, 1 Kings Coll Circle,Med Sci Bldg,Room 4326, Toronto, ON M5S 1A8, Canada. EM r.tyndale@utoronto.ca FU Endowed Chair in Addictions; NIH PGRN grant [DA020830]; CAMH; Canada Foundation for Innovation [20289, 16014]; CAMH Foundation; Ontario Ministry of Research and Innovation; NIH TCORS grants [1P50DA036151]; NIH grant from the National Institute On Drug Abuse [DA012393] FX This work was supported by an Endowed Chair in Addictions (to R.F. Tyndale), NIH PGRN grant DA020830 (to R.F. Tyndale, N.L. Benowitz, T.P. George, and C. Lerman), CAMH, the Canada Foundation for Innovation (#20289 and #16014, to R.F. Tyndale), the CAMH Foundation, and the Ontario Ministry of Research and Innovation. NIH TCORS grants 1P50DA036151 (to P. Jatlow) and NIH grant DA012393 (to N.L. Benowitz) from the National Institute On Drug Abuse. NR 23 TC 8 Z9 8 U1 2 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2015 VL 24 IS 8 BP 1239 EP 1246 DI 10.1158/1055-9965.EPI-14-1381 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CO7DY UT WOS:000359320500013 PM 26014804 ER PT J AU Engels, EA Jennings, L Kemp, TJ Chaturvedi, AK Pinto, LA Pfeiffer, RM Trotter, JF Acker, M Onaca, N Klintmalm, GB AF Engels, Eric A. Jennings, Linda Kemp, Troy J. Chaturvedi, Anil K. Pinto, Ligia A. Pfeiffer, Ruth M. Trotter, James F. Acker, Michelle Onaca, Nicholas Klintmalm, Goran B. TI Circulating TGF-beta 1 and VEGF and risk of cancer among liver transplant recipients SO CANCER MEDICINE LA English DT Article DE Cancer; platelet; solid organ transplantation; transforming growth factor beta; vascular endothelial growth factor ID ENDOTHELIAL GROWTH-FACTOR; MALIGNANT-MELANOMA; LUNG-CANCER; COLORECTAL-CANCER; PLASMA; PLATELETS; SIROLIMUS; MARKER; BLOOD; BETA AB Transplant recipients have elevated cancer risk, perhaps partly due to direct carcinogenic effects of immunosuppressive medications. Experimental evidence indicates that calcineurin inhibitors given to transplant recipients increase cellular expression of transforming growth factor beta 1 (TGF-beta 1) and vascular endothelial growth factor (VEGF), which could promote cancer. To assess the potential role of these pathways in the transplantation setting, we conducted a case-control study nested in a cohort of liver recipients. Cases had nonmelanoma skin cancer (N = 84), cancer of the lung (N = 29), kidney (N = 20), or colorectum (N = 17), or melanoma (N = 3). We selected N = 463 recipients without cancer as controls. TGF-beta 1 and VEGF levels were measured in sera obtained, on average, approximately 3 years before case diagnosis/control selection. We also measured platelet factor 4 (PF4), a marker of ex vivo platelet degranulation, because TGF-beta 1 and VEGF can be released from platelets, and we developed a statistical model to isolate the platelet-derived fraction from the remaining circulating component. Compared with controls, lung cancer cases had higher levels of TGF-beta 1 (median 22.8 vs. 19.4 ng/mL, P = 0.02) and VEGF (277 vs. 186 pg/mL, P = 0.02). However, lung cancer cases also had higher platelet counts (P = 0.08) and PF4 levels (P = 0.02), while residual serum levels of TGF-beta 1 and VEGF, after accounting for PF4, were unassociated with lung cancer (P = 0.40 and P = 0.15, respectively). Associations were not seen for other cancers. In conclusion, TGF-beta 1 and VEGF levels were increased in association with lung cancer among transplant recipients, which may be explained by increased platelet counts and platelet degranulation in lung cancer cases. C1 [Engels, Eric A.; Chaturvedi, Anil K.; Pfeiffer, Ruth M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Jennings, Linda; Trotter, James F.; Acker, Michelle; Onaca, Nicholas; Klintmalm, Goran B.] Baylor Univ, Med Ctr, Baylor Simmons Transplant Inst, Dallas, TX USA. [Kemp, Troy J.; Pinto, Ligia A.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, HPV Immunol Lab, Frederick, MD USA. RP Engels, EA (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E226 MSC 9767, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov RI Chaturvedi, Anil/J-2024-2015 OI Chaturvedi, Anil/0000-0003-2696-8899 FU National Cancer Institute FX This study was supported by the Intramural Research Program of the National Cancer Institute. NR 24 TC 7 Z9 7 U1 0 U2 1 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 2015 VL 4 IS 8 BP 1252 EP 1257 DI 10.1002/cam4.455 PG 6 WC Oncology SC Oncology GA CO7VR UT WOS:000359371500012 PM 25919050 ER PT J AU Seow, WJ Zhang, LP Vermeulen, R Tang, XJ Hu, W Bassig, BA Ji, ZY Shiels, MS Kemp, TJ Shen, M Qiu, CY Reiss, B Freeman, LEB Blair, A Kim, C Guo, WH Wen, CJ Li, LY Pinto, LA Huang, HL Smith, MT Hildesheim, A Rothman, N Lan, Q AF Seow, Wei Jie Zhang, Luoping Vermeulen, Roel Tang, Xiaojiang Hu, Wei Bassig, Bryan A. Ji, Zhiying Shiels, Meredith S. Kemp, Troy J. Shen, Min Qiu, Chuangyi Reiss, Boris Freeman, Laura E. Beane Blair, Aaron Kim, Christopher Guo, Weihong Wen, Cuiju Li, Laiyu Pinto, Ligia A. Huang, Hanlin Smith, Martyn T. Hildesheim, Allan Rothman, Nathaniel Lan, Qing TI Circulating immune/inflammation markers in Chinese workers occupationally exposed to formaldehyde SO CARCINOGENESIS LA English DT Article ID C-REACTIVE PROTEIN; NASOPHARYNGEAL CARCINOMA; CARDIOVASCULAR-DISEASE; PROTEOMIC ANALYSIS; T-CELLS; LEUKEMIA; HEALTH; RISK; APOPTOSIS; CHEMOKINE AB Background. Formaldehyde has been classified as a human myeloid leukemogen. However, the mechanistic basis for this association is still debated. Objectives. We aimed to evaluate whether circulating immune/inflammation markers were altered in workers occupationally exposed to formaldehyde. Methods. Using a multiplexed bead-based assay, we measured serum levels of 38 immune/inflammation markers in a cross-sectional study of 43 formaldehyde-exposed and 51 unexposed factory workers in Guangdong, China. Linear regression models adjusting for potential confounders were used to compare marker levels in exposed and unexposed workers. Results. We found significantly lower circulating levels of two markers among exposed factory workers compared with unexposed controls that remained significant after adjusting for potential confounders and multiple comparisons using a false discovery rate of 10%, including chemokine (C-X-C motif) ligand 11 (36.2 pg/ml in exposed versus 48.4 pg/ml in controls, P = 0.0008) and thymus and activation regulated chemokine (52.7 pg/ml in exposed versus 75.0 pg/ml in controls, P = 0.0028), suggesting immunosuppression among formaldehyde-exposed workers. Conclusions. Our findings are consistent with recently emerging understanding that immunosuppression might be associated with myeloid diseases. These findings, if replicated in a larger study, may provide insights into the mechanisms by which formaldehyde promotes leukemogenesis. C1 [Seow, Wei Jie; Hu, Wei; Bassig, Bryan A.; Shiels, Meredith S.; Shen, Min; Freeman, Laura E. Beane; Blair, Aaron; Kim, Christopher; Wen, Cuiju; Hildesheim, Allan; Rothman, Nathaniel; Lan, Qing] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Zhang, Luoping; Ji, Zhiying; Guo, Weihong; Smith, Martyn T.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Vermeulen, Roel; Reiss, Boris] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, Utrecht, Netherlands. [Tang, Xiaojiang; Qiu, Chuangyi; Li, Laiyu; Huang, Hanlin] Guangdong Poison Control Ctr, Guangzhou, Guangdong, Peoples R China. [Kemp, Troy J.; Pinto, Ligia A.] Leidos Biomed Res Inc, HPV Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Seow, WJ (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. EM weijie.seow2@nih.gov RI Beane Freeman, Laura/C-4468-2015; Vermeulen, Roel/F-8037-2011 OI Beane Freeman, Laura/0000-0003-1294-4124; Vermeulen, Roel/0000-0003-4082-8163 FU National Cancer Institute (Intramural fund); National Institute of Environmental Health Sciences [R01ES017452, P42ES004705] FX National Cancer Institute (Intramural fund) and National Institute of Environmental Health Sciences (R01ES017452 to L.Z. and P42ES004705 to M.T.S.) NR 41 TC 0 Z9 0 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2015 VL 36 IS 8 BP 852 EP 857 DI 10.1093/carcin/bgv055 PG 6 WC Oncology SC Oncology GA CO7CH UT WOS:000359314600005 PM 25908645 ER PT J AU Kenchaiah, S Vasan, RS AF Kenchaiah, Satish Vasan, Ramachandran S. TI Heart Failure in Women - Insights from the Framingham Heart Study SO CARDIOVASCULAR DRUGS AND THERAPY LA English DT Review DE Biomarkers; Epidemiology; Framingham heart study; Gender; Heart failure; Incidence; Men; Mortality; Risk factors; Sex-differences; Survival; Women ID REDUCED EJECTION FRACTION; LEFT-VENTRICULAR HYPERTROPHY; PRIOR MYOCARDIAL-INFARCTION; NATRIURETIC PEPTIDE LEVELS; LONG-TERM TRENDS; SYSTOLIC DYSFUNCTION; PLASMA HOMOCYSTEINE; ELDERLY INDIVIDUALS; ATRIAL-FIBRILLATION; SERUM ALDOSTERONE AB In the latter half of the 20th century, among participants of the Framingham Heart Study, incidence of heart failure (HF) has declined by about a third in women but not in men and survival after the onset of HF has improved in both sexes; however, HF remains highly lethal with over 50 % dying within 5 years after onset of HF. Overall, the 8-year relative risk of HF is 24 % lower in women compared with men. The 8-year incidence rates of HF with preserved ejection fraction (HFPEF; EF > 45 %) and HF with reduced EF (HFREF; EF a parts per thousand currency sign45 %) in women and HFPEF in men are similar; however, men have a 2-fold higher cumulative incidence of HFREF than HFPEF. The lifetime risk of HF is about 20 % in both women and men at 40, 50, 60, 70, and 80 years of age. Contribution of hypertension and diabetes mellitus to the risk of HF was more prominent in women than in men. Serum levels of several biomarkers were distinctly different in women compared with men and had differential effects on left ventricular structure and function; however, the strength and direction of the association between biomarkers levels and HF risk were generally similar in women and men. In individuals with HF, about two-thirds of the underlying cause of death and about one-half of the immediate cause of death were due to cardiovascular causes. Non-cardiovascular underlying and immediate causes of death were more evident in HFPEF. C1 [Kenchaiah, Satish] Univ Arkansas Med Sci, Div Cardiovasc Med, Dept Internal Med, Little Rock, AR 72205 USA. [Kenchaiah, Satish; Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Kenchaiah, Satish] NHLBI, Bethesda, MD 20892 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med & Epidemiol, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. RP Kenchaiah, S (reprint author), Univ Arkansas Med Sci, Div Cardiovasc Med, Dept Internal Med, 4301 W Markham St,532, Little Rock, AR 72205 USA. EM SKenchaiah@uams.edu RI Kenchaiah, Satish/A-1519-2016; OI Ramachandran, Vasan/0000-0001-7357-5970 FU Translational Research Institute (TRI) through the National Institutes of Health (NIH) National Center for Research Resources [UL1TR000039, KL2TR000063]; National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute, Bethesda, Maryland [N01-HC-25195] FX Dr. Kenchaiah was partly supported by the Translational Research Institute (TRI), grants UL1TR000039 and KL2TR000063 through the National Institutes of Health (NIH) National Center for Research Resources and the National Center for Advancing Translational Sciences. This work was also partly supported by grant No. N01-HC-25195 (Dr. Vasan) from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 58 TC 2 Z9 3 U1 0 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-3206 EI 1573-7241 J9 CARDIOVASC DRUG THER JI Cardiovasc. Drugs Ther. PD AUG PY 2015 VL 29 IS 4 BP 377 EP 390 DI 10.1007/s10557-015-6599-0 PG 14 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA CP3UH UT WOS:000359807400008 PM 26245740 ER PT J AU Crocker-Buque, A Brown, SM Kind, PC Isaac, JTR Daw, MI AF Crocker-Buque, Alex Brown, Sarah M. Kind, Peter C. Isaac, John T. R. Daw, Michael I. TI Experience-Dependent, Layer-Specific Development of Divergent Thalamocortical Connectivity SO CEREBRAL CORTEX LA English DT Article DE barrel cortex; LTP; plasticity; somatosensory ID LONG-TERM POTENTIATION; RAT BARREL CORTEX; SOMATOSENSORY CORTEX; CRITICAL-PERIOD; IN-VIVO; SYNAPTIC PLASTICITY; KAINATE RECEPTOR; VISUAL-CORTEX; SYNAPSES; NEURONS AB The main input to primary sensory cortex is via thalamocortical (TC) axons that form the greatest number of synapses in layer 4, but also synapse onto neurons in layer 6. The development of the TC input to layer 4 has been widely studied, but less is known about the development of the layer 6 input. Here, we show that, in neonates, the input to layer 6 is as strong as that to layer 4. Throughout the first postnatal week, there is an experience-dependent strengthening specific to layer 4, which correlates with the ability of synapses in layer 4, but not in layer 6, to undergo long-term potentiation (LTP). This strengthening consists of an increase in axon branching and the divergence of connectivity in layer 4 without a change in the strength of individual connections. We propose that experience-driven LTP stabilizes transient TC synapses in layer 4 to increase strength and divergence specifically in layer 4 over layer 6. C1 [Crocker-Buque, Alex; Brown, Sarah M.; Kind, Peter C.; Daw, Michael I.] Univ Edinburgh, Ctr Integrat Physiol, Edinburgh, Midlothian, Scotland. [Isaac, John T. R.] NINDS, Dev Synapt Plast Sect, NIH, Bethesda, MD 20892 USA. RP Daw, MI (reprint author), Ctr Integrat Physiol, Hugh Robson Bldg,George Sq, Edinburgh EH8 9XD, Midlothian, Scotland. EM mdaw@staffmail.ed.ac.uk OI Daw, Michael/0000-0002-8374-5977 FU Medical Research Council Grant MRC [G0900461/1]; RCUK block grant FX This work was supported by Medical Research Council Grant MRC (grant G0900461/1) to M.D. Funding to pay the Open Access publication charges for this article was provided by an RCUK block grant to the University of Edinburgh. NR 47 TC 6 Z9 6 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD AUG PY 2015 VL 25 IS 8 BP 2255 EP 2266 DI 10.1093/cercor/bhu031 PG 12 WC Neurosciences SC Neurosciences & Neurology GA CO7DU UT WOS:000359320000022 PM 24610243 ER PT J AU Doney, B Hnizdo, E Dillon, CF Paulose-Ram, R Tilert, T Wolz, M Beeckman-Wagner, LA AF Doney, Brent Hnizdo, Eva Dillon, Charles F. Paulose-Ram, Ryne Tilert, Timothy Wolz, Michael Beeckman-Wagner, Lu-Ann TI Prevalence of Airflow Obstruction in US Adults Aged 40-79 Years: NHANES Data 1988-1994 and 2007-2010 SO COPD-JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE LA English DT Article DE airflow obstruction; chronic obstructive pulmonary disease; NHANES; spirometry ID CURRENT CIGARETTE-SMOKING; LUNG-FUNCTION; UNITED-STATES; PULMONARY-DISEASE; REFERENCE VALUES; SPIROMETRY USE; RISK-FACTORS; COPD; BURDEN; POPULATION AB Background: The study evaluated the change in the prevalence of airflow obstruction in the U.S. population 40-79 years of age from years 1988-1994 to 2007-2010. Methods: Spirometry data from two representative samples of the U.S. population, the National Health and Nutrition Examination Surveys (NHANES) conducted in 1988-1994 and 2007-2010, were used. The American Thoracic Society/European Respiratory Society (ATS/ERS) criteria were used to define airflow obstruction. Results: Based on ATS/ERS criteria, the overall age-adjusted prevalence of airflow obstruction among adults aged 40-79 years decreased from 16.6% to 14.5% (p < 0.05). Significant decreases were observed for the older age category 60-69 years (20.2% vs. 15.4%; p < 0.01), for males (19.0% vs. 15.4%; p < 0.01), and for Mexican American adults (12.7% vs. 8.4%; p < 0.001). The prevalence of moderate and more severe airflow obstruction decreased also (6.4% vs. 4.4%; p < 0.01). Based on ATS/ERS criteria, during 2007-2010, an estimated 18.3 million U.S. adults 40-79 years had airflow obstruction, 5.6 million had moderate or severe airflow obstruction and 1.4 million had severe airflow obstruction. Conclusions: The overall age-adjusted prevalence of airflow obstruction among U.S. adults aged 40-79 years decreased from 1988-1994 to 2007-2010, especially among older adults, Mexican Americans, and males. C1 [Doney, Brent; Hnizdo, Eva; Beeckman-Wagner, Lu-Ann] NIOSH, Div Repiratory Dis Studies, Ctr Dis Control & Prevent, Morgantown, WV 26505 USA. [Dillon, Charles F.; Paulose-Ram, Ryne; Tilert, Timothy] Ctr Dis Control & Prevent, Div Hlth & Nutr Examinat Surveys, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Wolz, Michael] NHLBI, NIH, Bethesda, MD 20892 USA. RP Doney, B (reprint author), NIOSH, Div Repiratory Dis Studies, Ctr Dis Control & Prevent, 1095 Willowdale Rd, Morgantown, WV 26505 USA. EM bdoney@cdc.gov FU National Institute for Occupational Safety and Health, National Center for Health Statistics; National Heart, Lung, and Blood Institute FX The authors have no financial, consulting, and personal relationships that could influence this work product. The National Institute for Occupational Safety and Health, National Center for Health Statistics, or National Heart, Lung, and Blood Institute supported the salaries of the authors. This work was performed by U.S. Federal Government employees as part of their work; no non-governmental funding supported this work. The authors alone are responsible for the content and writing of the paper. The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the National Heart, Lung, and Blood Institute. NR 40 TC 5 Z9 5 U1 1 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1541-2555 EI 1541-2563 J9 COPD JI COPD-J. Chronic Obstr. Pulm. Dis. PD AUG PY 2015 VL 12 IS 4 BP 355 EP 365 DI 10.3109/15412555.2014.948998 PG 11 WC Respiratory System SC Respiratory System GA CP4JY UT WOS:000359849000002 PM 25244575 ER PT J AU Freudenthal, BD Beard, WA Wilson, SH AF Freudenthal, Bret D. Beard, William A. Wilson, Samuel H. TI New structural snapshots provide molecular insights into the mechanism of high fidelity DNA synthesis SO DNA REPAIR LA English DT Article DE Base excision repair; DNA polymerase; DNA repair; Fidelity Function; Cenome instability; Structure; X-family; X-ray crystallography ID POLYMERASE ACTIVE-SITE; BETA; NUCLEOTIDE; CRYSTAL; INTERMEDIATE; REPLICATION; CHEMISTRY; INSERTION; VARIANT AB Time-lapse X-ray crystallography allows visualization of intermediate structures during the DNA polymerase catalytic cycle. Employing time-lapse crystallography with human DNA polymerase beta has recently allowed us to capture and solve novel intermediate structures that are not stable enough to be analyzed by traditional crystallography. The structures of these intermediates reveals exciting surprises about active site metal ions and enzyme conformational changes as the reaction proceeds from the ground state to product release. In this perspective, we provide an overview of recent advances in understanding the DNA polymerase nucleotidyl transferase reaction and highlight both the significance and mysteries of enzyme efficiency and specificity that remain to be solved. Published by Elsevier B.V. C1 [Freudenthal, Bret D.; Beard, William A.; Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES050158, Z01-ES050159] FX We thank K. Bebenek and J. K. Horton for critical reading of the manuscript. This research was supported by Research Project Numbers Z01-ES050158 and Z01-ES050159 in the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 29 TC 0 Z9 0 U1 5 U2 11 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 2015 VL 32 SI SI BP 3 EP 9 DI 10.1016/j.dnarep.2015.04.007 PG 7 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CO4ZN UT WOS:000359169500002 PM 26002198 ER PT J AU Chen, J Furano, AV AF Chen, Jia Furano, Anthony V. TI Breaking bad: The mutagenic effect of DNA repair SO DNA REPAIR LA English DT Article DE DNA repair; Mutagenesis; APOBEC deaminase; Base excision repair; Mismatch repair; Cancer; CRISPR/Cas ID BASE EXCISION-REPAIR; SHUTTLE VECTOR PLASMID; MALE-DRIVEN EVOLUTION; MISMATCH REPAIR; MAMMALIAN-CELLS; HUMAN CANCERS; SOMATIC HYPERMUTATION; MUTATION-RATE; HUMAN GENOME; ERROR-PRONE AB Species survival depends on the faithful replication of genetic information, which is continually monitored and maintained by DNA repair pathways that correct replication errors and the thousands of lesions that arise daily from the inherent chemical lability of DNA and the effects of genotoxic agents. Nonetheless, neutrally evolving DNA (not under purifying selection) accumulates base substitutions with time (the neutral mutation rate). Thus, repair processes are not 100% efficient. The neutral mutation rate varies both between and within chromosomes. For example it is 10-50 fold higher at CpGs than at non-CpG positions. Interestingly, the neutral mutation rate at non-CpG sites is positively correlated with CpG content. Although the basis of this correlation was not immediately apparent, some bioinformatic results were consistent with the induction of non-CpG mutations by DNA repair at flanking CpG sites. Recent studies with a model system showed that in vivo repair of preformed lesions (mismatches, abasic sites, single stranded nicks) can in fact induce mutations in flanking DNA. Mismatch repair (MMR) is an essential component for repair-induced mutations, which can occur as distant as 5 kb from the introduced lesions. Most, but not all, mutations involved the C of TpCpN (G of NpGpA) which is the target sequence of the C-preferring single-stranded DNA specific APOBEC deaminases. APOBEC-mediated mutations are not limited to our model system: Recent studies by others showed that some tumors harbor mutations with the same signature, as can intermediates in RNA-guided endonuclease-mediated genome editing. APOBEC deaminases participate in normal physiological functions such as generating mutations that inactivate viruses or endogenous retrotransposons, or that enhance immunoglobulin diversity in B cells. The recruitment of normally physiological error-prone processes during DNA repair would have important implications for disease, aging and evolution. This perspective briefly reviews both the bioinformatic and biochemical literature relevant to repair-induced mutagenesis and discusses future directions required to understand the mechanistic basis of this process. Published by Elsevier B.V. C1 [Chen, Jia] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China. [Furano, Anthony V.] NIDDK, Sect Genom Struct & Funct, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Furano, AV (reprint author), NIDDK, Sect Genom Struct & Funct, Lab Cell & Mol Biol, NIH, Bldg 8,Room 203,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM avf@helix.nih.gov FU Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); ShanghaiTech University start-up funds FX This research was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and by ShanghaiTech University start-up funds to JC. NR 123 TC 1 Z9 1 U1 8 U2 35 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 2015 VL 32 SI SI BP 43 EP 51 DI 10.1016/j.dnarep.2015.04.012 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CO4ZN UT WOS:000359169500007 PM 26073774 ER PT J AU Zhao, XN Usdin, K AF Zhao, Xiao-Nan Usdin, Karen TI The Repeat Expansion Diseases: The dark side of DNA repair SO DNA REPAIR LA English DT Article DE Repeat Expansion Diseases; Mismatch repair; Base excision repair; Transcription coupled repair; Global genome repair; Oxidative damage ID BASE EXCISION-REPAIR; FRAGILE-X-SYNDROME; GROUP-B PROTEIN; DOMINANT CEREBELLAR-ATAXIA; CAG TRINUCLEOTIDE REPEAT; PALLIDOLUYSIAN ATROPHY DRPLA; TRANSCRIPTION-COUPLED REPAIR; MYOTONIC-DYSTROPHY TYPE-2; PREMATURE OVARIAN FAILURE; FRAXE MENTAL-RETARDATION AB DNA repair normally protects the genome against mutations that threaten genome integrity and thus cell viability. However, growing evidence suggests that in the case of the Repeat Expansion Diseases, disorders that result from an increase in the size of a disease-specific microsatellite, the disease-causing mutation is actually the result of aberrant DNA repair. A variety of proteins from different DNA repair pathways have thus far been implicated in this process. This review will summarize recent findings from patients and from mouse models of these diseases that shed light on how these pathways may interact to cause repeat expansion. Published by Elsevier B.V. C1 [Zhao, Xiao-Nan; Usdin, Karen] Natl Inst Diabet Digest & Kidney Dis, Sect Genom Struct & Funct, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIH, Bldg 8,Room 2A19,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. EM ku@helix.nih.gov RI Zhao, Xiaonan/S-3139-2016 FU Intramural NIH HHS [Z01 DK057808-01] NR 164 TC 6 Z9 6 U1 2 U2 14 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 2015 VL 32 SI SI BP 96 EP 105 DI 10.1016/j.dnarep.2015.04.019 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CO4ZN UT WOS:000359169500014 PM 26002199 ER PT J AU Akbari, M Morevati, M Croteau, D Bohr, VA AF Akbari, Mansour Morevati, Marya Croteau, Deborah Bohr, Vilhelm A. TI The role of DNA base excision repair in brain homeostasis and disease SO DNA REPAIR LA English DT Article DE Base excision repair; Oxidative damage; Mitochondrial DNA; Neurodegeneration; PARP-1 ID STRAND BREAK REPAIR; COCKAYNE-SYNDROME-B; ISCHEMIA-REPERFUSION INJURY; ALZHEIMERS-DISEASE; MITOCHONDRIAL-DNA; OXIDATIVE STRESS; HUNTINGTONS-DISEASE; ATAXIA-TELANGIECTASIA; PARKINSONS-DISEASE; PROTECTS NEURONS AB Chemical modification and spontaneous loss of nucleotide bases from DNA are estimated to occur at the rate of thousands per human cell per day. DNA base excision repair (BER) is a critical mechanism for repairing such lesions in nuclear and mitochondrial DNA. Defective expression or function of proteins required for BER or proteins that regulate BER have been consistently associated with neurological dysfunction and disease in humans. Recent studies suggest that DNA lesions in the nuclear and mitochondrial compartments and the cellular response to those lesions have a profound effect on cellular energy homeostasis, mitochondrial function and cellular bioenergetics, with especially strong influence on neurological function. Further studies in this area could lead to novel approaches to prevent and treat human neurodegenerative disease. Published by Elsevier B.V. C1 [Akbari, Mansour; Morevati, Marya; Bohr, Vilhelm A.] Univ Copenhagen, Ctr Hlth Aging, SUND, DK-1168 Copenhagen, Denmark. [Croteau, Deborah; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd,Suite 100,Rm 068133, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Akbari, Mansour/0000-0002-6490-7766 FU Intramural Research Program of the NIH, National Institute on Aging; Nordea Foundation, Denmark FX We thank Dr. Mimi Sander, Page One Editorial Services for editing. We thank Thomas Wynn for assistance with graphics. We also thank Drs. Evandro Fang and Beverly Baptiste for critical comments on the article. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging, and by the Nordea Foundation, Denmark. NR 136 TC 6 Z9 6 U1 1 U2 8 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 2015 VL 32 SI SI BP 172 EP 179 DI 10.1016/j.dnarep.2015.04.029 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CO4ZN UT WOS:000359169500024 PM 26002197 ER PT J AU Desrosiers, NA Scheidweiler, KB Huestis, MA AF Desrosiers, Nathalie A. Scheidweiler, Karl B. Huestis, Marilyn A. TI Quantification of six cannabinoids and metabolites in oral fluid by liquid chromatography-tandem mass spectrometry SO DRUG TESTING AND ANALYSIS LA English DT Article DE cannabinoids; oral fluid; THC; THCCOOH; LC-MS; MS ID CONTROLLED SMOKED CANNABIS; 11-NOR-DELTA(9)-TETRAHYDROCANNABINOL-9-CARBOXYLIC ACID; DELTA(9)-TETRAHYDROCANNABINOL; 11-NOR-9-CARBOXY-DELTA(9)-TETRAHYDROCANNABINOL; TETRAHYDROCANNABINOL; IDENTIFICATION; DISPOSITION; VALIDATION; EXTRACTION; MARIJUANA AB (9)-Tetrahydrocannabinol (THC) is the most commonly analyzed cannabinoid in oral fluid (OF); however, its metabolite 11-nor-9-carboxy-THC (THCCOOH) offers the advantage of documenting active consumption, as it is not detected in cannabis smoke. Analytical challenges such as low (ng/L) THCCOOH OF concentrations hampered routine OF THCCOOH monitoring. Presence of minor cannabinoids like cannabidiol and cannabinol offer the advantage of identifying recent cannabis intake. Published OF cannabinoids methods have limitations, including few analytes and lengthy derivatization. We developed and validated a sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for THC, its metabolites, 11-hydroxy-THC and THCCOOH quantification, and other natural cannabinoids including tetrahydrocannabivarin (THCV), cannabidiol (CBD), and cannabigerol (CBG) in 1mL OF collected with the Quantisal device. After solid-phase extraction, chromatography was performed on a Selectra PFPP column with a 0.15% formic acid in water and acetonitrile gradient with a 0.5mL/min flow rate. All analytes were monitored in positive mode atmospheric pressure chemical ionization (APCI) with multiple reaction monitoring. Limits of quantification were 15ng/L THCCOOH and 0.2 mu g/L for all other analytes. Linear ranges extended to 3750ng/L THCCOOH, 100 mu g/L THC, and 50 mu g/L for all other analytes. Inter-day analytical recoveries (bias) and imprecision at low, mid, and high quality control (QC) concentrations were 88.7-107.3% and 2.3-6.7%, respectively (n=20). Mean extraction efficiencies and matrix effects evaluated at low and high QC were 75.9-86.1% and 8.4-99.4%, respectively. This method will be highly useful for workplace, criminal justice, drug treatment and driving under the influence of cannabis OF testing. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Desrosiers, Nathalie A.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Desrosiers, Nathalie A.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab IRP, NIH, Biomed Res Ctr, 251 Bayview Blvd Suite 200 Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health FX The authors recognize Sarah Himes and Ariane Wohlfarth for their assistance. NAD acknowledges the Graduate Partnership Program, NIH and the Fondation Baxter et Alma Ricard. This research was supported by the intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 34 TC 8 Z9 8 U1 7 U2 36 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD AUG PY 2015 VL 7 IS 8 BP 684 EP 694 DI 10.1002/dta.1753 PG 11 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA CP0YU UT WOS:000359603700004 PM 25428610 ER PT J AU Wilmshurst, JM Gaillard, WD Vinayan, KP Tsuchida, TN Plouin, P Van Bogaert, P Carrizosa, J Elia, M Craiu, D Jovic, NJ Nordli, D Hirtz, D Wong, V Glauser, T Mizrahi, EM Cross, JH AF Wilmshurst, Jo M. Gaillard, William D. Vinayan, Kollencheri Puthenveettil Tsuchida, Tammy N. Plouin, Perrine Van Bogaert, Patrick Carrizosa, Jaime Elia, Maurizio Craiu, Dana Jovic, Nebojsa J. Nordli, Doug Hirtz, Deborah Wong, Virginia Glauser, Tracy Mizrahi, Eli M. Cross, J. Helen TI Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics SO EPILEPSIA LA English DT Article DE Infants; Seizures; Recommendations; Guidelines; Standard care; Optimal care ID VAGUS-NERVE-STIMULATION; COMPLEX FEBRILE SEIZURES; MULTICENTER RANDOMIZED-TRIAL; KETOGENIC DIET; UNPROVOKED SEIZURES; RISK-FACTORS; EPILEPTIC SYNDROMES; YOUNG-CHILDREN; WEST-SYNDROME; 1ST YEAR AB Evidence-based guidelines, or recommendations, for the management of infants with seizures are lacking. A Task Force of the Commission of Pediatrics developed a consensus document addressing diagnostic markers, management interventions, and outcome measures for infants with seizures. Levels of evidence to support recommendations and statements were assessed using the American Academy of Neurology Guidelines and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The report contains recommendations for different levels of care, noting which would be regarded as standard care, compared to optimal care, or state of the art interventions. The incidence of epilepsy in the infantile period is the highest of all age groups (strong evidence), with epileptic spasms the largest single subgroup and, in the first 2years of life, febrile seizures are the most commonly occurring seizures. Acute intervention at the time of a febrile seizure does not alter the risk for subsequent epilepsy (class 1 evidence). The use of antipyretic agents does not alter the recurrence rate (class 1 evidence), and there is no evidence to support initiation of regular antiepileptic drugs for simple febrile seizures (class 1 evidence). Infants with abnormal movements whose routine electroencephalography (EEG) study is not diagnostic, would benefit from video-EEG analysis, or home video to capture events (expert opinion, level U recommendation). Neuroimaging is recommended at all levels of care for infants presenting with epilepsy, with magnetic resonance imaging (MRI) recommended as the standard investigation at tertiary level (level A recommendation). Genetic screening should not be undertaken at primary or secondary level care (expert opinion). Standard care should permit genetic counseling by trained personal at all levels of care (expert opinion). Genetic evaluation for Dravet syndrome, and other infantile-onset epileptic encephalopathies, should be available in tertiary care (weak evidence, level C recommendation). Patients should be referred from primary or secondary to tertiary level care after failure of one antiepileptic drug (standard care) and optimal care equates to referral of all infants after presentation with a seizure (expert opinion, level U evidence). Infants with recurrent seizures warrant urgent assessment for initiation of antiepileptic drugs (expert opinion, level U recommendation). Infantile encephalopathies should have rapid introduction and increment of antiepileptic drug dosage (expert opinion, level U recommendation). There is no high level evidence to support any particular current agents for use in infants with seizures. For focal seizures, levetiracetam is effective (strong evidence); for generalized seizures, weak evidence supports levetiracetam, valproate, lamotrigine, topiramate, and clobazam; for Dravet syndrome, strong evidence supports that stiripentol is effective (in combination with valproate and clobazam), whereas weak evidence supports that topiramate, zonisamide, valproate, bromide, and the ketogenic diet are possibly effective; and for Ohtahara syndrome, there is weak evidence that most antiepileptic drugs are poorly effective. For epileptic spasms, clinical suspicion remains central to the diagnosis and is supported by EEG, which ideally is prolonged (level C recommendation). Adrenocorticotropic hormone (ACTH) is preferred for short-term control of epileptic spasms (level B recommendation), oral steroids are probably effective in short-term control of spasms (level C recommendation), and a shorter interval from the onset of spasms to treatment initiation may improve long-term neurodevelopmental outcome (level C recommendation). The ketogenic diet is the treatment of choice for epilepsy related to glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency (expert opinion, level U recommendation). The identification of patients as potential candidates for epilepsy surgery should be part of standard practice at primary and secondary level care. Tertiary care facilities with experience in epilepsy surgery should undertake the screening for epilepsy surgical candidates (level U recommendation). There is insufficient evidence to conclude if there is benefit from vagus nerve stimulation (level U recommendation). The key recommendations are summarized into an executive summary. The full report is available as Supporting Information. This report provides a comprehensive foundation of an approach to infants with seizures, while identifying where there are inadequate data to support recommended practice, and where further data collection is needed to address these deficits. C1 [Wilmshurst, Jo M.] Univ Cape Town, Red Cross War Mem Childrens Hosp, Dept Paediat & Child Hlth, Paediat Neurol, ZA-7700 Cape Town, South Africa. [Gaillard, William D.] George Washington Univ, Comprehens Pediat Epilepsy Program, Div Epilepsy & Neurophysiol, Pediat & Neurol, Washington, DC USA. [Vinayan, Kollencheri Puthenveettil] Amrita Inst Med Sci, Div Pediat Neurol, Dept Neurol, Cochin, Kerala, India. [Tsuchida, Tammy N.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Plouin, Perrine] Hosp Sick Children, INSERM, U663, Dept Clin Neurophysiol, Paris, France. [Van Bogaert, Patrick] Univ Libre Bruxelles, Erasme Hosp, Dept Pediat, Paediat Neurol, Brussels, Belgium. [Carrizosa, Jaime] Univ Antioquia, Pediat Dept Child Neurol Serv, Medellin, Colombia. [Elia, Maurizio] IRCCS Italy Oasi Inst Res Mental Retardat & Brain, Unit Neurol & Clin Neurophysiopathol, Troina, EN, Italy. [Craiu, Dana] Carol Davila Univ Med Bucharest, Dept Neurol, Pediat Neurol, Psychiat,Neurosurg, Bucharest, Romania. [Craiu, Dana] Alexandru Obregia Clin Hosp, Bucharest, Romania. [Jovic, Nebojsa J.] Univ Belgrade, Clin Neurol & Psychiat Children & Youth, Neurol, Fac Med, Belgrade, Serbia. [Nordli, Doug] Childrens Mem Hosp, Epilepsy Ctr, Chicago, IL 60614 USA. [Hirtz, Deborah] NINDS, Off Clin Res, NIH, Rockville, MD USA. [Wong, Virginia] Univ Hong Kong, LKS Fac Med, Dept Paediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R China. [Wong, Virginia] Queen Mary Hosp, Duchess Kent Children Hosp, Div Paediat Neurol Dev Behav Paediat NeuroHabilit, Hong Kong, Hong Kong, Peoples R China. [Glauser, Tracy] Cincinnati Childrens Hosp Med Ctr, Div Neurol, Comprehens Epilepsy Ctr, Cincinnati, OH 45229 USA. [Mizrahi, Eli M.] Baylor Coll Med, Dept Neurol, Peter Kellaway Sect Neurophysiol, Houston, TX 77030 USA. [Mizrahi, Eli M.] Baylor Coll Med, Dept Pediat, Sect Pediat Neurol, Houston, TX 77030 USA. [Cross, J. Helen] NHS Fdn Trust, Great Ormond St Hosp Children NHS Trust, UCL Inst Child Hlth, Childhood Epilepsy,Paediat Neurol, London, England. RP Wilmshurst, JM (reprint author), Univ Cape Town, Red Cross War Mem Childrens Hosp, Dept Paediat & Child Hlth, ZA-7700 Cape Town, South Africa. EM Jo.wilmshurst@uct.ac.za RI Elia, Maurizio/K-3285-2016 OI Elia, Maurizio/0000-0002-0414-1359 FU Novartis; Epilepsy Foundation New Therapy Research Grant for Dry Sensor-based Neonatal EEG Monitoring (NEMO); Epilepsy Foundation of America; American Epilepsy Society; Infantile Epilepsy Research Foundation (Lundbeck); Citizens United for Research in Epilepsy (CURE); Vitaflo; Action Medical Research; Epilepsy Research United Kingdom; Sparks - Children's Medical Research Charity; National Institute for Health and Research; Great Ormond Street Hospital Children's Charity; European Union FX JM Wilmshurst is a member of the Tuberous Sclerosis Complex advisory board for South Africa, which is sponsored by Novartis.; Tammy Tsuchida is a site primary investigator for a multicenter study Prevent West syndrome and has funding from Epilepsy Foundation New Therapy Research Grant for Dry Sensor-based Neonatal EEG Monitoring (NEMO).; WD Gaillard's income derives from clinical revenue generated for Children's National Medical Center (CNMC) clinical care. Federal support provided by the National Institute of Neurological Disorders and Stroke (NINDS) 1P30HD40677-01, 2K12NS052159-06A1; the National Institute of Mental Health (NIMH) RO1 MH084961, 1R21MH092615, the National Science Foundation (NSF) 095998; the Centers for Disease Control and Prevention (CDC) 1UO1DP003255; Department of Defense/United States Army Medical Research Acquisitions Activity (DOD/USAMRAA) W81XWH-11-2-0198: and Patient-Centered Outcomes Research Institute (PCORI) 527. Foundation support from the Epilepsy Foundation of America, American Epilepsy Society, Infantile Epilepsy Research Foundation (Lundbeck), and Citizens United for Research in Epilepsy (CURE). The CNMC conducts industry-supported trials form which no salary support is derived including from Ovation Pharmaceuticals, King Pharmaceuticals, PRA International/Eisai. Stock (held with spouse): Johnson and Johnson; Lily, Glaxo Smith Kline, Pfizer, Siemens, and General Electric. Editorial board of Epilepsia and Epilepsy Research.; J. Helen Cross holds an endowed Chair through University College, London. She has sat on Advisory Panels for Eisai, GW Pharma, and Viropharma, for which remuneration has been paid to her department. Her department has received honoraria from Nutricia and UCB for speaking. Her Department has received a research grant from Vitaflo. She currently holds grants for research as from Action Medical Research, Epilepsy Research United Kingdom, Sparks - Children's Medical Research Charity, National Institute for Health and Research, the Great Ormond Street Hospital Children's Charity, and the European Union. She worked as clinical advisor to the update of the National Institute for Health and Care Excellence (NICE) guidelines on the diagnosis and management of epilepsy (2009-12) and is currently clinical advisor to the Children's Epilepsy Surgery Service (England and Wales), for which remuneration is made to her department. She is currently Secretary General to the ILAE. NR 75 TC 25 Z9 26 U1 2 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD AUG PY 2015 VL 56 IS 8 BP 1185 EP 1197 DI 10.1111/epi.13057 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA CO2AX UT WOS:000358958700004 PM 26122601 ER PT J AU Guittard, G Kortum, RL Balagopalan, L Cuburu, N Nguyen, P Sommers, CL Samelson, LE AF Guittard, Geoffrey Kortum, Robert L. Balagopalan, Lakshmi Cuburu, Nicolas Nguyen, Phan Sommers, Connie L. Samelson, Lawrence E. TI Absence of both Sos-1 and Sos-2 in peripheral CD4+T cells leads to PI3K pathway activation and defects in migration SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CD62L; Erk; Grb2; PI3K/AKT; Sos; Signaling; T cell ID NUCLEOTIDE EXCHANGE FACTOR; MEDIATED ERK ACTIVATION; T-CELLS; ADAPTER PROTEIN; RAS ACTIVATION; GRB2 ADAPTER; KINASE; LAT; COMPLEXES; RECEPTOR AB Sos-1 and Sos-2 are ubiquitously expressed Ras-guanine exchange factors involved in Erk-MAP kinase pathway activation. Using mice lacking genes encoding Sos-1 and Sos-2, we evaluated the role of these proteins in peripheral T-cell signaling and function. Our results confirmed that TCR-mediated Erk activation in peripheral CD4(+) T cells does not depend on Sos-1 and Sos-2, although IL-2-mediated Erk activation does. Unexpectedly, however, we show an increase in AKT phosphorylation in Sos-1/2dKO CD4(+) T cells upon TCR and IL-2 stimulation. Activation of AKT was likely a consequence of increased recruitment of PI3K to Grb2 upon TCR and/or IL-2 stimulation in Sos-1/2dKO CD4(+) T cells. The increased activity of the PI3K/AKT pathway led to downregulation of the surface receptor CD62L in Sos-1/2dKO T cells and a subsequent impairment in T-cell migration. C1 [Guittard, Geoffrey; Kortum, Robert L.; Balagopalan, Lakshmi; Nguyen, Phan; Sommers, Connie L.; Samelson, Lawrence E.] NCI, Ctr Canc Res, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. [Cuburu, Nicolas] NCI, Ctr Canc Res, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Samelson, LE (reprint author), NCI, Ctr Canc Res, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. EM samelsonl@helix.nih.gov OI Guittard, Geoffrey/0000-0002-6061-8553 FU Center for Cancer Research, NCI, NIH FX We are grateful to the NCI building 37 animal facility for their help with tail injections and cardiac puncture. This research was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH. NR 24 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD AUG PY 2015 VL 45 IS 8 BP 2389 EP 2395 DI 10.1002/eji.201445226 PG 7 WC Immunology SC Immunology GA CP1YQ UT WOS:000359674200023 PM 25973715 ER PT J AU Gorrepati, L Krause, MW Chen, WP Brodigan, TM Correa-Mendez, M Eisenmann, DM AF Gorrepati, Lakshmi Krause, Michael W. Chen, Weiping Brodigan, Thomas M. Correa-Mendez, Margarita Eisenmann, David M. TI Identification of Wnt Pathway Target Genes Regulating the Division and Differentiation of Larval Seam Cells and Vulval Precursor Cells in Caenorhabditis elegans SO G3-GENES GENOMES GENETICS LA English DT Article DE Wnt signaling; mRNA tagging; seam cells; vulval precursor cells; C. elegans; differentiation ID DEPENDENT KINASE INHIBITOR; HEDGEHOG-RELATED GENES; CATENIN HOMOLOG BAR-1; C-ELEGANS; BETA-CATENIN; ASYMMETRIC DIVISION; EXPRESSED GENES; TERMINAL DIFFERENTIATION; TRANSCRIPTION FACTORS; SIGNALING CONTROLS AB The evolutionarily conserved Wnt/beta-catenin signaling pathway plays a fundamental role during metazoan development, regulating numerous processes including cell fate specification, cell migration, and stem cell renewal. Wnt ligand binding leads to stabilization of the transcriptional effector beta-catenin and up-regulation of target gene expression to mediate a cellular response. During larval development of the nematode Caenorhabditis elegans, Wnt/beta-catenin pathways act in fate specification of two hypodermal cell types, the ventral vulval precursor cells (VPCs) and the lateral seam cells. Because little is known about targets of the Wnt signaling pathways acting during larval VPC and seam cell differentiation, we sought to identify genes regulated by Wnt signaling in these two hypodermal cell types. We conditionally activated Wnt signaling in larval animals and performed cell type-specific "mRNA tagging" to enrich for VPC and seam cell-specific mRNAs, and then used microarray analysis to examine gene expression compared to control animals. Two hundred thirty-nine genes activated in response to Wnt signaling were identified, and we characterized 50 genes further. The majority of these genes are expressed in seam and/or vulval lineages during normal development, and reduction of function for nine genes caused defects in the proper division, fate specification, fate execution, or differentiation of seam cells and vulval cells. Therefore, the combination of these techniques was successful at identifying potential cell type-specific Wnt pathway target genes from a small number of cells and at increasing our knowledge of the specification and behavior of these C. elegans larval hypodermal cells. C1 [Gorrepati, Lakshmi; Correa-Mendez, Margarita; Eisenmann, David M.] Univ Maryland Baltimore Cty, Dept Biol Sci, Baltimore, MD 21250 USA. [Krause, Michael W.; Chen, Weiping; Brodigan, Thomas M.] NIDDK, Intramural Res Program, Bethesda, MD 20814 USA. RP Eisenmann, DM (reprint author), Univ Maryland Baltimore Cty, Dept Biol Sci, 1000 Hilltop Circle, Baltimore, MD 21250 USA. EM eisenman@umbc.edu OI Krause, Michael/0000-0001-6127-3940 FU NIH Office of Research Infrastructure Programs [P40 OD010440]; National BioResource Project of Japan; NSF [IBN-0131485]; NIH [GM65424]; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX We thank S. Von Stetina, J. D. Watson, D. M. Miller, B. M. Jackson, J. E. Gleason, I. Hamza, A. Golden, and C. Wolkow for helpful advice and sharing of reagents, strains, and unpublished information. We thank members of the Eisenmann lab for advice and support. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440), and by the National BioResource Project of Japan. This work was partially supported by NSF grant IBN-0131485 and NIH grant GM65424 (to D. M. E.). This work was supported, in part, by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 140 TC 1 Z9 1 U1 3 U2 8 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD AUG 1 PY 2015 VL 5 IS 8 BP 1551 EP 1566 DI 10.1534/g3.115.017715 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA CO6KO UT WOS:000359265800002 PM 26048561 ER PT J AU Yoon, JH Jo, MH White, EJF De, S Hafner, M Zucconi, BE Abdelmohsen, K Martindale, JL Yang, XL Wood, WH Shin, YM Song, JJ Tuschl, T Becker, KG Wilson, GM Hohng, S Gorospe, M AF Yoon, Je-Hyun Jo, Myung Hyun White, Elizabeth J. F. De, Supriyo Hafner, Markus Zucconi, Beth E. Abdelmohsen, Kotb Martindale, Jennifer L. Yang, Xiaoling Wood, William H., III Shin, Yu Mi Song, Ji-Joon Tuschl, Thomas Becker, Kevin G. Wilson, Gerald M. Hohng, Sungchul Gorospe, Myriam TI AUF1 promotes let-7b loading on Argonaute 2 SO GENES & DEVELOPMENT LA English DT Article DE Argonaute; RISC; hnRNP D; microRNA; ribonucleoprotein complex ID MESSENGER-RNA DECAY; MICRORNA TARGET SITES; PAR-CLIP; WIDE IDENTIFICATION; BINDING PROTEIN; EXPRESSION; AFFINITY AB Eukaryotic gene expression is tightly regulated post-transcriptionally by RNA-binding proteins (RBPs) and microRNAs. The RBP AU-rich-binding factor 1 (AUF1) isoform p37 was found to have high affinity for the microRNA let-7b in vitro (K-d = similar to 6 nM) in cells. Ribonucleoprotein immunoprecipitation, in vitro association, and single-molecule-binding analyses revealed that AUF1 promoted let-7b loading onto Argonaute 2 (AGO2), the catalytic component of the RNA-induced silencing complex (RISC). In turn, AGO2-let-7 triggered target mRNA decay. Our findings uncover a novel mechanism by which AUF1 binding and transfer of microRNA let-7 to AGO2 facilitates let-7-elicited gene silencing. C1 [Yoon, Je-Hyun; De, Supriyo; Abdelmohsen, Kotb; Martindale, Jennifer L.; Yang, Xiaoling; Wood, William H., III; Becker, Kevin G.; Gorospe, Myriam] NIA, Lab Genet, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Jo, Myung Hyun; Hohng, Sungchul] Seoul Natl Univ, Dept Phys & Astron, Inst Appl Phys, Natl Ctr Creat Res Initiat, Seoul 151747, South Korea. [White, Elizabeth J. F.; Zucconi, Beth E.; Wilson, Gerald M.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Hafner, Markus] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Shin, Yu Mi; Song, Ji-Joon] Korea Adv Inst Sci & Technol, Canc Metastasis Control Ctr, Inst BioCentury, Taejon 305338, South Korea. [Tuschl, Thomas] Rockefeller Univ, Howard Hughes Med Inst, Lab RNA Mol Biol, New York, NY 10065 USA. RP Yoon, JH (reprint author), NIA, Lab Genet, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM yoonjehyun@gmail.com; shohng@snu.ac.kr RI Song, Ji-Joon/C-1721-2011; OI Hafner, Markus/0000-0002-4336-6518; De, Supriyo/0000-0002-2075-7655 FU National Institute on Aging-Intramural Research Program (National Institutes of Health); American Heart Association grant [11PRE6900008]; National Institutes of Health grant [R01 CA102428]; National Institute of Arthritis and Musculoskeletal and Skin Diseases-Intramural Research Program (National Institutes of Health); Charles H. Revson Foundation; Howard Hughes Medical Institute; Starr Cancer Foundation; Creative Research Initiatives (Physical Genetics Laboratory) of the National Research Foundation of Korea [2009-0081562]; Korean Ministry of Science, ICT, and Future Planning [NRF-M1AXA002-2011-0031416, 2011-0031955, N1014002] FX We thank R.J. Schneider for providing reagents and information, and J.A. Steitz for critical reading of the manuscript. J.-H.Y., S.D., K.A., X.Y., K.G.B., J.L.M., W.H.W., and M.G. were supported by the National Institute on Aging-Intramural Research Program (National Institutes of Health). E.J. F.W., B.E.Z., and G.M.W. were supported by American Heart Association grant 11PRE6900008 and National Institutes of Health grant R01 CA102428. M.H. was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases-Intramural Research Program (National Institutes of Health) and the Charles H. Revson Foundation. T.T. was supported by the Howard Hughes Medical Institute, the Starr Cancer Foundation, and the National Institutes of Health. M.H.J. and S.H. were supported by Creative Research Initiatives (Physical Genetics Laboratory, 2009-0081562) of the National Research Foundation of Korea. Y.M.S. and J.-J.S. were funded by grants NRF-M1AXA002-2011-0031416, 2011-0031955, and N1014002 from the Korean Ministry of Science, ICT, and Future Planning. J.-H.Y., M.H.J., E.J.F.W., S.D., M.H., B.E.Z., K.A., X.Y., Y.M.S., J.L.M., W.H.W., J.-J.S., and K.G.B. designed and performed experiments. J.-H.Y., M.G., G.M.W., M.H., S.H., and T.T. prepared the manuscript. The authors discussed the results and implications throughout. NR 28 TC 3 Z9 3 U1 3 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD AUG 1 PY 2015 VL 29 IS 15 BP 1599 EP 1604 DI 10.1101/gad.263749.115 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA CO7ET UT WOS:000359323100003 PM 26253535 ER PT J AU Lee, KP Shin, YJ Panda, AC Abdelmohsen, K Kim, JY Lee, SM Bahn, YJ Choi, JY Kwon, ES Baek, SJ Kim, SY Gorospe, M Kwon, KS AF Lee, Kwang-Pyo Shin, Yeo Jin Panda, Amaresh C. Abdelmohsen, Kotb Kim, Ji Young Lee, Seung-Min Bahn, Young Jae Choi, Jeong Yi Kwon, Eun-Soo Baek, Su-Jin Kim, Seon-Young Gorospe, Myriam Kwon, Ki-Sun TI miR-431 promotes differentiation and regeneration of old skeletal muscle by targeting Smad4 SO GENES & DEVELOPMENT LA English DT Article DE miR-431; SMAD4; muscle aging; myoblast; differentiation; regeneration ID STEM-CELLS; MYOGENIC DIFFERENTIATION; MOLECULAR REGULATION; SATELLITE CELLS; MYOMIR NETWORK; MICRORNAS; MASS; STRENGTH; MICE; TRANSCRIPTION AB The myogenic capacity of myoblasts decreases in skeletal muscle with age. In addition to environmental factors, intrinsic factors are important for maintaining the regenerative potential of muscle progenitor cells, but their identities are largely unknown. Here, comparative analysis of microRNA (miRNA) expression profiles in young and old myoblasts uncovered miR-431 as a novel miRNA showing markedly reduced abundance in aged myoblasts. Importantly, elevating miR-431 improved the myogenic capacity of old myoblasts, while inhibiting endogenous miR-431 lowered myogenesis. Bioinformatic and biochemical analyses revealed that miR-431 directly interacted with the 3' untranslated region (UTR) of Smad4 mRNA, which encodes one of the downstream effectors of TGF-beta signaling. In keeping with the low levels of miR-431 in old myoblasts, SMAD4 levels increased in this myoblast population. Interestingly, in an in vivo model of muscle regeneration following cardiotoxin injury, ectopic miR-431 injection greatly improved muscle regeneration and reduced SMAD4 levels. Consistent with the finding that the mouse miR-431 seed sequence in the Smad4 3' UTR is conserved in the human SMAD4 3' UTR, inhibition of miR-431 also repressed the myogenic capacity of human skeletal myoblasts. Taken together, our results suggest that the age-associated miR-431 plays a key role in maintaining the myogenic ability of skeletal muscle with age. C1 [Lee, Kwang-Pyo; Shin, Yeo Jin; Kim, Ji Young; Lee, Seung-Min; Bahn, Young Jae; Choi, Jeong Yi; Kwon, Eun-Soo; Kwon, Ki-Sun] Korea Res Inst Biosci & Biotechnol, Aging Res Inst, Taejon 305806, South Korea. [Shin, Yeo Jin; Baek, Su-Jin; Kim, Seon-Young; Kwon, Ki-Sun] Korea Univ Sci & Technol, Dept Funct Genom, Taejon 305333, South Korea. [Panda, Amaresh C.; Abdelmohsen, Kotb; Gorospe, Myriam] NIA, Lab Genet, NIH, Baltimore, MD 21224 USA. [Baek, Su-Jin; Kim, Seon-Young] Korea Res Inst Biosci & Biotechnol, Genome Struct Res Ctr, Taejon 305806, South Korea. RP Kwon, KS (reprint author), Korea Res Inst Biosci & Biotechnol, Aging Res Inst, Taejon 305806, South Korea. EM kwonks@kribb.re.kr OI PANDA, AMARESH/0000-0003-3189-8995 FU Bio and Medical Technology Development Program of National Research Foundation - Korean government (Ministry of Science, ICT, and Future Planning) [20110030133, 2013M3A9B6076413, 20120009022]; Korea Research Institute of Bioscience and Biotechnology Research Initiative Program; National Institute on Aging Intramural Research Program of National Institutes of Health FX We thank B. Vogelstein for providing the 4xSBE-luc plasmid. This study was supported by grants from the Bio and Medical Technology Development Program (20110030133, 2013M3A9B6076413, and 20120009022 to K.-S.K.) of the National Research Foundation, which is funded by the Korean government (Ministry of Science, ICT, and Future Planning), and the Korea Research Institute of Bioscience and Biotechnology Research Initiative Program. A.C.P., K.A., and M.G. were supported by the National Institute on Aging Intramural Research Program of the National Institutes of Health. NR 52 TC 6 Z9 6 U1 0 U2 12 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD AUG 1 PY 2015 VL 29 IS 15 BP 1605 EP 1617 DI 10.1101/gad.263574.115 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA CO7ET UT WOS:000359323100004 PM 26215566 ER PT J AU Phillips, SM Dodd, KW Steeves, J McClain, J Alfano, CM McAuley, E AF Phillips, Siobhan M. Dodd, Kevin W. Steeves, Jeremy McClain, James Alfano, Catherine M. McAuley, Edward TI Physical activity and sedentary behavior in breast cancer survivors: New insight into activity patterns and potential intervention targets SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Physical activity; Sedentary behavior; Breast cancer survivors; Exercise ID QUALITY-OF-LIFE; UNITED-STATES; TIME SPENT; ACTIVITY TRIALS; HEALTH; ACCELEROMETER; ASSOCIATIONS; METAANALYSIS; EXERCISE AB Background. Inactivity and sedentary behavior are related to poorer health outcomes in breast cancer survivors. However, few studies examining these behaviors in survivors have used objective measures, considered activities other than moderate-to-vigorous intensity activity (MVPA) and/or sedentary behavior (i.e. low intensity activities) or compared survivors to healthy controls. The purpose of the present study is to compare accelerometer-measured activity of various intensities (total, light, lifestyle, MVPA) and sedentary behavior between breast cancer survivors and non-cancer controls. Methods. An imputation-based approach of independent sample t-tests adjusting for multiple comparisons was used to compare estimates of participation in each activity and sedentary behavior between survivors [n = 398; M(SD)(age) = 56.95 (9.11)] and block-matched non-cancer controls [n = 1120; M(SD)(age) = 54.88 (16.11)]. Potential moderating effects of body mass index (BMI), age, and education were also examined. Results. Breast cancer survivors registered less daily total (282.8 v. 346.9) light (199.1 v. 259.3) and lifestyle (62.0 v. 71.7) activity minutes and more MVPA (21.6 v. 15.9) and sedentary behavior (555.7 v. 500.6) minutes than controls (p < 0.001 for all). These relationships were largely consistent across BMI, age and education. On average, survivors spent an estimated 66.4% of their waking time sedentary and 31.1% in light/lifestyle activity and 2.6% in MVPA. Conclusions. Breast cancer survivors are more sedentary and participate in less low intensity activity than controls. Although survivors registered more MVPA, these levels were insufficient. Future research should explore these differences and potential benefits of targeting low intensity activities and reducing sedentary time in this population. (C) 2015 Published by Elsevier Inc. C1 [Phillips, Siobhan M.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Dodd, Kevin W.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Steeves, Jeremy] Univ Wisconsin, Dept Kinesiol, Milwaukee, WI 53201 USA. [McClain, James; Alfano, Catherine M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [McAuley, Edward] Univ Illinois, Dept Kinesiol & Community Hlth, Champaign, IL USA. RP Phillips, SM (reprint author), Northwestern Univ, 680 N Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. EM smphillips@northwestern.edu FU National Institute on Aging [F31AG034025, AG020118]; National Cancer Institute Cancer Prevention Fellowship Program Cancer Research Training Award; Shahid and Ann Carlson Khan endowed professorship FX This work was supported by: grant #F31AG034025 from The National Institute on Aging (SP); a National Cancer Institute Cancer Prevention Fellowship Program Cancer Research Training Award (SP); shahid and ann carlson khan endowed professorship (EM) and grant #AG020118 from the National Institute on Aging (EM). NR 35 TC 7 Z9 8 U1 0 U2 8 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 2015 VL 138 IS 2 BP 398 EP 404 DI 10.1016/j.ygyno.2015.05.026 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CO5CY UT WOS:000359178400030 PM 26026737 ER PT J AU Dogan, BA Tuna, MM Arduc, A Basaran, MN Kucukler, K Dagdelen, I Berker, D Guler, S AF Dogan, B. A. Tuna, M. M. Arduc, A. Basaran, M. N. Kucukler, K. Dagdelen, I. Berker, D. Guler, S. TI Increased Risk of Unfavorable Metabolic Outcome in Patients with Clinically Nonfunctioning Pituitary Adenomas SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE androgens; atherosclerotic risk markers; clinically nonfunctioning pituitary adenomas ID MEAN PLATELET VOLUME; CHORIONIC-GONADOTROPIN; CUSHINGS-SYNDROME; PROLACTIN; DISEASE; CRITERIA; EXCESS AB The aim of this study was to investigate atherosclerotic risk markers in women with clinically nonfunctioning pituitary adenomas (CNFAs). Records of 47 women with CNFAs and 73 healthy women who were treated as outpatients between January 2010 and March 2014 were evaluated retrospectively. All study data were obtained from file records. Lipid parameters, mean platelet volume (MPV), total testosterone (TT), androstenedione (AS), and dehydroepiandrostenedione sulfate (DHEAS) were recorded. Insulin resistance (IR) was calculated with homeostatic model assessment-insulin resistance (HOMA-IR). Among the atherosclerotic risk markers, the HOMA-IR and AS levels were higher in patients with CNFAs than in healthy subjects (p=0.003, p=0.021, respectively). A positive correlation between AS and insulin/HOMA-IR levels was found among the metabolic parameters in the patients with CNFAs (p=0.001, r=0.550, p=0.004, r=0.498, respectively). The data showed that patients with CNFAs had high atherosclerotic risk markers such as insulin resistance and hyperandrogenemia. Insulin resistance may also cause hyperandrogenemia in patients with CNFAs. C1 [Dogan, B. A.] Darca Farabi State Hosp, Endocrinol & Metab Dis, Kocaeli, Turkey. [Tuna, M. M.] Dicle Univ, Endocrinol & Metab Dis, Diyarbakr, Turkey. [Arduc, A.] NIDDK, Endocrine & Obes Branch, NIH, Bethesda, MD 20892 USA. [Basaran, M. N.; Dagdelen, I.; Berker, D.; Guler, S.] Ankara Numune Training & Res Hosp, Endocrinol & Metab Dis, Ankara, Turkey. [Kucukler, K.; Guler, S.] Hitit Univ, Endocrinol & Metab Dis, Corum, Turkey. RP Dogan, BA (reprint author), Darica Farabi State Hosp, Dept Endocrinol & Metab, Darica, Kocaeli, Turkey. EM bercemay@gmail.com NR 29 TC 2 Z9 2 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 2015 VL 47 IS 9 BP 652 EP 655 DI 10.1055/s-0035-1547234 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CP0WL UT WOS:000359597300005 PM 25750077 ER PT J AU Andrews, MA Schliep, KC Wactawski-Wende, J Stanford, JB Zarek, SM Radin, RG Sjaarda, LA Perkins, NJ Kalwerisky, RA Hammoud, AO Mumford, SL AF Andrews, Mary A. Schliep, Karen C. Wactawski-Wende, Jean Stanford, Joseph B. Zarek, Shvetha M. Radin, Rose G. Sjaarda, Lindsey A. Perkins, Neil J. Kalwerisky, Robyn A. Hammoud, Ahmad O. Mumford, Sunni L. TI Dietary factors and luteal phase deficiency in healthy eumenorrheic women SO HUMAN REPRODUCTION LA English DT Article DE luteal phase deficiency; menstrual cycle; Mediterranean diet; fiber; selenium ID MENSTRUAL-CYCLE DISTURBANCES; FOOD FREQUENCY QUESTIONNAIRE; MEDITERRANEAN DIET; SEX-HORMONES; SELENIUM STATUS; PREMENOPAUSAL WOMEN; FERTILITY MONITOR; OXIDATIVE STRESS; YOUNG-WOMEN; LIFE-STYLE AB STUDY QUESTION: Are prospectively assessed dietary factors, including overall diet quality, macronutrients and micronutrients, associated with luteal phase deficiency (LPD) in healthy reproductive aged women with regular menstrual cycles? SUMMARY ANSWER: Mediterranean Diet Score (MDS), fiber and isoflavone intake were positively associated with LPD while selenium was negatively associated with LPD after adjusting for age, percentage body fat and total energy intake. WHAT IS KNOWN ALREADY: LPD may increase the risk of infertility and early miscarriage. Prior research has shown positive associations between LPD and low energy availability, either through high dietary restraint alone or in conjunction with high energy expenditure via exercise, but few studies with adequate sample sizes have been conducted investigating dietary factors and LPD among healthy, eumenorrheic women. STUDY DESIGN, SIZE, DURATION: The BioCycle Study (2005-2007) prospectively enrolled 259 women from Western New York state, USA, and followed them for one (n = 9) or two (n = 250) menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-44 years, with self-reported BMI between 18 and 35 kg/m(2) and cycle lengths between 21 and 35 days, were included in the study. Participants completed baseline questionnaires, four 24-h dietary recalls per cycle and daily diaries capturing vigorous exercise, perceived stress and sleep; they also provided up to eight fasting serum samples during clinic visits timed to specific phases of the menstrual cycle using a fertility monitor. Cycles were included for this analysis if the peak serum luteal progesterone was >1 ng/ml and a urine or serum LH surge was detected. Associations between prospectively assessed diet quality, macronutrients and micronutrients and LPD (defined as luteal duration <10 days) were evaluated using generalized linear models adjusting for age, percentage body fat and total energy intake. MAIN RESULTS AND THE ROLE OF CHANCE: LPD occurred in 41 (8.9%) of the 463 cycles from 246 women in the final analysis. After adjusting for age, percentage body fat and total energy intake, LPD was positively associated with MDS, adjusted odds ratio (aOR): 1.70 (95% confidence interval [CI]: 1.17, 2.48), P = 0.01. In separate macro- and micronutrient adjusted models, increased fiber and isoflavone intake showed modest positive associations with LPD: fiber (per g), aOR: 1.10 (95% CI: 0.99, 1.23), P = 0.07; and isoflavones (per 10 mg), aOR: 1.38 (95% CI: 0.99, 1.92), P = 0.06. In contrast, selenium (per 10 mcg) was inversely associated with LPD, aOR: 0.80 (95% CI: 0.65, 0.97), P = 0.03. Additional adjustments for relevant lifestyle factors including vigorous exercise, perceived stress and sleep did not appreciably alter estimates. LIMITATIONS, REASONS FOR CAUTION: The number of LPD cycles was limited, and thus these findings are exploratory. We relied on participant self-report of their medical history to apply exclusion criteria; it is possible that we admitted to the study women with a gynecologic or medical disease who were unaware of their diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that diet quality may be associated with LPD among healthy eumenorrheic women. As LPD may contribute to infertility and early miscarriage, further research is warranted to elucidate how dietary factors, such as MDS, may influence LPD. The inverse association we found with selenium is supported by previous research and deserves further investigation to determine whether this finding has pathophysiologic and therapeutic implications. C1 [Andrews, Mary A.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Andrews, Mary A.] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Andrews, Mary A.] Walter Reed Natl Mil Med Ctr, Dept Med, Bethesda, MD 20889 USA. [Schliep, Karen C.; Zarek, Shvetha M.; Radin, Rose G.; Sjaarda, Lindsey A.; Perkins, Neil J.; Kalwerisky, Robyn A.; Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY 14214 USA. [Stanford, Joseph B.] Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT 84108 USA. [Zarek, Shvetha M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Div Intramural Res, Bethesda, MD 20892 USA. [Hammoud, Ahmad O.] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Hammoud, Ahmad O.] IVF Michigan Fertil Ctr, Bloomfield Hills, MI 48304 USA. RP Mumford, SL (reprint author), 6100 Execut Blvd Room 7B05,MSC 7510, Rockville, MD 20852 USA. EM mumfords@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110 FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 51 TC 2 Z9 2 U1 5 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD AUG PY 2015 VL 30 IS 8 BP 1942 EP 1951 DI 10.1093/humrep/dev133 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CP2YG UT WOS:000359743300023 PM 26082480 ER PT J AU Reigstad, MM Larsen, IK Myklebust, TA Robsahm, TE Oldereid, NB Omland, AK Vangen, S Brinton, LA Storeng, R AF Reigstad, M. M. Larsen, I. K. Myklebust, T. A. Robsahm, T. E. Oldereid, N. B. Omland, A. K. Vangen, S. Brinton, L. A. Storeng, R. TI Cancer risk among parous women following assisted reproductive technology SO HUMAN REPRODUCTION LA English DT Article DE brain tumor; neoplasm of the central nervous system; cancer; IVF; assisted reproductive technology ID IN-VITRO FERTILIZATION; OVULATION-STIMULATING DRUGS; HORMONE REPLACEMENT THERAPY; EPITHELIAL OVARIAN-CANCER; LARGE DANISH COHORT; FERTILITY DRUGS; BREAST-CANCER; UNITED-STATES; CERVICAL-CANCER; THYROID-CANCER AB STUDY QUESTION: Do women who give birth after assisted reproductive technology (ART) have an increased risk of cancer compared with women who give birth without ART? SUMMARY ANSWER: Without correction, the results indicate an increase in overall cancer risk, as well as a 50% increase in risk of CNS cancer for women giving birth after ART, however the results were not significant after correcting for multiple analyses. WHAT IS KNOWN ALREADY: Studies regarding the effects of hormonal treatments involved with ART on subsequent cancer risk have provided inconsistent results, and it has also been suggested that infertility itself could be a contributory factor. STUDY DESIGN, SIZE, DURATION: A population-based cohort consisting of all women registered in the Medical Birth Registry of Norway as having given birth between 1 January 1984 and 31 December 2010 was assembled (n = 812 986). Cancers were identified by linkage to the Cancer Registry of Norway. Study subjects were followed from start of first pregnancy during the observational period until the first cancer, death, emigration, or 31 December 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the total study population (n = 806 248), 16 525 gave birth to a child following ART. Cox regression analysis computed hazard ratios (HR) and 95% confidence intervals (CI) comparing cancer risk between ART women and non-ART women; for overall cancer, and for cervical, ovarian, uterine, central nervous system (CNS), colorectal and thyroid cancers, and for malignant melanoma. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 22 282 cohort members were diagnosed with cancer, of which 338 were ART women and 21 944 non-ART women. The results showed an elevated risk in one out of seven sites for ART women. The HR for cancer of the CNS was 1.50 (95% CI 1.03- 2.18), and among those specifically subjected to IVF (without ICSI) the HR was 1.83 (95% CI 1.22-2.73). Analysis of risk of overall cancer gave an HR of 1.16 (95% CI 1.04-1.29). Among those who had delivered only one child by the end of follow-up, the HR for ovarian cancer was 2.00 (95% CI 1.08-3.65), and for those nulliparous at entry the HR was 1.80 (95% CI 1.04-3.11). However, all findings became non-significant after correcting for multiple analyses. LIMITATIONS, REASONS FOR CAUTION: The results of elevated risk of overall cancer and CNS cancer lost significance when adjusting for multiple analyses, implying an important limitation of the study. The follow-up time was relatively short, especially for ART women. In addition, as the cohort was relatively young, there were few incident cancers, especially for some rarer cancer forms, such as uterine cancer. Risk assessments according to different causes of infertility could not be done. WIDER IMPLICATIONS OF THE FINDINGS: In light of the findings in the present study, further studies should be made on risk of CNS and ovarian cancer, and continued monitoring of all those treated with ART is encouraged. Our findings may only be generalizable to women who give birth after ART, and the risk for women who remain nulliparous after ART remains to be assessed. C1 [Reigstad, M. M.; Vangen, S.; Storeng, R.] Oslo Univ Hosp, Rikshosp, Norwegian Natl Advisory Unit Womens Hlth, N-0424 Oslo, Norway. [Reigstad, M. M.; Larsen, I. K.; Myklebust, T. A.; Robsahm, T. E.] Canc Registry Norway, Inst Populat Based Canc Res, Oslo, Norway. [Oldereid, N. B.; Omland, A. K.] Oslo Univ Hosp, Rikshosp, Sect Reprod Med, N-0424 Oslo, Norway. [Brinton, L. A.] NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Bethesda, MD 20892 USA. RP Reigstad, MM (reprint author), Oslo Univ Hosp, Rikshosp, Norwegian Natl Advisory Unit Womens Hlth, POB 4950 Nydalen, N-0424 Oslo, Norway. EM martereigstad@gmail.com FU Norwegian National Advisory unit on Women's Health, Oslo University Hospital, Oslo, Norway; Norwegian National Advisory Unit on Women's Health, Oslo University Hospital FX This work was funded by the Norwegian National Advisory unit on Women's Health, Oslo University Hospital, Oslo, Norway. Funding to pay the Open Access publication charges for this article was provided by The Norwegian National Advisory Unit on Women's Health, Oslo University Hospital. NR 57 TC 10 Z9 10 U1 3 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD AUG PY 2015 VL 30 IS 8 BP 1952 EP 1963 DI 10.1093/humrep/dev124 PG 12 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CP2YG UT WOS:000359743300024 PM 26113657 ER PT J AU Gershen, LD Zanotti-Fregonara, P Dustin, IH Liow, JS Hirvonen, J Kreisl, WC Jenko, KJ Inati, SK Fujita, M Morse, CL Brouwer, C Hong, JS Pike, VW Zoghbi, SS Innis, RB Theodore, WH AF Gershen, Leah D. Zanotti-Fregonara, Paolo Dustin, Irene H. Liow, Jeih-San Hirvonen, Jussi Kreisl, William C. Jenko, Kimberly J. Inati, Sara K. Fujita, Masahiro Morse, Cheryl L. Brouwer, Chad Hong, Jinsoo S. Pike, Victor W. Zoghbi, Sami S. Innis, Robert B. Theodore, William H. TI Neuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator Protein SO JAMA NEUROLOGY LA English DT Article ID VIVO RADIOLIGAND BINDING; BLOOD-BRAIN-BARRIER; TOLL-LIKE RECEPTOR; IN-VIVO; CORTICAL DEVELOPMENT; SPONTANEOUS SEIZURES; ADAPTIVE IMMUNITY; PET LIGAND; EPILEPTOGENESIS; TSPO AB IMPORTANCE Neuroinflammation may play a role in epilepsy. Translocator protein 18 kDa (TSPO), a biomarker of neuroinflammation, is overexpressed on activated microglia and reactive astrocytes. A preliminary positron emission tomographic (PET) imaging study using carbon 11 ([C-11])-labeled PBR28 in patients with temporal lobe epilepsy (TLE) found increased TSPO ipsilateral to seizure foci. Full quantitation of TSPO in vivo is needed to detect widespread inflammation in the epileptic brain. OBJECTIVES To determine whether patients with TLE have widespread TSPO overexpression using [C-11]PBR28 PET imaging, and to replicate relative ipsilateral TSPO increases in patients with TLE using [C-11]PBR28 and another TSPO radioligand, [C-11]DPA-713. DESIGN, SETTING, AND PARTICIPANTS In a cohort study from March 2009 through September 2013 at the Clinical Epilepsy Section of the National Institute of Neurological Disorders and Stroke, participants underwent brain PET and a subset had concurrent arterial sampling. Twenty-three patients with TLE and 11 age-matched controls were scanned with [C-11]PBR28, and 8 patients and 7 controls were scanned with [C-11]DPA-713. Patients with TLE had unilateral temporal seizure foci based on ictal electroencephalography and structural magnetic resonance imaging. Participants with homozygous low-affinity TSPO binding were excluded. MAIN OUTCOMES AND MEASURES The [C-11]PBR28 distribution volume (V-T) corrected for free fraction (f(P)) was measured in patients with TLE and controls using FreeSurfer software and T1-weighted magnetic resonance imaging for anatomical localization of bilateral temporal and extratemporal regions. Side-to-side asymmetry in patients with TLE was calculated as the ratio of ipsilateral to contralateral [C-11]PBR28 and [C-11]DPA-713 standardized uptake values from temporal regions. RESULTS The [C-11]PBR28 V-T to f(P) ratio was higher in patients with TLE than in controls for all ipsilateral temporal regions (27%-42%; P < .05) and in contralateral hippocampus, amygdala, and temporal pole (approximately 30%-32%; P < .05). Individually, 12 patients, 10 with mesial temporal sclerosis, had asymmetrically increased hippocampal [C-11]PBR28 uptake exceeding the 95% confidence interval of the controls. Binding of [C-11]PBR28 was increased significantly in thalamus. Relative [C-11]PBR28 and [C-11] DPA-713 uptakes were higher ipsilateral than contralateral to seizure foci in patients with TLE ([C-11]PBR28: 2%-6%; [C-11]DPA-713: 4%-9%). Asymmetry of [C-11]DPA-713 was greater than that of [C-11]PBR28 (F = 29.4; P = .001). CONCLUSIONS AND RELEVANCE Binding of TSPO is increased both ipsilateral and contralateral to seizure foci in patients with TLE, suggesting ongoing inflammation. Anti-inflammatory therapy may play a role in treating drug-resistant epilepsy. C1 [Gershen, Leah D.; Zanotti-Fregonara, Paolo; Liow, Jeih-San; Kreisl, William C.; Jenko, Kimberly J.; Fujita, Masahiro; Morse, Cheryl L.; Brouwer, Chad; Hong, Jinsoo S.; Pike, Victor W.; Zoghbi, Sami S.; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Zanotti-Fregonara, Paolo] Univ Bordeaux, Aquitaine Inst Cognit & Integrat Neurosci, Natl Ctr Sci Res, Talence, France. [Dustin, Irene H.; Inati, Sara K.; Theodore, William H.] NINCDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. [Hirvonen, Jussi] Univ Turku, Dept Radiol, Turku, Finland. RP Theodore, WH (reprint author), NINCDS, Clin Epilepsy Sect, NIH, Bldg 10,Room 7D-43, Bethesda, MD 20892 USA. EM theodorw@ninds.nih.gov FU Intramural Research Programs of National Institute of Mental Health and National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Mental Health and National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 31 TC 17 Z9 18 U1 2 U2 15 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD AUG PY 2015 VL 72 IS 8 BP 882 EP 888 DI 10.1001/jamaneurol.2015.0941 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CO8GE UT WOS:000359404000008 PM 26052981 ER PT J AU Grant, BF Goldstein, RB Saha, TD Chou, SP Jung, J Zhang, HT Pickering, RP Ruan, WJ Smith, SM Huang, BJ Hasin, DS AF Grant, Bridget F. Goldstein, Rise B. Saha, Tulshi D. Chou, S. Patricia Jung, Jeesun Zhang, Haitao Pickering, Roger P. Ruan, W. June Smith, Sharon M. Huang, Boji Hasin, Deborah S. TI Epidemiology of DSM-5 Alcohol Use Disorder Results From the National Epidemiologic Survey on Alcohol and Related Conditions III SO JAMA PSYCHIATRY LA English DT Article ID GENERAL-POPULATION SAMPLE; SUBSTANCE USE DISORDERS; INTERVIEW SCHEDULE AUDADIS; COMORBIDITY SURVEY REPLICATION; FOLLOW-UP INTERVAL; IV ALCOHOL; UNITED-STATES; GLOBAL BURDEN; DRUG MODULES; PRIMARY-CARE AB IMPORTANCE National epidemiologic information from recently collected data on the new DSM-5 classification of alcohol use disorder (AUD) using a reliable, valid, and uniform data source is needed. OBJECTIVE To present nationally representative findings on the prevalence, correlates, psychiatric comorbidity, associated disability, and treatment of DSM-5 AUD diagnoses overall and according to severity level (mild, moderate, or severe). DESIGN, SETTING, AND PARTICIPANTS We conducted face-to-face interviews with a representative US noninstitutionalized civilian adult (>= 18 years) sample (N = 36 309) as the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions III (NESARC-III). Data were collected from April 2012 through June 2013 and analyzed in October 2014. MAIN OUTCOMES AND MEASURES Twelve-month and lifetime prevalences of AUD. RESULTS Twelve-month and lifetime prevalences of AUD were 13.9% and 29.1%, respectively. Prevalence was generally highest for men (17.6% and 36.0%, respectively), white (14.0% and 32.6%, respectively) and Native American (19.2% and 43.4%, respectively), respondents, and younger (26.7% and 37.0%, respectively) and previously married (11.4% and 27.1%, respectively) or never married (25.0% and 35.5%, respectively) adults. Prevalence of 12-month and lifetime severe AUD was greatest among respondents with the lowest income level (1.8% and 1.5%, respectively). Significant disability was associated with 12-month and lifetime AUD and increased with the severity of AUD. Only 19.8% of respondents with lifetime AUD were ever treated. Significant associations were found between 12-month and lifetime AUD and other substance use disorders, major depressive and bipolar I disorders, and antisocial and borderline personality disorders across all levels of AUD severity, with odds ratios ranging from 1.2 (95% CI, 1.08-1.36) to 6.4 (95% CI, 5.76-7.22). Associations between AUD and panic disorder, specific phobia, and generalized anxiety disorder were modest (odds ratios ranged from 1.2 (95% CI, 1.01-1.43) to 1.4 (95% CI, 1.13-1.67) across most levels of AUD severity. CONCLUSIONS AND RELEVANCE Alcohol use disorder defined by DSM-5 criteria is a highly prevalent, highly comorbid, disabling disorder that often goes untreated in the United States. The NESARC-III data indicate an urgent need to educate the public and policy makers about AUD and its treatment alternatives, to destigmatize the disorder, and to encourage those who cannot reduce their alcohol consumption on their own, despite substantial harm to themselves and others, to seek treatment. C1 [Grant, Bridget F.; Goldstein, Rise B.; Saha, Tulshi D.; Chou, S. Patricia; Jung, Jeesun; Zhang, Haitao; Pickering, Roger P.; Ruan, W. June; Smith, Sharon M.; Huang, Boji] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Rockville, MD 20852 USA. [Hasin, Deborah S.] Columbia Univ, Coll Phys & Surg, Mailman Sch Publ Hlth, Dept Psychiat, New York, NY USA. [Hasin, Deborah S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Ln,Room 3077, Rockville, MD 20852 USA. EM 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; National Institutes of Health [K05AA014223]; Intramural Research Program of the NIAAA FX This study was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse; by grant K05AA014223 from the National Institutes of Health (Dr Hasin); and by the Intramural Research Program of the NIAAA. NR 73 TC 149 Z9 150 U1 11 U2 37 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD AUG PY 2015 VL 72 IS 8 BP 757 EP 766 DI 10.1001/jamapsychiatry.2015.0584 PG 10 WC Psychiatry SC Psychiatry GA CO5LG UT WOS:000359200000004 PM 26039070 ER PT J AU Rower, JE Meissner, EG Jimmerson, LC Osinusi, A Sims, Z Petersen, T Bushman, LR Wolfe, P McHutchison, JG Kottilil, S Kiser, JJ AF Rower, Joseph E. Meissner, Eric G. Jimmerson, Leah C. Osinusi, Anu Sims, Zayani Petersen, Tess Bushman, Lane R. Wolfe, Pamela McHutchison, John G. Kottilil, Shyamasundaran Kiser, Jennifer J. TI Serum and cellular ribavirin pharmacokinetic and concentration-effect analysis in HCV patients receiving sofosbuvir plus ribavirin SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE ribavirin monophosphate; anaemia; SVR; interferon-free therapy; red blood cells ID CHRONIC HEPATITIS-C; GENOTYPE 1 INFECTION; TREATMENT-NAIVE PATIENTS; RENAL-FUNCTION; INTERFERON; ANEMIA; QUANTIFICATION; VIRUS; BLOOD; ABT-450/R-OMBITASVIR AB Objectives: Ribavirin concentrations may impact hepatitis C virus (HCV) treatment outcome. We modelled ribavirin serum and intracellular ribavirin monophosphate (RBV-MP) and ribavirin triphosphate (RBV-TP) pharmacokinetics in red blood cells (RBC) using samples collected during the NIAID SPARE trial to explore associations with treatment outcome and the development of anaemia. Patients and methods: Individuals infected with HCV genotype 1 (GT1) received 400 mg of sofosbuvir and either low-dose or weight-based ribavirin as part of the NIAID SPARE trial. Concentrations were modelled using NONMEM and associated with treatment outcomes using unpaired t-tests or Pearson's rho correlations. Results: Average day 14 RBV-MP concentrations were higher in subjects with haemoglobin nadir,10 g/dL relative to patients with haemoglobin nadir >= 10 g/dL (6.54 versus 4.48 pmol/10(6) cells; P = 0.02). Additionally, day 14 RBV-MP average concentrations trended towards being higher in subjects that achieved sustained virological response (SVR) as compared with patients who relapsed (4.97 versus 4.09 pmol/106 cells; P = 0.07). Receiver operating characteristic curves suggested day 14 RBV-MP concentration thresholds of 4.4 pmol/10(6) cells for SVR (P = 0.06) and 6.1 pmol/10(6) cells for haemoglobin nadir <10 versus >= 10 g/dL (P = 0.02), with sensitivity and specificity >= 60%. Dosing simulations showed that 800 mg of ribavirin once daily produced day 14 RBV-MP concentrations within the 4.4-6.1 pmol/10(6) cells range. Conclusions: RBV-MP concentrations in RBC at day 14 were related to anaemia and SVR. A therapeutic range was identified for RBV-MP in persons with HCV GT1 disease receiving 24 weeks of sofosbuvir plus ribavirin, suggesting a potential pharmacological basis for individualized ribavirin dosing in IFN-free regimens. C1 [Rower, Joseph E.; Jimmerson, Leah C.; Bushman, Lane R.; Kiser, Jennifer J.] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO USA. [Meissner, Eric G.; Osinusi, Anu; Sims, Zayani; Petersen, Tess; Kottilil, Shyamasundaran] NIAID, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. [Osinusi, Anu; McHutchison, John G.] Gilead Sci Inc, Foster City, CA 94404 USA. [Wolfe, Pamela] Univ Colorado, Sch Publ Hlth, Aurora, CO USA. RP Kiser, JJ (reprint author), Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO USA. EM jennifer.kiser@ucdenver.edu FU National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health [R03 DK 096121]; National Institute of Allergy and Infectious Diseases, NIH, Bethesda FX This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (grant number R03 DK 096121 to J. J. K.) and the intramural programme of the National Institute of Allergy and Infectious Diseases, NIH, Bethesda. NR 35 TC 10 Z9 10 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 EI 1460-2091 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD AUG PY 2015 VL 70 IS 8 BP 2322 EP 2329 DI 10.1093/jac/dkv122 PG 8 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA CP2RB UT WOS:000359723600024 PM 25971261 ER PT J AU Moser, DK Robinson, S Biddle, MJ Pelter, MM Nesbitt, TS Southard, J Cooper, L Dracup, K AF Moser, Debra K. Robinson, Susan Biddle, Martha J. Pelter, Michele M. Nesbitt, Thomas S. Southard, Jeffery Cooper, Lawton Dracup, Kathleen TI Health Literacy Predicts Morbidity and Mortality in Rural Patients With Heart Failure SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE Health literacy; heart failure; rural ID SELF-CARE; HOSPITAL READMISSION; RANDOMIZED-TRIAL; DEPRESSION; ADHERENCE; KNOWLEDGE; INTERVENTION; DEATH; RATES; RISK AB Background: Patients hospitalized with heart failure are often readmitted. Health literacy may play a substantial role in the high rate of readmissions. The purpose of this study was to examine the association of health literacy with the composite end point of heart failure readmission rates and all-cause mortality in patients with heart failure living in rural areas. Methods and Results: Rural adults (n = 575), hospitalized for heart failure within the past 6 months, completed the Short Test of Functional Health Literacy in Adults (STOMA) to measure health literacy and were followed for >= 2 years. The percentage of patients with the end point of heart failure readmission or all-cause death was different (P = .001) among the 3 STOFHLA score levels. Unadjusted analysis revealed that patients with inadequate and marginal health literacy were 1.94 (95% confidence interval [CI] 1.43-2.63; P < .001) times, and 1.91 (95% CI 1.36-2.67; P < .001) times, respectively, more likely to experience the outcome. After adjustment for covariates, health literacy remained a predictor of outcomes. Of the other covariates, worse functional class, higher comorbidity burden, and higher depression score predicted worse outcomes. Conclusions: Inadequate or marginal health literacy is a risk factor for heart failure rehospitalization or all-cause mortality among rural patients with heart failure. C1 [Moser, Debra K.; Biddle, Martha J.] Univ Kentucky, Coll Nursing, Lexington, KY 40536 USA. [Robinson, Susan; Dracup, Kathleen] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Pelter, Michele M.] Univ Reno, Reno, NV USA. [Nesbitt, Thomas S.; Southard, Jeffery] Univ Calif Davis, Davis, CA 95616 USA. [Cooper, Lawton] NHLBI, NIH, Bethesda, MD 20892 USA. RP Moser, DK (reprint author), Univ Kentucky, Coll Nursing, 527 CON,751 Rose St, Lexington, KY 40536 USA. EM dmoser@uky.edu FU National Heart, Lung, and Blood Institute; National Institute of Nursing Research [5R01HL83176-5] FX Funding: National Heart, Lung, and Blood Institute and the National Institute of Nursing Research: 5R01HL83176-5. NR 47 TC 8 Z9 8 U1 3 U2 17 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2015 VL 21 IS 8 BP 612 EP 618 DI 10.1016/j.cardfail.2015.04.004 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CO8CG UT WOS:000359392000002 PM 25908018 ER PT J AU de Denus, S Rouleau, JL Mann, DL Huggins, GS Cappola, TP Shah, SH Keleti, J Zada, YF Provost, S Bardhadi, A Phillips, MS Normand, V Mongrain, I Dube, MP AF de Denus, Simon Rouleau, Jean L. Mann, Douglas L. Huggins, Gordon S. Cappola, Thomas P. Shah, Svati H. Keleti, Julianna Zada, Yassamin Feroz Provost, Sylvie Bardhadi, Amina Phillips, Michael S. Normand, Valerie Mongrain, Ian Dube, Marie-Pierre TI A Pharmacogenetic Investigation of Intravenous Furosemide in Decompensated Heart Failure: A Meta-Analysis of 3 Clinical Trials SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 26-29, 2015 CL National Harbor, MD SP Heart Failure Soc Amer C1 [de Denus, Simon; Rouleau, Jean L.; Zada, Yassamin Feroz; Provost, Sylvie; Bardhadi, Amina; Phillips, Michael S.; Normand, Valerie; Mongrain, Ian; Dube, Marie-Pierre] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Mann, Douglas L.] Washington Univ, Sch Med, St Louis, MO USA. [Huggins, Gordon S.] Tufts Med Ctr, Boston, MA USA. [Cappola, Thomas P.] Univ Penn, Philadelphia, PA 19104 USA. [Shah, Svati H.] Duke Univ, Sch Med, Div Cardiol, Durham, NC USA. [Keleti, Julianna] NHLBI, Bethesda, MD 20892 USA. RI Dube, Marie-Pierre/B-9364-2008 OI Dube, Marie-Pierre/0000-0001-8442-4393 NR 0 TC 0 Z9 0 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2015 VL 21 IS 8 SU S MA 259 BP S16 EP S17 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CO8CI UT WOS:000359392200037 ER PT J AU Desvigne-Nickens, P Regan, K Costello, R Ershow, A AF Desvigne-Nickens, Patrice Regan, Karen Costello, Rebecca Ershow, Abby TI Trials are Needed to Evaluate Nutrition Interventions for HF: Analysis of the Federal Nutrition and HF Research Portfolio SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 26-29, 2015 CL National Harbor, MD SP Heart Failure Soc Amer C1 [Desvigne-Nickens, Patrice] NHLBI, Bethesda, MD 20892 USA. [Regan, Karen; Costello, Rebecca; Ershow, Abby] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2015 VL 21 IS 8 SU S MA 091 BP S47 EP S47 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CO8CI UT WOS:000359392200116 ER PT J AU Kuzmina, Z Stroncek, D Pavletic, SZ AF Kuzmina, Zoya Stroncek, David Pavletic, Steven Z. TI Extracorporeal Photopheresis as a Therapy for Autoimmune Diseases SO JOURNAL OF CLINICAL APHERESIS LA English DT Article DE photopheresis; extracorporeal; autoimmune disease; cellular therapy; immunomodulation ID VERSUS-HOST-DISEASE; REGULATORY T-CELLS; SEVERE ATOPIC-DERMATITIS; PLACEBO-CONTROLLED TRIAL; NEPHROGENIC FIBROSING DERMOPATHY; EPIDERMOLYSIS-BULLOSA ACQUISITA; PROGRESSIVE MULTIPLE-SCLEROSIS; REFRACTORY CROHNS-DISEASE; ORAL LICHEN-PLANUS; SYSTEMIC-SCLEROSIS AB Systemic autoimmune diseases (AID) have multiorgan, heterogeneous clinical presentations and are characterized by dysregulation of the immune system, immunodeficiency, irreversible organ damage and increased morbidity and mortality. Preventing or decreasing flares of AID correlate with durable disease control, significant reduction of inflammation and prevention of disability or therapy-related toxicity. There is an urgent need for better treatment of severe, therapy-refractory AID. Extracorporeal photopheresis (ECP) is a cell-based immunomodulatory treatment which has been extensively used in variety of autoimmune disorders for the last two decades. ECP treatment is FDA approved for the treatment of cutaneous T-cell lymphoma (CTCL) with particularly promising results seen in graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Prolonged therapy is safe, well tolerated and allows reduction of systemic immunosuppression in therapy-refractory patients. Both clinical and experimental evidence suggest that ECP mechanism of action is characterized by apoptosis and phagocytosis of activated cells by antigen-presenting cells (APC), secretion of anti-inflammatory cytokines and stimulation of regulatory T cells (Tregs). The focus of this paper is to review the current evidence of ECP use in the treatment of AID. Here, we summarize the experience of nine major AID from 65 published reports. The key findings demonstrate substantial evidence of ECP feasibility, safety and in some AID also promising efficacy. However, the role of ECP in AID therapy is not established as most published studies are retrospective with limited number of patients and the trials are small or poorly standardized. The available data support future investigations of ECP as a therapeutic modality for the treatment of AID in well-designed prospective clinical studies. J. Clin. Apheresis 30:224-237, 2015. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Kuzmina, Zoya; Pavletic, Steven Z.] NCI, Graft Versus Host & Autoimmun Unit, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Stroncek, David] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Pavletic, SZ (reprint author), NCI, Graft Versus Host & Autoimmun Unit, Expt Transplantat & Immunol Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pavletis@mail.nih.gov NR 116 TC 3 Z9 3 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2459 EI 1098-1101 J9 J CLIN APHERESIS JI J. Clin. Apheresis PD AUG PY 2015 VL 30 IS 4 BP 224 EP 237 DI 10.1002/jca.21367 PG 14 WC Hematology SC Hematology GA CP3NK UT WOS:000359786400005 PM 25546289 ER PT J AU Paoletta, S Sabbadin, D von Kugelgen, I Hinz, S Katritch, V Hoffmann, K Abdelrahman, A Strassburger, J Baqi, Y Zhao, Q Stevens, RC Moro, S Muller, CE Jacobson, KA AF Paoletta, Silvia Sabbadin, Davide von Kuegelgen, Ivar Hinz, Sonja Katritch, Vsevolod Hoffmann, Kristina Abdelrahman, Aliaa Strassburger, Jens Baqi, Younis Zhao, Qiang Stevens, Raymond C. Moro, Stefano Mueller, Christa E. Jacobson, Kenneth A. TI Modeling ligand recognition at the P2Y(12) receptor in light of X-ray structural information SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Article DE G protein-coupled receptors; Purines; Molecular modeling; Nucleotides; Structure-activity relationship; X-ray crystallographic structures ID PIPERAZINYL-GLUTAMATE-PYRIDINES; HUMAN PLATELET P2Y(12)-RECEPTOR; POTENT ANTAGONISTS; P2Y RECEPTORS; HIGH-AFFINITY; AGGREGATION; ADENOSINE; IDENTIFICATION; NUCLEOTIDES; INHIBITION AB The G protein-coupled P2Y(12) receptor (P2Y(12)R) is an important antithrombotic target and of great interest for pharmaceutical discovery. Its recently solved, highly divergent crystallographic structures in complex either with nucleotides (full or partial agonist) or with a nonnucleotide antagonist raise the question of which structure is more useful to understand ligand recognition. Therefore, we performed extensive molecular modeling studies based on these structures and mutagenesis, to predict the binding modes of major classes of P2Y(12)R ligands previously reported. Various nucleotide derivatives docked readily to the agonist-bound P2Y(12)R, but uncharged nucleotide-like antagonist ticagrelor required a hybrid receptor resembling the agonist-bound P2Y(12)R except for the top portion of TM6. Supervised molecular dynamics (SuMD) of ticagrelor binding indicated interactions with the extracellular regions of P2Y(12)R, defining possible meta-binding sites. Ureas, sulfonylureas, sulfonamides, anthraquinones and glutamic acid piperazines docked readily to the antagonist-bound P2Y(12)R. Docking dinucleotides at both agonist- and antagonist-bound structures suggested interactions with two P2Y(12)R pockets. Thus, our structure-based approach consistently rationalized the main structure-activity relationships within each ligand class, giving useful information for designing improved ligands. C1 [Paoletta, Silvia; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Hinz, Sonja; Abdelrahman, Aliaa; Baqi, Younis; Mueller, Christa E.] Univ Bonn, Pharmaceut Inst Pharmaceut Chem 1, PharmaCtr Bonn, Pharmaceut Sci Bonn, D-53121 Bonn, Germany. [Katritch, Vsevolod; Stevens, Raymond C.] Univ So Calif, Bridge Inst, Dornsife Coll Letters Arts & Sci, Los Angeles, CA 90089 USA. [Zhao, Qiang] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China. [Sabbadin, Davide; Moro, Stefano] Univ Padua, Dipartimento Sci Farmaco, MMS, I-35131 Padua, Italy. [Baqi, Younis] Sultan Qaboos Univ, Fac Sci, Dept Chem, Muscat, Oman. [von Kuegelgen, Ivar; Hoffmann, Kristina; Strassburger, Jens] Univ Bonn, Dept Pharmacol, D-53127 Bonn, Germany. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A 19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; Moro, Stefano/A-2979-2012; Baqi, Younis/I-8240-2016; Katritch, Vsevolod/Q-8357-2016; Muller, Christa/C-7748-2014; Stevens, Raymond/K-7272-2015 OI Jacobson, Kenneth/0000-0001-8104-1493; Moro, Stefano/0000-0002-7514-3802; Baqi, Younis/0000-0002-9659-8419; Muller, Christa/0000-0002-0013-6624; Stevens, Raymond/0000-0002-4522-8725 FU National Institutes of Health (Intramural Research Program of NIDDK) [R01HL077707] FX This research was supported by the National Institutes of Health (Intramural Research Program of the NIDDK and R01HL077707). NR 56 TC 6 Z9 6 U1 3 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X EI 1573-4951 J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD AUG PY 2015 VL 29 IS 8 BP 737 EP 756 DI 10.1007/s10822-015-9858-z PG 20 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA CO9ZM UT WOS:000359535600006 PM 26194851 ER PT J AU Cai, WS Mao, FB Teng, HJ Cai, T Zhao, FQ Wu, JY Sun, ZS AF Cai, Wanshi Mao, Fengbiao Teng, Huajing Cai, Tao Zhao, Fangqing Wu, Jinyu Sun, Zhong Sheng TI MBRidge: an accurate and cost-effective method for profiling DNA methylome at single-base resolution SO JOURNAL OF MOLECULAR CELL BIOLOGY LA English DT Article DE DNA methylome; MB-seq; ridge regression; single-base resolution ID HUMAN OVARIAN-CANCER; HUMAN-CELLS; METHYLATION ANALYSIS; NONCODING RNAS; HUMAN GENOME; WIDE; REVEALS; MODEL; 5-HYDROXYMETHYLCYTOSINE; ENRICHMENT AB Organisms and cells, in response to environmental influences or during development, undergo considerable changes in DNA methylation on a genome-wide scale, which are linked to a variety of biological processes. Using MethylC-seq to decipher DNA methylome at single-base resolution is prohibitively costly. In this study, we develop a novel approach, named MBRidge, to detect the methylation levels of repertoire CpGs, by innovatively introducing C-hydroxylmethylated adapters and bisulfate treatment into the MeDIP-seq protocol and employing ridge regression in data analysis. A systematic evaluation of DNA methylome in a human ovarian cell line 129 showed that MBRidge achieved high correlation (R > 0.90) with much less cost (,,,10%) in comparison with MethylC-seq. We further applied MBRidge to profiling DNA methylome in T29H, an oncogenic counterpart of T29's. By comparing methylomes of T29H and 129, we identified 131790 differential methylation regions (DMRs), which are mainly enriched in carcinogenesis-related pathways. These are substantially different from 7567 DMRs that were obtained by RRBS and related with cell development or differentiation. The integrated analysis of DMRs in the promoter and expression of DMR-corresponding genes revealed that DNA methylation enforced reverse regulation of gene expression, depending on the distance from the proximal DM R to transcription starting sites in both mRNA and lncRNA. Taken together, our results demonstrate that MBRidge is an efficient and cost-effective method that can be widely applied to profiling DNA methylomes. C1 [Cai, Wanshi; Mao, Fengbiao; Teng, Huajing; Zhao, Fangqing; Wu, Jinyu; Sun, Zhong Sheng] Chinese Acad Sci, Beijing Inst Life Sci, Beijing 100101, Peoples R China. [Cai, Wanshi; Mao, Fengbiao] Univ Chinese Acad Sci, Beijing 100049, Peoples R China. [Teng, Huajing] Chinese Acad Sci, Inst Zool, Beijing 100101, Peoples R China. [Cai, Tao] NIDCR, Expt Med Sect, NIH, Bethesda, MD 20892 USA. [Wu, Jinyu; Sun, Zhong Sheng] Wenzhou Med Univ, Inst Genom Med, Wenzhou 325035, Peoples R China. RP Sun, ZS (reprint author), Chinese Acad Sci, Beijing Inst Life Sci, Beijing 100101, Peoples R China. EM iamwujy@gmail.com; sunzs@mail.biols.ac.cn FU National High Technology Research and Development Program of China [2012AA02A201, 2012AA02A202]; Ministry of Science and Technology of China [2011DFA30670]; National Natural Science Foundation of China [31171236/C060503]; AstraZeneca Innovation Centre China FX This work was supported by grants from the National High Technology Research and Development Program of China (2012AA02A201, 2012AA02A202), China-Canada Collaboration Project from the Ministry of Science and Technology of China (2011DFA30670), the National Natural Science Foundation of China (31171236/C060503), and the AstraZeneca Innovation Centre China. NR 62 TC 0 Z9 1 U1 6 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1674-2788 EI 1759-4685 J9 J MOL CELL BIOL JI J. Mol. Cell Biol. PD AUG PY 2015 VL 7 IS 4 BP 299 EP 313 DI 10.1093/jmcb/mjv037 PG 15 WC Cell Biology SC Cell Biology GA CP1VS UT WOS:000359665200003 PM 26078362 ER PT J AU Hughes, AK Rostant, OS Pelon, S AF Hughes, Anne K. Rostant, Ola S. Pelon, Sally TI Sexual Problems Among Older Women by Age and Race SO JOURNAL OF WOMENS HEALTH LA English DT Article ID HELP-SEEKING BEHAVIOR; SELF-RATED HEALTH; UNITED-STATES; LATER LIFE; DYSFUNCTION; PREVALENCE; ADULTS; SATISFACTION; CARE; ATTITUDES AB Background: The purpose of our study was to examine the prevalence of sexual problems by age and race among older women in the United States and to examine quality of life correlates to sexual dysfunction among non-Hispanic white and African American older women. Methods: A cross-sectional study using self-report surveys was conducted among community-dwelling U.S. women, aged 60 years and over. A total of 807 women aged 61-89 years were included. Self-administered questionnaires assessed sexual dysfunction, satisfaction with life, depressive symptomatology, and self-rated health. Analyses included multivariate logistic regression. Results: The mean age of the sample was 66 years. Two-thirds of the sample had at least one sexual dysfunction; the most common for both African American and non-Hispanic white women were lack of interest in sex and vaginal dryness. Prevalence varied by age for each of the sexual dysfunctions. The odds of experiencing sexual dysfunction varied with age and race. Compared with non-Hispanic white women, African American women had lower odds of reporting lack of interest in sex or vaginal dryness. Poor self-rated health, depressive symptomatology, and lower satisfaction with life were associated with higher odds of having some sexual dysfunction. Conclusions: Improved understanding of how sexual dysfunction affects women across multiple age ranges and racial/ethnic groups can assist providers in making recommendations for care that are patient centered. The associations that we identified with quality of life factors highlight the need to assess sexual health care in the aging female population. C1 [Hughes, Anne K.; Pelon, Sally] Michigan State Univ, Sch Social Work, E Lansing, MI 48824 USA. [Rostant, Ola S.] NIA, Aging Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Hughes, AK (reprint author), Michigan State Univ, Sch Social Work, Baker Hall Room 240 655 Auditorium Rd, E Lansing, MI 48824 USA. EM hughesa@msu.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [K12HD065879] FX The project described was supported by Award Number K12HD065879 (Hughes) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health. NR 32 TC 2 Z9 2 U1 0 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD AUG 1 PY 2015 VL 24 IS 8 BP 663 EP 669 DI 10.1089/jwh.2014.5010 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA CP1FL UT WOS:000359621600008 PM 26061291 ER PT J AU Tong, EK Fagan, P Cooper, L Canto, M Carroll, W Foster-Bey, J Hebert, JR Lopez-Class, M Ma, GX Henderson, PN Perez-Stable, EJ Santos, L Smith, JH Tan, Y Tsoh, J Chu, K AF Tong, Elisa K. Fagan, Pebbles Cooper, Leslie Canto, Maria Carroll, William Foster-Bey, John Hebert, James R. Lopez-Class, Maria Ma, Grace X. Henderson, Patricia Nez Perez-Stable, Eliseo J. Santos, LorrieAnn Smith, Justin H. Tan, Yin Tsoh, Janice Chu, Kenneth TI Working to Eliminate Cancer Health Disparities from Tobacco: A Review of the National Cancer Institute's Community Networks Program SO NICOTINE & TOBACCO RESEARCH LA English DT Review ID VIETNAMESE-AMERICAN ADOLESCENTS; SMOKING-CESSATION; CIGARETTE-SMOKING; ASIAN-AMERICANS; CARCINOGEN 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE; RACIAL-DIFFERENCES; SECONDHAND SMOKE; LATINO SMOKERS; LUNG-CANCER; CHINESE AB Introduction: In 2005, the National Cancer Institute funded the Community Networks Program (CNP), which aimed to reduce cancer health disparities in minority racial/ethnic and underserved groups through community-based participatory research, education, and training. The purpose of this study was to describe the CNP model and their tobacco-related work in community-based research, education, and training using a tobacco disparities research framework. Methods: We conducted a comprehensive review of the CNP tobacco-related activities including publications, published abstracts, research activities, trainee pilot studies, policy-related activities, educational outreach, and reports produced from 2005-2009. Two authors categorized the tobacco-related activities and publications within the framework. Results: Although there was no mandate to address tobacco, the CNPs produced 103 tobacco-related peer-reviewed publications, which reflects the largest proportion (12%) of all CNP cancer-related publications. Selected publications and research activities were most numerous under the framework areas "Psychosocial Research," "Surveillance," "Epidemiology," and "Treatment of Nicotine Addiction." Thirteen CNPs participated in tobacco control policymaking in mainstream efforts that affected their local community and populations, and 24 CNPs conducted 1147 tobacco-related educational outreach activities. CNP activities that aimed to build research and infrastructure capacity included nine tobacco-related pilot projects representing 16% of all CNP cancer-related pilot projects, and 17 publications acknowledging leveraged partnerships with other organizations, a strategy encouraged by the CNP. Conclusions: The CNP is a promising academic- community model for working to eliminate tobacco-related health disparities. Future efforts may address scientific gaps, consider collaboration across groups, assess the extent of operationalizing community-based participatory research, and improve common tracking measures. C1 [Tong, Elisa K.] Univ Calif Davis, Dept Internal Med, Sacramento, CA 95817 USA. [Fagan, Pebbles] Univ Hawaii, Ctr Canc, Canc Prevent & Control Program, Honolulu, HI 96822 USA. [Canto, Maria] Natl Inst Gen Med Sci, Ctr Res Capac Bldg, Bethesda, MD USA. [Carroll, William] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Foster-Bey, John] CSR Inc, Arlington, VA USA. [Hebert, James R.] Univ S Carolina, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Lopez-Class, Maria] Natl Childrens Study, Bethesda, MD USA. [Ma, Grace X.; Tan, Yin] Temple Univ, Dept Publ Hlth, Philadelphia, PA 19122 USA. [Henderson, Patricia Nez] Black Hills Ctr Amer Indian Hlth, Rapid City, SD USA. [Perez-Stable, Eliseo J.] Univ Calif San Francisco, Dept Internal Med, San Francisco, CA 94143 USA. [Santos, LorrieAnn] Queens Med Ctr, Honolulu, HI USA. [Tsoh, Janice] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Chu, Kenneth] NCI, Ctr Reduce Canc Hlth Dispar, Bethesda, MD 20892 USA. RP Tong, EK (reprint author), Univ Calif Davis, Dept Internal Med, 4150 V St,Suite 2400, Sacramento, CA 95817 USA. EM ektong@ucdavis.edu FU National Cancer Institute's Center to Reduce Cancer Health Disparities; Community Networks To Reduce Cancer Health Disparities [RFA-CA-05-012, U01 CA114601, U01 CA114640, U01 CA114582, U01 CA114630, U01CA86117, U01CA114619] FX This work was supported by the National Cancer Institute's Center to Reduce Cancer Health Disparities with the Cooperative Agreement, Community Networks To Reduce Cancer Health Disparities (RFA-CA-05-012), including the specific contributions of: U01 CA114601 (South Carolina Cancer Disparities Community Network, PI: JRH); U01 CA114640 (Asian American Network for Cancer Awareness, Research and Training, PI: M. Chen); U01 CA114582 (ATECAR-Asian Community Cancer Network, PI: GXM); U01 CA114630 ('Imi Hale Native Hawaiian Cancer Network, PI: C. Chong); U01CA86117 (Redes en Accion, PI: A. G. Ramirez); U01CA114619 (Deep South Network for Cancer Control, PI: Edward E. Partridge). NR 82 TC 1 Z9 1 U1 3 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD AUG PY 2015 VL 17 IS 8 BP 908 EP 923 DI 10.1093/ntr/ntv069 PG 16 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CP1SH UT WOS:000359655000004 PM 26180215 ER PT J AU Robinson, CD Pickworth, WB Heishman, SJ Wetter, DW Cinciripini, PM Li, YS Rowell, B Waters, AJ AF Robinson, Cendrine D. Pickworth, Wallace B. Heishman, Stephen J. Wetter, David W. Cinciripini, Paul M. Li, Yisheng Rowell, Brigid Waters, Andrew J. TI Black Cigarette Smokers Report More Attention to Smoking Cues Than White Smokers: Implications for Smoking Cessation SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID FAGERSTROM TOLERANCE QUESTIONNAIRE; NICOTINE DEPENDENCE; RACIAL/ETHNIC DISPARITIES; RETAIL DISPLAYS; TOBACCO; RACE; RELIABILITY; ABSTINENCE; REACTIVITY; ADDICTION AB Introduction: Black cigarette smokers have lower rates of smoking cessation compared with Whites. However, the mechanisms underlying these differences are not clear. Many Blacks live in communities saturated by tobacco advertisements. These cue-rich environments may undermine cessation attempts by provoking smoking. Moreover, attentional bias to smoking cues (attention capture by smoking cues) has been linked to lower cessation outcomes. Cessation attempts among Blacks may be compromised by attentional bias to smoking cues and a cue-rich environment. Method: Attention to smoking cues in Black and White smokers was examined in 2 studies. In both studies, assessments were completed during 2 laboratory visits: a nonabstinent session and an abstinent session. In study 1, nontreatment-seeking smokers (99 Whites, 104 Blacks) completed the Subjective Attentional Bias Questionnaire (SABQ; a self-report measure of attention to cues) and the Smoking Stroop task (a reaction time measure of attentional bias to smoking cues). In study 2, 110 White and 74 Black treatment-seeking smokers completed these assessments and attempted to quit. Results: In study 1, Blacks reported higher ratings than Whites on the SABQ (p = .005). In study 2, Blacks also reported higher ratings than Whites on the SABQ (p = .003). In study 2, Blacks had lower biochemical-verified point prevalence abstinence than Whites, and the between-race difference in outcome was partially mediated by SABQ ratings. Conclusion: Blacks reported greater attention to smoking cues than Whites, possibly due to between-race differences in environments. Greater attention to smoking cues may undermine cessation attempts. C1 [Robinson, Cendrine D.; Waters, Andrew J.] Univ Hlth Sci, Dept Med & Clin Psychol, Uniformed Serv, Bethesda, MD 20814 USA. [Pickworth, Wallace B.] Battelle Mem Inst, Ctr Publ Hlth Res & Evaluat, Baltimore, MD USA. [Heishman, Stephen J.] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. [Wetter, David W.; Cinciripini, Paul M.; Li, Yisheng] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Rowell, Brigid] Univ Michigan, Ann Arbor, MA USA. RP Robinson, CD (reprint author), Univ Hlth Sci, Uniformed Serv, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM cendrine.robinson@usuhs.edu OI LI, Yisheng/0000-0001-9847-8544; Wetter, David/0000-0002-6366-0108 FU NIH [R01 DA020436] FX This study was funded by NIH R01 DA020436 (AJW). NR 42 TC 2 Z9 2 U1 2 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD AUG PY 2015 VL 17 IS 8 BP 1022 EP 1028 DI 10.1093/ntr/ntu263 PG 7 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CP1SH UT WOS:000359655000018 PM 26180228 ER PT J AU Salazar, J Amri, H Noursi, D Abu-Asab, M AF Salazar, Jose Amri, Hakima Noursi, David Abu-Asab, Mones TI Computational Tools for Parsimony Phylogenetic Analysis of Omics Data SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID LARGE DATA SETS; GENE-EXPRESSION; MICROARRAY DATA; HETEROGENEITY; MEDICINE; CANCER AB High-throughput assays from genomics, proteomics, metabolomics, and next generation sequencing produce massive omics datasets that are challenging to analyze in biological or clinical contexts. Thus far, there is no publicly available program for converting quantitative omics data into input formats to be used in off-the-shelf robust phylogenetic programs. To the best of our knowledge, this is the first report on creation of two Windows-based programs, OmicsTract and SynpExtractor, to address this gap. We note, as a way of introduction and development of these programs, that one particularly useful bioinformatics inferential modeling is the phylogenetic cladogram. Cladograms are multidimensional tools that show the relatedness between subgroups of healthy and diseased individuals and the latter's shared aberrations; they also reveal some characteristics of a disease that would not otherwise be apparent by other analytical methods. The OmicsTract and SynpExtractor were written for the respective tasks of (1) accommodating advanced phylogenetic parsimony analysis (through standard programs of MIX [from PHYLIP] and TNT), and (2) extracting shared aberrations at the cladogram nodes. OmicsTract converts comma-delimited data tables through assigning each data point into a binary value ("0" for normal states and "1" for abnormal states) then outputs the converted data tables into the proper input file formats for MIX or with embedded commands for TNT. SynapExtractor uses outfiles from MIX and TNT to extract the shared aberrations of each node of the cladogram, matching them with identifying labels from the dataset and exporting them into a comma-delimited file. Labels may be gene identifiers in gene-expression datasets or m/z values in mass spectrometry datasets. By automating these steps, OmicsTract and SynpExtractor offer a veritable opportunity for rapid and standardized phylogenetic analyses of omics data; their model can also be extended to next generation sequencing (NGS) data. We make OmicsTract and SynpExtractor publicly and freely available for non-commercial use in order to strengthen and build capacity for the phylogenetic paradigm of omics analysis. C1 [Salazar, Jose; Noursi, David; Abu-Asab, Mones] NEI, Immunopathol Sect, Immunol Lab, Bethesda, MD 20892 USA. [Amri, Hakima] Georgetown Univ, Med Ctr, Dept Biochem & Cellular & Mol Biol, Div Integrat Physiol, Washington, DC 20007 USA. RP Abu-Asab, M (reprint author), NEI, Immunopathol Sect, Immunol Lab, Bethesda, MD 20892 USA. EM mones@mail.nih.gov FU intramural program of the National Institutes of Health FX The research presented here was partially supported by the intramural program of the National Institutes of Health. NR 24 TC 4 Z9 4 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 EI 1557-8100 J9 OMICS JI OMICS PD AUG 1 PY 2015 VL 19 IS 8 BP 471 EP 477 DI 10.1089/omi.2015.0018 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CO9ZH UT WOS:000359535100005 PM 26230532 ER PT J AU Drozdovitch, V Minenko, V Golovanov, I Khrutchinsky, A Kukhta, T Kutsen, S Luckyanov, N Ostroumova, E Trofimik, S Voilleque, P Simon, SL Bouville, A AF Drozdovitch, Vladimir Minenko, Victor Golovanov, Ivan Khrutchinsky, Arkady Kukhta, Tatiana Kutsen, Semion Luckyanov, Nickolas Ostroumova, Evgenia Trofimik, Sergey Voilleque, Paul Simon, Steven L. Bouville, Andre TI Thyroid Dose Estimates for a Cohort of Belarusian Children Exposed to I-131 from the Chernobyl Accident: Assessment of Uncertainties SO RADIATION RESEARCH LA English DT Article ID MONTE-CARLO; RADIATION; CANCER; RECONSTRUCTION; DOSIMETRY; IODINE; POPULATION; REANALYSIS; BYELARUS; DISEASE AB Deterministic thyroid radiation doses due to iodine-131 (I-131) intake were reconstructed in a previous article for 11,732 participants of the Belarusian-American cohort study of thyroid cancer and other thyroid diseases in individuals exposed during childhood or adolescence to fallout from the Chernobyl accident. The current article describes an assessment of uncertainties in reconstructed thyroid doses that accounts for the shared and unshared errors. Using a Monte Carlo simulation procedure, 1,000 sets of cohort thyroid doses due to I-131 intake were calculated. The arithmetic mean of the stochastic thyroid doses for the entire cohort was 0.68 Gy. For two-thirds of the cohort the arithmetic mean of individual stochastic thyroid doses was less than 0.5 Gy. The geometric standard deviation of stochastic doses varied among cohort members from 1.33 to 5.12 with an arithmetic mean of 1.76 and a geometric mean of 1.73. The uncertainties in thyroid dose were driven by the unshared errors associated with the estimates of values of thyroid mass and of the I-131 activity in the thyroid of the subject; the contribution of shared errors to the overall uncertainty was small. These multiple sets of cohort thyroid doses will be used to evaluate the radiation risks of thyroid cancer and noncancer thyroid diseases, taking into account the structure of the errors in the dose estimates. (C) 2015 by Radiation Research Society C1 [Drozdovitch, Vladimir; Luckyanov, Nickolas; Ostroumova, Evgenia; Simon, Steven L.; Bouville, Andre] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Minenko, Victor; Khrutchinsky, Arkady; Kutsen, Semion; Trofimik, Sergey] Res Inst Nucl Problems, Minsk, Byelarus. [Golovanov, Ivan] Burnasyan Fed Med Biophys Ctr, Moscow, Russia. [Kukhta, Tatiana] United Inst Informat Problems, Minsk, Byelarus. [Voilleque, Paul] MJP Risk Assessment Inc, Denver, CO USA. RP Drozdovitch, V (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 9609 Med Ctr Dr,Room 7E548 MSC 9778, Bethesda, MD 20892 USA. EM drozdovv@mail.nih.gov RI Kuten, Semen/F-6699-2016 OI Kuten, Semen/0000-0003-0827-8421 FU National Institutes of Health, National Cancer Institute [HHSN261201000021C]; ISTC Project [B-488p]; NIAID [Y2-Al-5077]; NCI [Y3-CO-5117]; National Institute of Allergy and Infectious Diseases; National Cancer Institute FX This article is dedicated to the memory of the late Dr. Valeri Khrouch who contributed to the development of uncertainty analysis of thyroid doses in the cohort. Special thanks are extended to our colleagues who participated in the development and analysis of the parameters used for dose calculation at different stages of the study: Drs. Yury Gavrilin, Sergey Shinkarev (Moscow, Russia), Victor Averin (Gomel, Belarus), Yury Konstantinov (Sankt-Petersburg, Russia) and Nikolay Talerko (Kyiv, Ukraine). The authors thank Drs. Valentina Drozd and Olga Polyanskaya (Minsk, Belarus) for providing the information on stable iodine supplementation in Belarus from the 1970s-2000s. The authors would also like to thank the reviewers for their thoughtful and comprehensive input. This work was supported by: the National Institutes of Health, National Cancer Institute within the framework of the Belarus-U.S. Study of Thyroid Cancer and Other Disease Following the Chernobyl Accident (contract no. HHSN261201000021C); the ISTC Project no. B-488p; and the Intra-Agency Agreement between the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, NIAID agreement no. Y2-Al-5077 and NCI agreement no. Y3-CO-5117. NR 42 TC 4 Z9 4 U1 0 U2 6 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 2015 VL 184 IS 2 BP 203 EP 218 DI 10.1667/RR13791.1 PG 16 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA CP3IW UT WOS:000359773400009 PM 26207684 ER PT J AU Bittencourt, LK Litjens, G Hulsbergen-van de Kaa, CA Turkbey, B Gasparetto, EL Barentsz, JO AF Bittencourt, Leonardo Kayat Litjens, Geert Hulsbergen-van de Kaa, Christina A. Turkbey, Baris Gasparetto, Emerson Leandro Barentsz, Jelle O. TI Prostate Cancer: The European Society of Urogenital Radiology Prostate Imaging Reporting and Data System Criteria for Predicting Extraprostatic Extension by Using 3-T Multiparametric MR Imaging SO RADIOLOGY LA English DT Article ID RADICAL PROSTATECTOMY; MANAGEMENT; CONSENSUS; RISK AB Purpose: To retrospectively assess the use of the European Society of Urogenital Radiology (ESUR) Prostate Imaging Reporting and Data System (PI-RADS) criteria and 3-T multiparametric magnetic resonance (MR) imaging for detection of extraprostatic extension (EPE) of prostate cancer. Materials and Methods: The institutional review board approval requirement was waived. Consecutive patients with prostate cancer (n = 133) underwent 3-T multiparametric MR imaging before prostatectomy. Lesions were assessed by using ESUR/PI-RADS criteria for T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced imaging, and by using the sum of these scores. Zonal dominant parameters corresponding to the score of diffusion-weighted imaging for peripheral zone lesions and to T2-weighted imaging scores for transitional zone lesions were calculated. In addition, the presence of EPE in each patient was evaluated on the basis of subjective multiparametric MR imaging features. Histopathologic examination of whole-mount radical prostatectomy specimens was used as the reference standard. Sensitivity, specificity, positive predictive, and negative predictive values; likelihood ratios; and areas under the receiver operating characteristic curve were calculated for each parameter on the basis of its usefulness for prediction of EPE. Results: EPE was found in 60 of 133 (45%) patients. Receiver operating characteristic curve analysis for the prediction of EPE revealed an area under the curve of 0.72 for T2-weighted, 0.67 for diffusion-weighted, and 0.64 for dynamic contrast-enhanced imaging; 0.74 for the dominant parameter; and 0.74 for the sum of the PI-RADS scores, and a score of 5 was defined as the best threshold for the individual parameters, with a score greater than or equal to 13 as the threshold for the sum of the PI-RADS scores. By applying these thresholds, sensitivity, negative predictive value, and negative likelihood ratio (ruling out EPE) were 77%, 77%, and 0.36, respectively, and specificity, positive predictive value, and positive likelihood ratio (ruling in EPE) were 64%, 64%, and 2.15, respectively, for the dominant parameter. Feature analysis showed an area under the curve of 0.72; sensitivity, negative predictive value, and negative likelihood ratio of 63%, 72%, and 0.56, respectively, and specificity, positive predictive value, and positive likelihood ratio of 78%, 70%, and 3.77, respectively. Conclusion: ESUR/PI-RADS criteria showed moderate overall accuracy for use in the prediction of EPE, and these results were similar to those of multiparametric MR imaging assessment of features in this study sample. (C) RSNA, 2015 C1 [Bittencourt, Leonardo Kayat; Litjens, Geert; Hulsbergen-van de Kaa, Christina A.; Barentsz, Jelle O.] Radboud Univ Nijmegen, Med Ctr, Dept Radiol, NL-6525 ED Nijmegen, Netherlands. [Bittencourt, Leonardo Kayat; Gasparetto, Emerson Leandro] Ilha Fundao, Dept Radiol, BR-21941913 Rio De Janeiro, RJ, Brazil. [Bittencourt, Leonardo Kayat; Gasparetto, Emerson Leandro] Clin Diagnost Imagem CDPI, Dept Radiol, Rio De Janeiro, Brazil. [Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Bittencourt, LK (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Radiol, NL-6525 ED Nijmegen, Netherlands. EM lkayat@gmail.com RI Barentsz, Jelle/D-3515-2009; Hulsbergen-van de Kaa, C.A./L-4399-2015; Litjens, Geert/A-2319-2016 OI Litjens, Geert/0000-0003-1554-1291 FU ARRS FX L.K.B. disclosed no relevant relationships. G.L. disclosed no relevant relationships. C.A.H.v.d.K. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: payment for lectures from ARRS. Other relationships: disclosed no relevant relationships. B.T. disclosed no relevant relationships. E.L.G. disclosed no relevant relationships. J.O.B. disclosed no relevant relationships. NR 24 TC 4 Z9 4 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2015 VL 276 IS 2 BP 479 EP 489 DI 10.1148/radiol.15141412 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CP3QW UT WOS:000359796900017 ER PT J AU Grayson, PC Monach, PA Pagnoux, C Cuthbertson, D Carette, S Hoffman, GS Khalidi, NA Koening, CL Langford, CA Maksimowicz-McKinnon, K Seo, P Specks, U Ytterberg, SR Merkel, PA AF Grayson, Peter C. Monach, Paul A. Pagnoux, Christian Cuthbertson, David Carette, Simon Hoffman, Gary S. Khalidi, Nader A. Koening, Curry L. Langford, Carol A. Maksimowicz-McKinnon, Kathleen Seo, Philip Specks, Ulrich Ytterberg, Steven R. Merkel, Peter A. CA Vasculitis Clin Res Consortium TI Value of commonly measured laboratory tests as biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis SO RHEUMATOLOGY LA English DT Article DE vasculitis; eosinophilic granulomatosis with polyangiitis; Churg-Strauss syndrome; biomarker; eosinophil ID CHURG-STRAUSS-SYNDROME; TERM-FOLLOW-UP; VASCULITIS ACTIVITY SCORE; EOTAXIN-3; CYTOKINES; MARKER AB Objective. The aim of this study was to assess the clinical value of absolute eosinophil count, serum IgE, ESR and CRP as longitudinal biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA). Methods. Patients were selected from an observational EGPA cohort. Absolute eosinophil count, IgE, ESR and CRP were measured quarterly. Disease activity was defined by validated assessment tools. The association of tests with disease activity was assessed via regression models, adjusting for repeated measures and treatment status. Survival analysis was used to determine if laboratory tests were predictive of the 3 month future flare risk. Results. Seventy-four per cent of 892 study visits in 141 patients occurred while patients were on treatment, mostly during remission or mild disease activity, defined as a BVAS for Wegener's granulomatosis (BVAS/WG) of 1 or 2. Correlations between absolute eosinophil count, IgE, ESR and CRP were mostly low or non-significant (r = -0.08 to 0.44). There were few weak associations with disease activity [absolute eosinophil count: OR) 1.01/100U(95% CI 1.01, 1.02); ESR: OR 1.15/10 mg/l increase (95% CI 1.04, 1.27)]. When BVAS/WG >= 1 defined active disease, the absolute eosinophil count [hazard ratio (HR) 1.01/100U(95% CI 1.01, 1.02)] was weakly predictive of flare. When BVAS/WG >= 3 defined active disease, ESR was weakly predictive of flare [HR 1.52/10 mm/h increase (95% CI 1.17, 1.67)]. Conclusion. The absolute eosinophil count, IgE, ESR and CRP have limitations as longitudinal biomarkers of disease activity or predictors of flare in EGPA. These findings suggest that novel biomarkers of disease activity for EGPA are needed. C1 [Grayson, Peter C.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Monach, Paul A.] Boston Univ, Sch Med, Rheumatol Sect, Boston, MA 02215 USA. [Pagnoux, Christian; Carette, Simon] Mt Sinai Hosp, Div Rheumatol, Toronto, ON M5G 1X5, Canada. [Cuthbertson, David] Univ S Florida, Dept Biostat, Tampa, FL USA. [Hoffman, Gary S.; Langford, Carol A.] Cleveland Clin, Ctr Vasculitis Care & Res, Cleveland, OH 44106 USA. [Khalidi, Nader A.] McMaster Univ, Div Rheumatol, Hamilton, ON, Canada. [Koening, Curry L.] Univ Utah, Div Rheumatol, Salt Lake City, UT USA. [Maksimowicz-McKinnon, Kathleen] Univ Pittsburgh, Div Rheumatol, Pittsburgh, PA USA. [Seo, Philip] Johns Hopkins Univ, Div Rheumatol, Baltimore, MD USA. [Specks, Ulrich] Mayo Clin Med, Div Pulm & Crit Care Med, Rochester, MN USA. [Ytterberg, Steven R.] Mayo Clin, Coll Med, Div Rheumatol, Rochester, MN USA. [Merkel, Peter A.] Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. RP Merkel, PA (reprint author), Univ Penn, Div Rheumatol, 8th Floor Penn Tower,3400 Spruce St, Philadelphia, PA 19104 USA. EM pmerkel@upenn.edu RI Pagnoux, Christian/C-4612-2015 FU Vasculitis Clinical Research Consortium; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [U54 AR057319, U01 AR5187404]; National Center for Research Resources [U54 RR019497]; National Center for Advancing Translational Science; Office of Rare Diseases Research; Intramural Research Program at NIAMS FX This work was sponsored by the Vasculitis Clinical Research Consortium, which has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; U54 AR057319 and U01 AR5187404), the National Center for Research Resources (U54 RR019497), the National Center for Advancing Translational Science and the Office of Rare Diseases Research. This work was also supported through the Intramural Research Program at NIAMS. NR 23 TC 7 Z9 9 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD AUG PY 2015 VL 54 IS 8 BP 1351 EP 1359 DI 10.1093/rheumatology/keu427 PG 9 WC Rheumatology SC Rheumatology GA CP1WG UT WOS:000359667100004 PM 25406357 ER PT J AU Cantor, D AF Cantor, David TI Finding Historical Records at the National Institutes of Health SO SOCIAL HISTORY OF MEDICINE LA English DT Article DE National Institutes of Health; records; archives; access; preservation; destruction ID US BIOMEDICAL-RESEARCH; CONSENSUS DEVELOPMENT; NIH; POLITICS; PROGRAM; SCIENCE; OFFICE AB This paper provides a guide to finding historical records of the National Institutes of Health (NIH), the US biomedical research agency funded by the federal government, and one of the world's largest research funding bodies. Such records are important to an understanding of the development of medicine and biomedicine after the Second World War, yet they can be difficult to find in the organizational maze that is the NIH. This article provides information on where records might be found, the ways in which such records might be obtained, and how the NIH manages the vast quantity of records it produces. C1 NIH, Off Hist, Bethesda, MD 20892 USA. RP Cantor, D (reprint author), NIH, Off Hist, 1 Cloister Court,Suite 230, Bethesda, MD 20892 USA. EM cantord@mail.nih.gov NR 87 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0951-631X EI 1477-4666 J9 SOC HIST MED JI Soc. Hist. Med. PD AUG PY 2015 VL 28 IS 3 BP 617 EP 637 DI 10.1093/shm/hkv036 PG 21 WC History; History & Philosophy Of Science SC History; History & Philosophy of Science GA CP1KH UT WOS:000359634200010 ER PT J AU Sgambato, JA Park, TS Miller, D Panicker, LM Sidransky, E Lun, Y Awad, O Bentzen, SM Zambidis, ET Feldman, RA AF Sgambato, Judi A. Park, Tea Soon Miller, Diana Panicker, Leelamma M. Sidransky, Ellen Lun, Yu Awad, Ola Bentzen, Soren M. Zambidis, Elias T. Feldman, Ricardo A. TI Gaucher Disease-Induced Pluripotent Stem Cells Display Decreased Erythroid Potential and Aberrant Myelopoiesis SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Induced pluripotent stem cells; Hematopoiesis; Myeloid cells; Monocyte; Stem/progenitor cell; Hematopoietic stem cells; Erythropoiesis ID RED-BLOOD-CELLS; REGENERATIVE MEDICINE; DIFFERENTIATION; MODEL; ERYTHROPHAGOCYTOSIS; MACROPHAGES; PROGENITORS; EXPRESSION; GENERATION; MANAGEMENT AB Gaucher disease (GD) is the most common lysosomal storage disease resulting from mutations in the lysosomal enzyme glucocerebrosidase (GCase). The hematopoietic abnormalities in GD include the presence of characteristic Gaucher macrophages that infiltrate patient tissues and cytopenias. At present, it is not clear whether these cytopenias are secondary to the pathological activity of Gaucher cells or a direct effect of GCase deficiency on hematopoietic development. To address this question, we differentiated induced pluripotent stem cells (iPSCs) derived from patients with types 1, 2, and 3 GD to CD34(+)/CD45(+)/CD43(+)/CD143(+) hematopoietic progenitor cells (HPCs) and examined their developmental potential. The formation of GD-HPCs was unaffected. However, these progenitors demonstrated a skewed lineage commitment, with increased myeloid differentiation and decreased erythroid differentiation and maturation. Interestingly, myeloid colony-formation assays revealed that GD-HPCs, but not control-HPCs, gave rise to adherent, macrophage-like cells, another indication of abnormal myelopoiesis. The extent of these hematologic abnormalities correlated with the severity of the GCase mutations. All the phenotypic abnormalities of GD-HPCs observed were reversed by incubation with recombinant GCase, indicating that these developmental defects were caused by the mutated GCase. Our results show that GCase deficiency directly impairs hematopoietic development. Additionally, our results suggest that aberrant myelopoiesis might contribute to the pathological properties of Gaucher macrophages, which are central to GD manifestations. The hematopoietic developmental defects we observed reflect hematologic abnormalities in patients with GD, demonstrating the utility of GD-iPSCs for modeling this disease. C1 [Sgambato, Judi A.; Miller, Diana; Panicker, Leelamma M.; Lun, Yu; Awad, Ola; Feldman, Ricardo A.] Univ Maryland, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 USA. [Bentzen, Soren M.] Univ Maryland, Dept Epidemiol & Publ Hlth, Sch Med, Div Biostat & Bioinformat, Baltimore, MD 21201 USA. [Park, Tea Soon; Zambidis, Elias T.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Div Pediat Oncol, Baltimore, MD USA. [Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Feldman, RA (reprint author), Univ Maryland, Dept Microbiol & Immunol, Sch Med, 685 West Baltimore St,HSF-1,Room 380, Baltimore, MD 21201 USA. EM rfeldman@som.umaryland.edu RI Bentzen, Soren/E-3997-2012 OI Bentzen, Soren/0000-0002-7444-7564 FU Maryland Stem Cell Research Fund (MSCRF) [2009-MSCRFII-0082-00, 2007-MSCRFE-0110-00, 2011-MSCRF II-0008-00, 2007-MSCRF II-0379-00]; March of Dimes [6-FY10-334]; NIH/National Heart, Lung, and Blood Institute [U01HL099775]; MSCRF FX This work was supported by the Maryland Stem Cell Research Fund (MSCRF) (Grants 2009-MSCRFII-0082-00 and 2007-MSCRFE-0110-00 to R.A.F. and Grants 2011-MSCRF II-0008-00 and 2007-MSCRF II-0379-00 to E.T.Z.), the March of Dimes (Grant 6-FY10-334 to R.A.F.), and NIH/National Heart, Lung, and Blood Institute Grant U01HL099775 (to E.T.Z.). T.S.P. and O.A. are recipients of MSCRF postdoctoral fellowship grants. NR 49 TC 6 Z9 6 U1 0 U2 5 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD AUG PY 2015 VL 4 IS 8 BP 878 EP 886 DI 10.5966/sctm.2014-0213 PG 9 WC Cell & Tissue Engineering SC Cell Biology GA CO9QT UT WOS:000359511200004 PM 26062980 ER PT J AU Cora, MC Kooistra, L Travlos, G AF Cora, Michelle C. Kooistra, Linda Travlos, Greg TI Vaginal Cytology of the Laboratory Rat and Mouse: Review and Criteria for the Staging of the Estrous Cycle Using Stained Vaginal Smears SO TOXICOLOGIC PATHOLOGY LA English DT Review DE estrus; proestrus; diestrus; metestrus ID AGING C57BL-6J MICE; ALBINO-RAT; LENGTH; PROGESTERONE; WEIGHT; LIGHT AB Microscopic evaluation of the types of cells present in vaginal smears has long been used to document the stages of the estrous cycle in laboratory rats and mice and as an index of the functional status of the hypothalamic-pituitary-ovarian axis. The estrous cycle is generally divided into the four stages of proestrus, estrus, metestrus, and diestrus. On cytological evaluation, these stages are defined by the absence, presence, or proportion of 4 basic cell types as well as by the cell density and arrangement of the cells on the slide. Multiple references regarding the cytology of the rat and mouse estrous cycle are available. Many contemporary references and studies, however, have relatively abbreviated definitions of the stages, are in reference to direct wet mount preparations, or lack comprehensive illustrations. This has led to ambiguity and, in some cases, a loss of appreciation for the encountered nuances of dividing a steadily moving cycle into 4 stages. The aim of this review is to provide a detailed description, discussion, and illustration of vaginal cytology of the rat and mouse estrous cycle as it appears on smears stained with metachromatic stains. C1 [Cora, Michelle C.; Travlos, Greg] NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Kooistra, Linda] Charles River Labs Inc, Durham, NC USA. RP Cora, MC (reprint author), 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM coramc@niehs.nih.gov FU National Institutes of Health, 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 work was supported (in part) by the National Institutes of Health, National Institute of Environmental Health Sciences. NR 32 TC 13 Z9 15 U1 3 U2 11 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 2015 VL 43 IS 6 BP 776 EP 793 DI 10.1177/0192623315570339 PG 18 WC Pathology; Toxicology SC Pathology; Toxicology GA CO3WI UT WOS:000359091500003 PM 25739587 ER PT J AU Willson, CJ Herbert, RA Cline, JM AF Willson, Cynthia J. Herbert, Ronald A. Cline, J. Mark TI Hormone Receptor Expression in Spontaneous Uterine Adenocarcinoma in Fischer 344 Rats SO TOXICOLOGIC PATHOLOGY LA English DT Article DE endometrial adenocarcinoma; estrogen receptor; F344 rats; progesterone receptor; uterine neoplasms ID SPONTANEOUS ENDOMETRIAL ADENOCARCINOMA; ALPHA ER-ALPHA; PROGNOSTIC-SIGNIFICANCE; REPRODUCTIVE-TRACT; CANCER; CARCINOMA; BETA; TUMORS; CARCINOGENICITY; NEOPLASMS AB Most uterine cancers, the most common gynecological malignancies in women in developed countries, are hormone-dependent endometrial adenocarcinomas (EACs) that express estrogen and progesterone receptors. Although rat strains exist with a high spontaneous incidence of EAC, the Fischer 344 (F344) strain, previously one of the most commonly used strains in carcinogenicity testing, is not a high-incidence strain. To better understand the biology of this neoplasm, we assessed estrogen receptor (ER), progesterone receptor (PR), and Ki-67 expression using immunohistochemistry in spontaneous EAC in 18 F344 rats used as control animals in 2-year National Toxicology Program bioassays. Of the 18 tumors, 9 were well-differentiated and 9 were poorly differentiated. Most tumors, 7/18, were ER+PR+, as observed in women. Of the remainder, 6/18 were ER+PR-, 2/18 were ER-PR+, and 3/18 were ER-PR-. Well-differentiated tumors were ER+ (8/9) more often than poorly differentiated tumors (5/9). The percentage of ER+ tumors (72%) in rats was similar to that seen in women, but rats less frequently had PR+ (50%) tumors than women. The heterogeneous estrogen and progesterone receptor immunophenotypes observed in F344 rats in this study highlight the importance of evaluating hormone receptor expression in animal models used for chemical evaluations. C1 [Willson, Cynthia J.] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Herbert, Ronald A.] NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Cline, J. Mark] Wake Forest Sch Med, Dept Pathology, Comparat Med Sect, Winston Salem, NC 27157 USA. RP Cline, JM (reprint author), Wake Forest Sch Med, Dept Pathology, Comparat Med Sect, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jmcline@wakehealth.edu FU Silicones Environmental, Health, and Safety Council of North America; NIH [T32 OD010957]; 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 work was supported in part by the Silicones Environmental, Health, and Safety Council of North America; in part by NIH training grant T32 OD010957 (CJW); and in part by the NIH, National Institute of Environmental Health Sciences. NR 49 TC 0 Z9 0 U1 0 U2 1 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 2015 VL 43 IS 6 BP 865 EP 871 DI 10.1177/0192623315591839 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA CO3WI UT WOS:000359091500010 PM 26157037 ER PT J AU Hong, HHL Hoenerhoff, MJ Ton, TV Herbert, RA Kissling, GE Hooth, MJ Behl, M Witt, KL Smith-Roe, SL Sills, RC Pandiri, AR AF Hong, Hue-Hua L. Hoenerhoff, Mark J. Ton, Thai-Vu Herbert, Ronald A. Kissling, Grace E. Hooth, Michelle J. Behl, Mamta Witt, Kristine L. Smith-Roe, Stephanie L. Sills, Robert C. Pandiri, Arun R. TI Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal SO TOXICOLOGIC PATHOLOGY LA English DT Article DE animal models; lung; tumorigenesis ID OXIDATIVE DNA-DAMAGE; FACTOR-RECEPTOR GENE; HUMAN LUNG-CANCER; K-RAS; P53 MUTATIONS; COLORECTAL-CANCER; SIGNALING PATHWAY; MICE; ACTIVATION; TUMORS AB Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kirsten rat sarcoma oncogene homolog (Kras), epidermal growth factor receptor (Egfr), and tumor protein 53 (Tp53) mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD)-induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominant in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assay indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents. C1 [Hong, Hue-Hua L.; Hoenerhoff, Mark J.; Ton, Thai-Vu; Herbert, Ronald A.; Sills, Robert C.; Pandiri, Arun R.] NIEHS, Cellular & Mol Pathol Branch, Div Natl Toxicol Program NTP, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, NTP, Res Triangle Pk, NC 27709 USA. [Hooth, Michelle J.] NIEHS, Program Operat Branch, DNTP, Res Triangle Pk, NC 27709 USA. [Behl, Mamta] NIEHS, Toxicol Branch, NTP, Res Triangle Pk, NC 27709 USA. [Witt, Kristine L.; Smith-Roe, Stephanie L.] NIEHS, Biomol Screening Branch, NTP, Res Triangle Pk, NC 27709 USA. [Pandiri, Arun R.] Expt Pathol Labs Inc, Durham, NC USA. RP Pandiri, AR (reprint author), NIEHS, Cellular & Mol Pathol Branch, Div Natl Toxicol Program NTP, POB 12233, Res Triangle Pk, NC 27709 USA. EM pandiriak@niehs.nih.gov FU NIEHS, NIH FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Divisions of the National Toxicology Program and the Intramural Research Program at the NIEHS, NIH. We would like to thank the NIEHS DNA Sequencing Core for their technical expertise and the NTP tissue archives at the Experimental Pathology Laboratories, Inc. NR 58 TC 1 Z9 1 U1 1 U2 4 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 2015 VL 43 IS 6 BP 872 EP 882 DI 10.1177/0192623315581192 PG 11 WC Pathology; Toxicology SC Pathology; Toxicology GA CO3WI UT WOS:000359091500011 PM 26059825 ER PT J AU Mylne, AQN Pigott, DM Longbottom, J Shearer, F Duda, KA Messina, JP Weiss, DJ Moyes, CL Golding, N Hay, SI AF Mylne, Adrian Q. N. Pigott, David M. Longbottom, Joshua Shearer, Freya Duda, Kirsten A. Messina, Jane P. Weiss, Daniel J. Moyes, Catherine L. Golding, Nick Hay, Simon I. TI Mapping the zoonotic niche of Lassa fever in Africa SO TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE LA English DT Article DE Boosted regression trees; Lassa fever; LASV; Mastomys natalensis; Species distribution models; Viral haemorrhagic fever ID SPECIES DISTRIBUTION MODELS; VIRAL HEMORRHAGIC FEVERS; MARCH-APRIL 1972; VIRUS-DISEASE; SIERRA-LEONE; MASTOMYS-NATALENSIS; HOSPITAL EPIDEMIC; MANAGEMENT; TRANSMISSION; GUINEA AB Background: Lassa fever is a viral haemorrhagic illness responsible for disease outbreaks across West Africa. It is a zoonosis, with the primary reservoir species identified as the Natal multimammate mouse, Mastomys natalensis. The host is distributed across sub-Saharan Africa while the virus' range appears to be restricted to West Africa. The majority of infections result from interactions between the animal reservoir and human populations, although secondary transmission between humans can occur, particularly in hospital settings. Methods: Using a species distribution model, the locations of confirmed human and animal infections with Lassa virus (LASV) were used to generate a probabilistic surface of zoonotic transmission potential across sub-Saharan Africa. Results: Our results predict that 37.7 million people in 14 countries, across much of West Africa, live in areas where conditions are suitable for zoonotic transmission of LASV. Four of these countries, where at-risk populations are predicted, have yet to report any cases of Lassa fever. Conclusions: These maps act as a spatial guide for future surveillance activities to better characterise the geographical distribution of the disease and understand the anthropological, virological and zoological interactions necessary for viral transmission. Combining this zoonotic niche map with detailed patient travel histories can aid differential diagnoses of febrile illnesses, enabling a more rapid response in providing care and reducing the risk of onward transmission. C1 [Mylne, Adrian Q. N.; Longbottom, Joshua; Shearer, Freya; Moyes, Catherine L.; Golding, Nick; Hay, Simon I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Pigott, David M.; Duda, Kirsten A.; Messina, Jane P.; Weiss, Daniel J.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Hay, Simon I.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Mylne, AQN (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. EM adrian.mylne@well.ox.ac.uk; david.pigott@zoo.ox.ac.uk RI Hay, Simon/F-8967-2015; OI Golding, Nick/0000-0001-8916-5570; Longbottom, Joshua/0000-0002-4151-9031; Moyes, Catherine/0000-0002-8028-4079; Hay, Simon/0000-0002-0611-7272; Pigott, David/0000-0002-6731-4034 FU Bill & Melinda Gates Foundation [OPP1093011, OPP1068048]; Rhodes Trust; Department of Zoology; Wellcome Trust [0095066]; RAPIDD program of the Science & Technology Directorate; Department of Homeland Security; Fogarty International Center, National Institutes of Health; International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS, European Commission) [21803] FX AQNM, NG and CLM are funded by the Bill & Melinda Gates Foundation [OPP1093011]; FS is funded by a scholarship from the Rhodes Trust; DJW is funded by the Bill & Melinda Gates Foundation [OPP1068048]; DMP is funded by a Sir Richard Southwood Graduate Scholarship from the Department of Zoology; SIH is funded by a Senior Research Fellowship from the Wellcome Trust [0095066] that also supports KAD and JL, and a grant from the Bill & Melinda Gates Foundation [OPP1093011]. SIH would also like to acknowledge funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. JPM is funded by the International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS, European Commission 7th Framework Programme [#21803] http://www.idams.eu). NR 72 TC 10 Z9 10 U1 5 U2 31 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0035-9203 EI 1878-3503 J9 T ROY SOC TROP MED H JI Trans. Roy. Soc. Trop. Med. Hyg. PD AUG PY 2015 VL 109 IS 8 BP 483 EP 492 DI 10.1093/trstmh/trv047 PG 10 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CP1FW UT WOS:000359622700002 PM 26085474 ER PT J AU Messina, JP Pigott, DM Golding, N Duda, KA Brownstein, JS Weiss, DJ Gibson, H Robinson, TP Gilbert, M Wint, GRW Nuttall, PA Gething, PW Myers, MF George, DB Hay, SI AF Messina, Jane P. Pigott, David M. Golding, Nick Duda, Kirsten A. Brownstein, John S. Weiss, Daniel J. Gibson, Harry Robinson, Timothy P. Gilbert, Marius Wint, G. R. William Nuttall, Patricia A. Gething, Peter W. Myers, Monica F. George, Dylan B. Hay, Simon I. TI The global distribution of Crimean-Congo hemorrhagic fever SO TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE LA English DT Article DE Crimean-Congo hemorrhagic fever; Crimean-Congo hemorrhagic fever virus; Ecological niche modeling; Infectious diseases; Tick-borne diseases; Vector-borne diseases ID SPECIES DISTRIBUTION MODELS; HEALTH-CARE WORKERS; SPATIAL-DISTRIBUTION; PSEUDO-ABSENCES; VIRUS; DISEASE; RISK; EPIDEMIOLOGY; TRANSMISSION; AFRICA AB Background: Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne infection caused by a virus (CCHFV) from the Bunyaviridae family. Domestic and wild vertebrates are asymptomatic reservoirs for the virus, putting animal handlers, slaughter-house workers and agricultural labourers at highest risk in endemic areas, with secondary transmission possible through contact with infected blood and other bodily fluids. Human infection is characterized by severe symptoms that often result in death. While it is known that CCHFV transmission is limited to Africa, Asia and Europe, definitive global extents and risk patterns within these limits have not been well described. Methods: We used an exhaustive database of human CCHF occurrence records and a niche modeling framework to map the global distribution of risk for human CCHF occurrence. Results: A greater proportion of shrub or grass land cover was the most important contributor to our model, which predicts highest levels of risk around the Black Sea, Turkey, and some parts of central Asia. Sub-Saharan Africa shows more focalized areas of risk throughout the Sahel and the Cape region. Conclusions: These new risk maps provide a valuable starting point for understanding the zoonotic niche of CCHF, its extent and the risk it poses to humans. C1 [Messina, Jane P.; Pigott, David M.; Duda, Kirsten A.; Weiss, Daniel J.; Gibson, Harry; Wint, G. R. William; Nuttall, Patricia A.; Gething, Peter W.; Myers, Monica F.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Golding, Nick; Hay, Simon I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Brownstein, John S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Brownstein, John S.] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA USA. [Robinson, Timothy P.] Int Livestock Res Inst, LSE, Nairobi, Kenya. [Gilbert, Marius] Univ Libre Bruxelles, Biol Control & Spatial Ecol, Brussels, Belgium. [Gilbert, Marius] Fonds Natl Rech Sci, Brussels, Belgium. [George, Dylan B.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Hay, Simon I.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. RP Messina, JP (reprint author), Univ Oxford, Dept Zool, S Parks Rd, Oxford OX1 3PS, England. EM jane.messina@zoo.ox.ac.uk RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Pigott, David/0000-0002-6731-4034; Golding, Nick/0000-0001-8916-5570; Gething, Peter/0000-0001-6759-5449 FU Wellcome Trust [095066]; Bill & Melinda Gates Foundation [OPP1093011, OPP1068048, OPP1106023, OPP1053338]; International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS) [21803]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; UK Medical Research Council (MRC) [K00669X]; UK Department for International Development (DFID); National Library of Medicine; National Institutes of Health [5R01LM010812-05]; Department of Zoology at the University of Oxford; CGIAR Research Programme on the Humidtropics; CGIAR Research Programme on the Climate Change, Agriculture and Food Security (CCAFS); Agriculture for Nutrition and Health (A4NH) FX SIH is funded by a Senior Research Fellowship from the Wellcome Trust [#095066], which also supports AM and KAD, and a grant from the Bill & Melinda Gates Foundation [#OPP1093011]. JPM and SIH received funding from the International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS, [#21803], http://www.idams.eu). SIH would also like to acknowledge funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. PWG is a Career Development Fellow [#K00669X] jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and receives support from the Bill & Melinda Gates Foundation [#OPP1068048, #OPP1106023]. These grants also support DJW and HG. JSB is supported by a research grant from the National Library of Medicine, the National Institutes of Health [5R01LM010812-05]. DMP is funded by a Sir Richard Southwood Graduate Scholarship from the Department of Zoology at the University of Oxford. NG is funded by a grant from the Bill & Melinda Gates Foundation [#OPP1053338]. TPR is funded by the CGIAR Research Programmes on the Humidtropics, Climate Change, Agriculture and Food Security (CCAFS) and Agriculture for Nutrition and Health (A4NH). NR 87 TC 14 Z9 15 U1 5 U2 24 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0035-9203 EI 1878-3503 J9 T ROY SOC TROP MED H JI Trans. Roy. Soc. Trop. Med. Hyg. PD AUG PY 2015 VL 109 IS 8 BP 503 EP 513 DI 10.1093/trstmh/trv050 PG 11 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CP1FW UT WOS:000359622700004 PM 26142451 ER PT J AU Tang, YY Posner, MI Rothbart, MK Volkow, ND AF Tang, Yi-Yuan Posner, Michael I. Rothbart, Mary K. Volkow, Nora D. TI Circuitry of self-control and its role in reducing addiction SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID SHORT-TERM MEDITATION; ANTERIOR CINGULATE CORTEX; DRUG-ADDICTION; MINDFULNESS MEDITATION; THOUGHT SUPPRESSION; EMOTION REGULATION; DEVELOPING BRAIN; WORKING-MEMORY; PERSPECTIVE; ATTENTION AB We discuss the idea that addictions can be treated by changing the mechanisms involved in self-control with or without regard to intention. The core clinical symptoms of addiction include an enhanced incentive for drug taking (craving), impaired self-control (impulsivity and compulsivity), negative mood, and increased stress reactivity. Symptoms related to impaired self-control involve reduced activity in control networks including anterior cingulate (ACC), adjacent prefrontal cortex (mPFC), and striatum. Behavioral training such as mind-fulness meditation can increase the function of control networks and may be a promising approach for the treatment of addiction, even among those without intention to quit. C1 [Tang, Yi-Yuan] Texas Tech Univ, Dept Psychol Sci, Lubbock, TX 79409 USA. [Tang, Yi-Yuan; Posner, Michael I.; Rothbart, Mary K.] Univ Oregon, Dept Psychol, Eugene, OR 97403 USA. [Volkow, Nora D.] NIDA, NIH, Bethesda, MD 20892 USA. RP Tang, YY (reprint author), Texas Tech Univ, Dept Psychol Sci, Lubbock, TX 79409 USA. EM yiyuan.tang@ttu.edu; nvolkow@nida.nih.gov FU Office of Naval Research; National Institute of Child Health and Human Development FX This work was supported by the Office of Naval Research and the National Institute of Child Health and Human Development. NR 77 TC 17 Z9 17 U1 15 U2 55 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD AUG PY 2015 VL 19 IS 8 BP 439 EP 444 DI 10.1016/j.tics.2015.06.007 PG 6 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA CO9MH UT WOS:000359499400007 PM 26235449 ER PT J AU Sandrini, M Cohen, LG Censor, N AF Sandrini, Marco Cohen, Leonardo G. Censor, Nitzan TI Modulating reconsolidation: a link to causal systems-level dynamics of human memories SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID TRANSCRANIAL MAGNETIC STIMULATION; NONINVASIVE BRAIN-STIMULATION; POSTTRAUMATIC-STRESS-DISORDER; VERBAL EPISODIC MEMORY; DECLARATIVE MEMORY; PREFRONTAL CORTEX; PROTEIN-SYNTHESIS; FEAR MEMORIES; AUTOBIOGRAPHICAL MEMORIES; ENHANCES RECONSOLIDATION AB A vital property of the brain is its plasticity, which manifests as changes in behavioral performance. Invasive studies at the cellular level in animal models reveal time-restricted windows during which existing memories that are reactivated become susceptible to modification through reconsolidation, and evidence suggests similar effects in humans. In this review we summarize recent work utilizing noninvasive brain stimulation in humans to uncover the systems-level mechanisms underlying memory reconsolidation. This novel understanding of memory dynamics may have far-reaching clinical implications, including the potential to modulate reconsolidation in patients with memory disorders. C1 [Sandrini, Marco] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Sandrini, Marco; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Neurorehabilitat Sect, NIH, Bethesda, MD 20892 USA. [Censor, Nitzan] Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. [Censor, Nitzan] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. RP Censor, N (reprint author), Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. EM censornitzan@post.tau.ac.il RI Sandrini, Marco/J-2276-2014 OI Sandrini, Marco/0000-0002-1664-5722 FU US Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM) by Intramural Research Program of the NINDS-NIH (US); I-CORE program of the Planning and Budgeting Committee; Israel Science Foundation [51/11] FX This work was supported by funding from the US Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM) to M.S., by the Intramural Research Program of the NINDS-NIH (US) to L.G.C. and US., and by the I-CORE program of the Planning and Budgeting Committee and The Israel Science Foundation (grant 51/11) to N.C. NR 101 TC 6 Z9 8 U1 6 U2 27 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD AUG PY 2015 VL 19 IS 8 BP 475 EP 482 DI 10.1016/j.tics.2015.06.002 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA CO9MH UT WOS:000359499400011 PM 26170029 ER PT J AU Gorai, AK Tuluri, F Tchounwou, PB Shaw, N Jain, KG AF Gorai, Amit Kumar Tuluri, Francis Tchounwou, Paul B. Shaw, Neha Jain, Kumar Gourav TI Establishing the Association between Quarterly/Seasonal Air Pollution Exposure and Asthma Using Geospatial Approach SO AEROSOL AND AIR QUALITY RESEARCH LA English DT Article DE Air pollution; Asthma; Health; Texas State; GIS; Seasonal ID HOSPITAL ADMISSIONS; SUBTROPICAL CITY; RESPIRATORY-DISEASES; CHILDHOOD ASTHMA; SPATIAL-ANALYSIS; CASE-CROSSOVER; FUNGAL SPORES; MORTALITY; TAIWAN; TAIPEI AB Although it is known that air pollution may lead to increased asthma prevalence, no clear scientific evidence of direct association between air pollution and asthma rate has been reported. In the present study, a Geographical Information System (GIS) approach was developed to determine the association between asthma hospital discharge rate (ADR) and seasonal exposure to specific ambient air pollutants in eastern Texas, USA, during the period 2009 to 2011. Quarterly asthma data were obtained from Texas State Department of Health, National Asthma Survey surveillance of Texas State, USA. Quarterly mean concentrations of fine particular matter (PM2.5), nitrogen dioxide (NO2), and ozone (O-3) were determined from the corresponding measured daily data collected by various air quality monitoring stations distributed in different counties in the study area. Using Pearson correlation analysis, quarterly average of air pollutant concentrations was compared to quarterly Asthma discharge rate (ADR). The results revealed that the association between quarterly exposure of air pollution and ADR was not statistically significant in the study area. During the study period, a negative correlation coefficient was observed between the quarterly mean concentration of ozone and NO2 with the quarterly ADR. However, in most of the cases a positive correlation coefficient was observed between the quarterly mean concentration of PM2.5 and the quarterly ADR, indicating a probable association between ambient air pollution exposure and asthma prevalence. C1 [Gorai, Amit Kumar] Natl Inst Technol, Dept Min Engn, Rourkela 769008, Odisha, India. [Tuluri, Francis] Jackson State Univ, Dept Technol, Jackson, MS 39217 USA. [Tchounwou, Paul B.] Jackson State Univ, NIH NIMHD RCMI Ctr Environm Hlth, Jackson, MS 39217 USA. [Shaw, Neha; Jain, Kumar Gourav] Birla Inst Technol, Dept Civil & Environm Engn, Ranchi 835215, Bihar, India. RP Gorai, AK (reprint author), Natl Inst Technol, Dept Min Engn, Rourkela 769008, Odisha, India. EM amit_gorai@yahoo.co.uk; paul.b.tchounwou@jsums.edu FU UGC, New Delhi, India; DST, New Delhi [SR/FTP/ES-17/2012]; National Institutes of Health NIMHD through RCMI-Center for Environmental Health at Jackson State University [G12MD007581] FX This research work was carried out in part of the corresponding author's Raman Postdoctoral Fellowship awarded by UGC, New Delhi, India. Authors are also thankful to U.S. EPA for making air pollution data available on the website for public use, and to Texas State Department of Health for providing county-wise quarterly asthma data. The support from the DST, New Delhi Grant No. SR/FTP/ES-17/2012, and the National Institutes of Health NIMHD Grant No. G12MD007581 through the RCMI-Center for Environmental Health at Jackson State University, are also acknowledged. NR 45 TC 1 Z9 1 U1 5 U2 14 PU TAIWAN ASSOC AEROSOL RES-TAAR PI TAICHUNG COUNTY PA CHAOYANG UNIV TECH, DEPT ENV ENG & MGMT, PROD CTR AAQR, NO 168, JIFONG E RD, WUFONG TOWNSHIP, TAICHUNG COUNTY, 41349, TAIWAN SN 1680-8584 EI 2071-1409 J9 AEROSOL AIR QUAL RES JI Aerosol Air Qual. Res. PD AUG PY 2015 VL 15 IS 4 BP 1525 EP + DI 10.4209/aaqr.2014.09.0218 PG 21 WC Environmental Sciences SC Environmental Sciences & Ecology GA CO2PQ UT WOS:000358999400034 ER PT J AU Bier, DM Allison, DB Alpers, DH Astrup, A Cashman, KD Coates, PM Fukagawa, NK Klurfeld, DM Mattes, RD Uauy, R AF Bier, Dennis M. Allison, David B. Alpers, David H. Astrup, Arne Cashman, Kevin D. Coates, Paul M. Fukagawa, Naomi K. Klurfeld, David M. Mattes, Richard D. Uauy, Ricardo TI Introduction to the series "Best (but Oft-Forgotten) Practices" SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID REPRODUCIBILITY C1 [Bier, Dennis M.] Baylor Coll Med, Dept Pediat, USDA, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Allison, David B.] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL USA. [Alpers, David H.] Washington Univ, Sch Med, St Louis, MO USA. [Astrup, Arne] Univ Copenhagen, Dept Nutr Exercise & Sports, Copenhagen, Denmark. [Cashman, Kevin D.] Natl Univ Ireland Univ Coll Cork, Sch Food & Nutr Sci, Cork, Ireland. [Coates, Paul M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Fukagawa, Naomi K.] Univ Vermont, Coll Med, Burlington, VT USA. [Klurfeld, David M.] ARS, Off Natl Programs, USDA, Beltsville, MD USA. [Mattes, Richard D.] Purdue Univ, Dept Foods & Nutr, W Lafayette, IN 47907 USA. [Uauy, Ricardo] London Sch Hyg & Trop Med, London WC1, England. RP Bier, DM (reprint author), Baylor Coll Med, Dept Pediat, USDA, Childrens Nutr Res Ctr, Houston, TX 77030 USA. EM dbier@bcm.edu NR 6 TC 0 Z9 0 U1 0 U2 3 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 PY 2015 VL 102 IS 2 BP 239 EP 240 DI 10.3945/ajcn.115.117697 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CO3DW UT WOS:000359037800003 PM 26178729 ER PT J AU Beyerlein, A Liu, X Uusitalo, UM Harsunen, M Norris, JM Foterek, K Virtanen, SM Rewers, MJ She, JX Simell, O Lernmark, A Hagopian, W Akolkar, B Ziegler, AG Krischer, JP Hummel, S AF Beyerlein, Andreas Liu, Xiang Uusitalo, Ulla M. Harsunen, Minna Norris, Jill M. Foterek, Krishna Virtanen, Suvi M. Rewers, Marian J. She, Jin-Xiong Simell, Olli Lernmark, Ake Hagopian, William Akolkar, Beena Ziegler, Anette-G Krischer, Jeffrey P. Hummel, Sandra CA TEDDY Study Grp TI Dietary intake of soluble fiber and risk of islet autoimmunity by 5 y of age: results from the TEDDY study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE TEDDY study; soluble fiber; diet; autoimmunity; type 1 diabetes ID GUT MICROBIOTA; INTESTINAL MICROBIOME; CHILDREN; DISEASE; EUROPE; HEALTH; TRENDS; FOOD AB Background: Deficient soluble fiber intake has been suggested to dysregulate the immune response either directly or through alterations of the microbial composition in the gut. Objective: We hypothesized that a high intake of dietary soluble fiber in early childhood decreases the risk of type 1 diabetes (T1D)-associated islet autoimmunity. Design: We analyzed 17,620 food records collected between age 9 and 48 mo from 3358 children from the United States and Germany prospectively followed in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. HRs for the development of any/multiple islet autoantibodies (242 and 151 events, respectively) and T1D (71 events) by soluble fiber intake were calculated in Cox regression models and adjusted for potential confounders. Results: There were no statistically significantly protective associations observed between a high intake of soluble fiber and islet autoimmunity or T1D. For example, the adjusted HRs (95% CIs) for high intake (highest compared with lowest quintile) at age 12 mo were 0.90 (0.55, 1.45) for any islet autoantibody, 1.20 (0.69, 2.11) for multiple islet autoantibodies, and 1.24 (0.57, 2.70) for T1D. In analyzing soluble fiber intake as a time-varying covariate, there were also no short-term associations between soluble fiber intake and islet autoimmunity development, with adjusted HRs of 0.85 (0.51, 1.42) for high intake and development of any islet autoantibody, for example. Conclusion: These results indicate that the intake level of dietary soluble fiber is not associated with islet autoimmunity or T1D in early life. C1 [Beyerlein, Andreas; Harsunen, Minna; Ziegler, Anette-G; Hummel, Sandra] Helmholtz Zentrum Munchen, Diabet Res Inst, Munich, Germany. [Liu, Xiang; Uusitalo, Ulla M.; Krischer, Jeffrey P.] Univ S Florida, Dept Pediat, Pediat Epidemiol Ctr, Morsani Coll Med, Tampa, FL 33620 USA. [Norris, Jill M.; Rewers, Marian J.] Univ Colorado, Colorado Sch Publ Hlth, Aurora, CO USA. [Foterek, Krishna] Res Inst Child Nutr, Dortmund, Germany. [Virtanen, Suvi M.] Natl Inst Hlth & Welf, Unit Nutr, Helsinki, Finland. [Virtanen, Suvi M.] Univ Tampere, Sch Hlth Sci, FIN-33101 Tampere, Finland. [Virtanen, Suvi M.] Univ Tampere, Ctr Child Hlth Res, FIN-33101 Tampere, Finland. [Virtanen, Suvi M.] Tampere Univ Hosp, Tampere, Finland. [Virtanen, Suvi M.] Sci Ctr Pirkanmaa Hosp Dist, Tampere, Finland. [She, Jin-Xiong] Georgia Regents Univ, Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA USA. [Simell, Olli] Univ Turku, Dept Pediat, Turku, Finland. [Lernmark, Ake] Lund Univ, Dept Clin Sci, Clin Res Ctr, Skane Univ Hosp SUS, Malmo, Sweden. [Hagopian, William] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Akolkar, Beena] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. RP Beyerlein, A (reprint author), Helmholtz Zentrum Munchen, Diabet Res Inst, Munich, Germany. EM andreas.beyerlein@helmholtz-muenchen.de FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, HHSN267200700014C]; National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Juvenile Diabetes Research Foundation; CDC; NIH/National Center for Advancing Translational Sciences Clinical and Translational Science Awards [UL1 TR000064]; University of Colorado [UL1 TR001082] FX Supported by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, and UC4 DK100238 and contract no. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, Juvenile Diabetes Research Foundation, and CDC. This work was supported in part by the NIH/National Center for Advancing Translational Sciences Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR001082). NR 30 TC 3 Z9 3 U1 1 U2 3 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 PY 2015 VL 102 IS 2 BP 345 EP 352 DI 10.3945/ajcn.115.108159 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CO3DW UT WOS:000359037800015 PM 26156735 ER PT J AU Sanghvi, A Redman, LM Martin, CK Ravussin, E Hall, KD AF Sanghvi, Arjun Redman, Leanne M. Martin, Corby K. Ravussin, Eric Hall, Kevin D. TI Validation of an inexpensive and accurate mathematical method to measure long-term changes in free-living energy intake SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE caloric restriction; dietary assessment; energy balance; energy intake; mathematical modeling; weight loss ID DOUBLY-LABELED WATER; GE LUNAR IDXA; BODY-COMPOSITION; WEIGHT-LOSS; METABOLIC ADAPTATION; CALORIE RESTRICTION; HUMANS; ADULTS; EXPENDITURE; PRECISION AB Background: Accurate measurement of free-living energy intake (El) over long periods is imperative for understanding obesity and its treatment. Unfortunately, traditional methods rely on self-report and are notoriously inaccurate. Although El can be indirectly estimated by the intake-balance method, this technique is prohibitively labor-intensive and expensive, requiring repeated measures of energy expenditure via doubly labeled water (DLW) along with multiple dual-energy X-ray absorptiometry (DXA) scans to measure changes in body energy stores. Objective: Our objective was to validate a mathematical method to measure long-term changes in free-living energy intake. Design: We measured body weight and El changes (Delta EI) over 4 time intervals by using the intake-balance method in 140 individuals who underwent 2 y of caloric restriction as part of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy study. We compared the Delta EI values calculated by using DLW/DXA with those obtained by using a mathematical model of human metabolism whose only inputs were the initial demographic information and repeated body weight data. Results: The mean Delta EI values calculated by the model were within 40 kcal/d of the DLW/DXA method throughout the 2-y study. For individual subjects, the overall root mean square deviation between the model and DLW/DXA method was 215 kcal/d, and most of the model-calculated Delta EI values were within 132 kcal/d of the DLW/DXA method. Conclusions: Accurate and inexpensive estimates of Delta EI that are comparable to the DLW/DXA method can be obtained by using a mathematical model and repeated body weight measurements. This trial was registered at clinicaltrials.gov as NCT00427193. C1 [Sanghvi, Arjun; Hall, Kevin D.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. [Redman, Leanne M.; Martin, Corby K.; Ravussin, Eric] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. RP Hall, KD (reprint author), Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov FU Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases; NORC Center Grant [P30DK072476]; NIH [P30DK072476, U01AG022132, U01AG020478, U01AG020487, U01AG020480] FX Supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases, and by NORC Center Grant P30DK072476. The CALERIE project was funded by NIH grants U01AG022132, U01AG020478, U01AG020487, U01AG020480, and P30DK072476. NR 29 TC 9 Z9 9 U1 0 U2 5 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2015 VL 102 IS 2 BP 353 EP 358 DI 10.3945/ajcn.115.111070 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CO3DW UT WOS:000359037800016 PM 26040640 ER PT J AU Hara, S Kobayashi, N Sakamoto, K Ueno, T Manabe, S Takashima, Y Hamada, J Pastan, I Fukamizu, A Matsusaka, T Nagata, M AF Hara, Satoshi Kobayashi, Namiko Sakamoto, Kazuo Ueno, Toshiharu Manabe, Shun Takashima, Yasutoshi Hamada, Jun Pastan, Ira Fukamizu, Akiyoshi Matsusaka, Taiji Nagata, Michio TI Podocyte Injury-Driven Lipid Peroxidation Accelerates the Infiltration of Glomerular Foam Cells in Focal Segmental Glomerulosclerosis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; MONOCYTE CHEMOATTRACTANT PROTEIN-1; SMOOTH-MUSCLE-CELLS; RENAL INJURY; PATHOLOGICAL CLASSIFICATION; ENDOTHELIAL-CELLS; MASS-SPECTROMETRY; APOLIPOPROTEIN-E; UP-REGULATION; LYSOPHOSPHATIDYLCHOLINE AB Intracapillary foam cell infiltration with podocyte alterations is a characteristic pathology of focal segmental glomerulosclerosis (FSGS). We investigated the possible role of podocyte injury in glomerular macrophage and foam cellinfiltration in a podocyte-selective injury model (NEP25 mice) and hypercholesterolemic model [low-density lipoprotein receptor deficiency (LDLR-/-) mice] with doxorubicin induced nephropathy. Acute podocyte selective injury atone failed to induce glomerular macrophages in the NEP25 mice. However, in the doxorubicin-treated hypercholesterolemic LDLR-/- mice, glomerular macrophages/foam cells significantly increased and were accompanied by lipid deposition and the formation and ingestion of oxidized phospholipids (oxPLs). Glomerular macrophages significantly correlated with the amount of glomerular oxPL. The NEP25/LDLR-/- mice exhibited severe hypercholesterolemia, glomerular lipid deposition, and renal dysfunction. Imaging mass spectrometry revealed that a major component of oxidized low-density Lipoprotein, lysophosphatidylcholine 16:0 and 18:0, was present only in the glomeruli of NEP25/LDLR-/- mice. Lysophosphatidylcholine 16:0 stimulated mesangial cells and macrophages, and lysophosphatidylchotine 18:0 stimulated glomerular endothelial cells to express adhesion molecules and chemokines, promoting macrophage adhesion and migration in vitro. In human FSGS, glomerular macrophage-derived foam cells contained oxPLs accompanied by the expression of chemokines in the tuft. In conclusion, glomerular lipid modification represents a novel pathology by podocyte injury, promoting FSGS. Podocyte injury-driven Lysophosphatidylcholine de novo accelerated glomerular macrophage derived foam cell infiltration via lysophosphatidylcholine-mediated expression of adhesion molecules and chemokines in glomerular resident cells. C1 [Hara, Satoshi; Kobayashi, Namiko; Sakamoto, Kazuo; Ueno, Toshiharu; Manabe, Shun; Takashima, Yasutoshi; Nagata, Michio] Univ Tsukuba, Dept Kidney & Vasc Pathol, Grad Sch Life & Environm Sci, Tsukuba Adv Res Alliance, Tsukuba, Ibaraki 3058575, Japan. [Hamada, Jun; Fukamizu, Akiyoshi] Univ Tsukuba, Fac Med, Grad Sch Life & Environm Sci, Tsukuba Adv Res Alliance, Tsukuba, Ibaraki 3058575, Japan. [Hamada, Jun; Fukamizu, Akiyoshi] Univ Tsukuba, Life Sci Ctr, Grad Sch Life & Environm Sci, Tsukuba Adv Res Alliance, Tsukuba, Ibaraki 3058575, Japan. [Hara, Satoshi] Kanazawa Grad Sch Med, Dept Internal Med, Div Rheumatol, Kanazawa, Ishikawa, Japan. [Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Matsusaka, Taiji] Tokai Univ, Sch Med, Dept Internal Med, Inst Med Sci, Isehara, Kanagawa 25911, Japan. RP Nagata, M (reprint author), Univ Tsukuba, Fac Med, Dept Kidney & Vasc Pathol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan. EM nagatam@md.tsukuba.ac.jp FU NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research; Japan Society for the Promotion of Science [22590877, 26461210]; Ministry of Health, Labor, and Welfare of Japan Progressive Renal Disease Research FX Supported by the NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research (I.P.), Japan Society for the Promotion of Science grants in aid for scientific research projects 22590877 and 26461210, and Ministry of Health, Labor, and Welfare of Japan Progressive Renal Disease Research. NR 56 TC 4 Z9 4 U1 0 U2 3 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 2015 VL 185 IS 8 BP 2118 EP 2131 DI 10.1016/j.ajpath.2015.04.007 PG 14 WC Pathology SC Pathology GA CO3YD UT WOS:000359096300006 PM 26072030 ER PT J AU Thakur, S Viswanadhapalli, S Kopp, JB Shi, Q Barnes, JL Block, K Gorin, Y Abboudt, HE AF Thakur, Sachin Viswanadhapalli, Suryavathi Kopp, Jeffrey B. Shi, Qian Barnes, Jeffrey L. Block, Karen Gorin, Yves Abboudt, Hanna E. TI Activation of AMP-Activated Protein Kinase Prevents TGF-beta 1-Induced Epithelial-Mesenchymal Transition and Myofibroblast Activation SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID MESANGIAL MATRIX EXPANSION; MESSENGER-RNA TRANSLATION; NITRIC-OXIDE SYNTHASE; GROWTH-FACTOR; TRANSFORMING GROWTH-FACTOR-BETA-1; FIBRONECTIN EXPRESSION; DIABETIC-NEPHROPATHY; RENAL-INSUFFICIENCY; METABOLIC SYNDROME; GENE-EXPRESSION AB Transforming growth factor (TGF)-beta contributes to tubulointerstitial fibrosis. We investigated the mechanism by which TGF-beta exerts its profibrotic effects and specifically the role of AMP-activated protein kinase (AMPK) in kidney tubular epithelial cells and interstitial fibroblasts. In proximal tubular epithelial cells, TGF-beta 1 treatment causes a decrease in AMPK phosphorylation and activation together with increased fibronectin and a-smooth muscle actin expression and decreased in E-cadherin. TGF-beta 1 causes similar changes in interstitial fibroblasts. Activation of AMPK with 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside, metformin, or overexpression of constitutively active AMPK markedly attenuated TGF-beta 1 functions. Conversely, inhibition of AMPK with adenine 9-beta-D-arabinofuranoside or siRNA-mediated knockdown of AMPK (official name PRKAA1) mimicked the effect of TGF-beta 1 and enhanced basal and TGF-beta 1 induced phenotypic changes. Importantly, we found that tuberin contributed to the protective effects of AMPK and that TGF-beta 1 promoted cell injury by blocking AMPK-mediated tuberin phosphorylation and activation. In the kidney cortex of TGF-beta transgenic mice, the significant decrease in AMPK phosphorylation and tuberin phosphorylation on its AMPK-dependent activating site was associated with an increase in mesenchymal markers and a decrease in E-cadherin. Collectively, the data indicate that TGF-beta exerts its profibrotic action in vitro and in vivo via inactivation of AMPK. AMPK and tuberin activation prevent tubulointerstitial injury induced by TGF-beta. Activators of AMPK provide potential therapeutic strategy to prevent kidney fibrosis and progressive kidney disease. C1 [Thakur, Sachin; Viswanadhapalli, Suryavathi; Shi, Qian; Barnes, Jeffrey L.; Block, Karen; Gorin, Yves; Abboudt, Hanna E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. [Block, Karen; Abboudt, Hanna E.] South Texas Vet Healthcare Syst, Audie L Murphy Mem Hosp Div, San Antonio, TX USA. RP Viswanadhapalli, S (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Nephrol, MC 7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM viswanadhapa@uthscsa.edu FU Veterans Administration [1I01BX001815-01A1]; NIH [RO-1 DK033665, RO1 DK 079996]; NIH/National Institute of Diabetes and Digestive and Kidney Diseases; Juvenile Diabetes Research Foundation FX Supported by Merit Review grant 1I01BX001815-01A1 from the Veterans Administration (H.E.A. and J.L.B.), NIH grants RO-1 DK033665 (H.E.A., K.B., and Y.G.) and RO1 DK 079996 (Y.G.), and the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program (J.B.K.). Q.S. is supported by a fellowship grant from the Juvenile Diabetes Research Foundation. NR 47 TC 9 Z9 12 U1 2 U2 12 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 2015 VL 185 IS 8 BP 2168 EP 2180 DI 10.1016/j.ajpath.2015.04.014 PG 13 WC Pathology SC Pathology GA CO3YD UT WOS:000359096300010 PM 26071397 ER PT J AU Yang, J Cusimano, A Monga, JK Preziosi, ME Pullara, F Calero, G Lang, R Yamaguchi, TP Nejak-Bowen, KN Monga, SP AF Yang, Jing Cusimano, Antonella Monga, Jappmann K. Preziosi, Morgan E. Pullara, Filippo Calero, Guillermo Lang, Richard Yamaguchi, Terry P. Nejak-Bowen, Kari N. Monga, Satdarshan P. TI WNT5A Inhibits Hepatocyte Proliferation and Concludes beta-Catenin Signaling in Liver Regeneration SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; MOUSE HEPATOCYTES; PROTEIN; CELLS; CARCINOMA; PATHWAY; KINASE; MICE; HOMEOSTASIS; ACTIVATION AB Activation of Wnt/beta-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when hepatocyte proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless (Wls-LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls. This coincided with increased beta-catenin T-cell factor 4 interaction and cyclin-D1 expression. Wls-LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in beta-catenin T-cell factor activity, cyclin-D1 expression, and cell proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression. In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of beta-catenin signaling and hepatocyte proliferation, both in vitro and in vivo. We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses beta-catenin signaling in hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process. C1 [Yang, Jing; Cusimano, Antonella; Monga, Jappmann K.; Preziosi, Morgan E.; Nejak-Bowen, Kari N.; Monga, Satdarshan P.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA. [Pullara, Filippo; Calero, Guillermo] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15261 USA. [Monga, Satdarshan P.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15261 USA. [Cusimano, Antonella; Pullara, Filippo] Ri MED Fdn, Palermo, Italy. [Cusimano, Antonella] CNR, Inst Biomed & Mol Immunol Alberto Monroy, Palermo, Italy. [Lang, Richard] Cincinnati Childrens Hosp Med Ctr, Visual Syst Grp, Cincinnati, OH 45229 USA. [Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. RP Monga, SP (reprint author), Univ Pittsburgh, Sch Med, Dept Pathol, 200 Lothrop St,Rm S-422 BST, Pittsburgh, PA 15261 USA. EM smonga@pitt.edu FU NIH [1R01DK62277, 1R01DK100287]; Endowed Chair for Experimental Pathology; Ri.MED grant FX Supported by NIH grants 1R01DK62277 and 1R01DK100287 and Endowed Chair for Experimental Pathology (S.P.M.) and Ri.MED grant (A.C.). NR 36 TC 3 Z9 4 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2015 VL 185 IS 8 BP 2194 EP 2205 DI 10.1016/j.ajpath.2015.04.021 PG 12 WC Pathology SC Pathology GA CO3YD UT WOS:000359096300012 PM 26100214 ER PT J AU Song, WF Yu, ZH Doran, SF Ambalavanan, N Steele, C Garantziotis, S Matalon, S AF Song, Weifeng Yu, Zhihong Doran, Stephen F. Ambalavanan, Namasivayam Steele, Chad Garantziotis, Stavros Matalon, Sadis TI Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE flexiVent; methacholine; bronchoalveolar lavage; cytokines; inflammatory cells ID ALVEOLAR FLUID CLEARANCE; EPITHELIAL NA+ CHANNELS; LUNG INJURY; INHIBITION; GAS; INFLAMMATION; INHALATION; EXPOSURE; MICE; HYALURONAN AB Exposure to chlorine (Cl-2) damages airway and alveolar epithelia resulting in acute lung injury and reactive airway hyperresponsiveness (AHR) to methacholine. However, little is known about the effect of preexisting respiratory disease on Cl-2-induced lung injury. By using a murine respiratory syncytial virus (RSV) infection model, we found that preexisting RSV infection increases Cl-2 (187 ppm for 30 min)-induced lung inflammation and airway AHR at 24 h after exposure (5 days after infection). RSV infection and Cl-2 exposure synergistically induced oxygen desaturation and neutrophil infiltration and increased MCP-1, MIP-1 beta, IL-10, IFN-gamma, and RANTES concentrations in the bronchoalveolar lavage fluid (BALF). In contrast, levels of type 2 cytokines (i.e., IL-4, IL-5, IL-9, and IL-13) were not significantly affected by either RSV infection or Cl-2 exposure. Cl-2 exposure, but not RSV infection, induced AHR to methacholine challenge as measured by flexiVent. Moreover, preexisting RSV infection amplified BALF levels of hyaluronan (HA) and AHR. The Cl-2-induced AHR was mitigated by treatment with inter-alpha-trypsin inhibitor antibody, which inhibits HA signaling, suggesting a mechanism of HA-mediated AHR from exacerbated oxidative injury. Our results show for the first time that preexisting RSV infection predisposes the lung to Cl-2-induced injury. These data emphasize the necessity for further research on the effects of Cl-2 in vulnerable populations and the development of appropriate treatments. C1 [Song, Weifeng; Yu, Zhihong; Doran, Stephen F.; Matalon, Sadis] Univ Alabama Birmingham, Sch Med, Dept Anesthesiol, Birmingham, AL USA. [Ambalavanan, Namasivayam] Univ Alabama Birmingham, Sch Med, Dept Pediat Neonatol, Birmingham, AL USA. [Steele, Chad] Univ Alabama Birmingham, Sch Med, Dept Med Pulm Crit Care & Sleep, Birmingham, AL USA. [Steele, Chad] Univ Alabama Birmingham, Sch Med, Pulm Injury & Repair Ctr, Birmingham, AL USA. [Garantziotis, Stavros] NIEHS, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. RP Matalon, S (reprint author), BMR 2 224,901 19th St South, Birmingham, AL 35205 USA. EM sadis@uab.edu RI Garantziotis, Stavros/A-6903-2009; OI Garantziotis, Stavros/0000-0003-4007-375X; Ambalavanan, Namasivayam/0000-0003-0731-9092 FU CounterACT Program, National Institutes of Health Office of the Director (NIH OD), and the National Institute of Neurological Disorders and Stroke (NINDS) [5U01ES015676, 3U54ES017218, 5R21 ES024027 02, 1R21ES025423 01]; FAER research fellowship grant; Division of Intramural Research, National Institute of Environmental Health Sciences, NIH FX This research was supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD), and the National Institute of Neurological Disorders and Stroke (NINDS), Grant numbers 5U01ES015676, 3U54ES017218, 5R21 ES024027 02, and 1R21ES025423 01, and the Division of Intramural Research, National Institute of Environmental Health Sciences, NIH (S. Garantziotis). W. Song is the recipient of a FAER research fellowship grant. NR 42 TC 1 Z9 1 U1 0 U2 1 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 2015 VL 309 IS 3 BP L205 EP L210 DI 10.1152/ajplung.00159.2015 PG 6 WC Physiology; Respiratory System SC Physiology; Respiratory System GA CO1WA UT WOS:000358945600001 PM 26071553 ER PT J AU Leelahavanichkul, A Somparn, P Bootprapan, T Tu, HB Tangtanatakul, P Nuengjumnong, R Worasilchai, N Tiranathanagul, K Eiam-Ong, S Levine, M Chinampon, A Srisawat, N AF Leelahavanichkul, Asada Somparn, Poorichaya Bootprapan, Tanabodee Tu, Hongbin Tangtanatakul, Pattarin Nuengjumnong, Ratchanok Worasilchai, Navaporn Tiranathanagul, Khajohn Eiam-Ong, Somchai Levine, Mark Chinampon, Ariya Srisawat, Nattachai TI High-dose ascorbate with low-dose amphotericin B attenuates severity of disease in a model of the reappearance of candidemia during sepsis in the mouse SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE Candida albicans; ascorbate; sepsis; amphotericin B ID ACUTE KIDNEY INJURY; BLOOD-STREAM INFECTIONS; VITAMIN-C; SKELETAL-MUSCLE; ATTRIBUTABLE MORTALITY; SYSTEMIC CANDIDIASIS; HYDROGEN-PEROXIDE; CECAL LIGATION; AIDS PATIENTS; HOST-DEFENSE AB Amphotericin B (Ampho B) is a fungicidal drug that causes cell wall injury. Pharmacological ascorbate induces the extracellular prooxidants, which might enter the Ampho B-induced cell wall porosity and act synergistically. We tested low-dose Ampho B with a short course of pharmacological ascorbate using a mouse model of sepsis preconditioned with an injection of Candida albicans 6 h prior to cecal ligation and puncture (CLP). In this model, candidemia reappeared as early as 6 h after CLP with a predictably high mortality rate. This characteristic mimics sepsis in the phase of immunosuppression in patients. Using the model, at 12- and 18-h post-CLP, we administered isotonic (pH neutralized) pharmacological ascorbate intravenously with low-dose Ampho B or sodium deoxycholate, vehicle- controlled, administered IP. The survival rate of low-dose Ampho B plus ascorbate was 53%, compared with <11% for low-dose Ampho B or high-dose Ampho B alone. In addition, a beneficial effect was demonstrated in terms of kidney damage, liver injury, spleen histopathology, and serum markers at 24 h after CLP. Kidney injury was less severe in low-dose Ampho B plus ascorbate combination therapy due to less severe sepsis. Moreover, ascorbate enhanced the effectiveness of phagocytosis against C. albicans in human phagocytic cells. Taken together, the data indicate that the new mouse model simulates sepsis-induced immunosuppression and that the combination of pharmacological ascorbate with an antifungal drug is a potentially effective treatment that may reduce nephrotoxicity, and perhaps also increase fungicidal activity in patients with systemic candidiasis caused by Candida albicans. C1 [Leelahavanichkul, Asada; Bootprapan, Tanabodee; Tangtanatakul, Pattarin; Worasilchai, Navaporn; Chinampon, Ariya] Chulalongkorn Univ, Dept Microbiol, Bangkok 10330, Thailand. [Leelahavanichkul, Asada; Nuengjumnong, Ratchanok] Chulalongkorn Univ, Fac Med, Dept Microbiol, Ctr Excellence Immunol & Immune Mediated Dis, Bangkok 10330, Thailand. [Leelahavanichkul, Asada; Nuengjumnong, Ratchanok] Chulalongkorn Univ, Fac Dent, STAR Craniofacial & Skeletal Disorders, Bangkok 10330, Thailand. [Somparn, Poorichaya] Chulalongkorn Univ, Dept Med, Res Affairs, Bangkok 10330, Thailand. [Tu, Hongbin; Levine, Mark] NIDDK, NIH, Bethesda, MD USA. [Tiranathanagul, Khajohn; Srisawat, Nattachai] Chulalongkorn Univ, Dept Med, Nephrol Unit, Bangkok 10330, Thailand. RP Leelahavanichkul, A (reprint author), Chulalongkorn Univ, Dept Microbiol, Immunol Unit, Bangkok 10330, Thailand. FU Center of Excellence in Immunology and Immune-Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University; Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University; Grant for Development of New Faculty Staff, Chulalongkorn University; grant for Chula Research Scholar, Ratchadaphiseksomphotch Endowment Fund FX The authors would like to gratefully acknowledge the Center of Excellence in Immunology and Immune-Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University for its support of this research study. This study was funded by the following grants: the Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University; Grant for Development of New Faculty Staff, Chulalongkorn University, as well as a grant for Chula Research Scholar, Ratchadaphiseksomphotch Endowment Fund. We also thank Kevin P. Jones for the English language editing of the manuscript. NR 67 TC 2 Z9 2 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 EI 1522-1490 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD AUG 1 PY 2015 VL 309 IS 3 BP R223 EP R234 DI 10.1152/ajpregu.00238.2014 PG 12 WC Physiology SC Physiology GA CO1VT UT WOS:000358944700003 PM 25994956 ER PT J AU Palacios, T Bartelt, L Scheld, W Lopes, MB Kelting, SM Holland, S Lipkin, WI Quan, PL Borish, L Lawrence, M AF Palacios, Thamiris Bartelt, Luther Scheld, William Lopes, M. Beatriz Kelting, Sarah M. Holland, Steven Lipkin, W. Ian Quan, Phenix-Lan Borish, Larry Lawrence, Monica TI Fatal Coxsackie meningoencephalitis in a patient with B-cell lymphopenia and hypogammaglobulinemia following rituximab therapy SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Letter ID ENTEROVIRAL MENINGOENCEPHALITIS; INFECTION; FEATURES C1 [Palacios, Thamiris; Borish, Larry; Lawrence, Monica] Univ Virginia, Sch Med, Div Asthma Allergy & Immunol, Charlottesville, VA 22908 USA. [Bartelt, Luther; Scheld, William] Univ Virginia, Sch Med, Dept Med, Div Infect Dis, Charlottesville, VA 22908 USA. [Lopes, M. Beatriz; Kelting, Sarah M.] Univ Virginia, Sch Med, Dept Pathol, Charlottesville, VA 22908 USA. [Holland, Steven] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Lipkin, W. Ian; Quan, Phenix-Lan] Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY USA. [Borish, Larry] Univ Virginia, Sch Med, Dept Microbiol, Charlottesville, VA 22908 USA. RP Palacios, T (reprint author), Univ Virginia, Sch Med, Div Asthma Allergy & Immunol, Charlottesville, VA 22908 USA. EM TVP9Z@hscmail.mcc.virginia.edu FU NIAID NIH HHS [R56 AI120055, R01 AI057438] NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1081-1206 EI 1534-4436 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD AUG PY 2015 VL 115 IS 2 BP 148 EP 150 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA CO4QY UT WOS:000359146900014 PM 26048250 ER PT J AU Morales, J Solovey, G Maniscalco, B Rahnev, D de Lange, FP Lau, H AF Morales, Jorge Solovey, Guillermo Maniscalco, Brian Rahnev, Dobromir de Lange, Floris P. Lau, Hakwan TI Low attention impairs optimal incorporation of prior knowledge in perceptual decisions SO ATTENTION PERCEPTION & PSYCHOPHYSICS LA English DT Article DE Attention: divided attention and inattention; Signal detection theory; Cognitive and attentional control; Ideal observer Bayesian models ID PRIMARY VISUAL-CORTEX; PERFORMANCE; CONFIDENCE; RESPONSES; CATEGORIZATION; REPRESENTATION; PROBABILITY; UNCERTAINTY; INFORMATION; AWARENESS AB When visual attention is directed away from a stimulus, neural processing is weak and strength and precision of sensory data decreases. From a computational perspective, in such situations observers should give more weight to prior expectations in order to behave optimally during a discrimination task. Here we test a signal detection theoretic model that counter-intuitively predicts subjects will do just the opposite in a discrimination task with two stimuli, one attended and one unattended: when subjects are probed to discriminate the unattended stimulus, they rely less on prior information about the probed stimulus' identity. The model is in part inspired by recent findings that attention reduces trial-by-trial variability of the neuronal population response and that they use a common criterion for attended and unattended trials. In five different visual discrimination experiments, when attention was directed away from the target stimulus, subjects did not adjust their response bias in reaction to a change in stimulus presentation frequency despite being fully informed and despite the presence of performance feedback and monetary and social incentives. This indicates that subjects did not rely more on the priors under conditions of inattention as would be predicted by a Bayes-optimal observer model. These results inform and constrain future models of Bayesian inference in the human brain. C1 [Morales, Jorge] Columbia Univ, Dept Philosophy, New York, NY 10027 USA. [Solovey, Guillermo; Maniscalco, Brian; Rahnev, Dobromir; Lau, Hakwan] Columbia Univ, Dept Psychol, New York, NY 10027 USA. [Solovey, Guillermo] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Inst Calculo, RA-1428 Buenos Aires, DF, Argentina. [Solovey, Guillermo] Lab Neurociencia Integrat, Buenos Aires, DF, Argentina. [Solovey, Guillermo] Consejo Nacl Invest Cient & Tecn, RA-1033 Buenos Aires, DF, Argentina. [Maniscalco, Brian] NINDS, NIH, Bethesda, MD 20892 USA. [Rahnev, Dobromir] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [de Lange, Floris P.; Lau, Hakwan] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6500 HB Nijmegen, Netherlands. [Lau, Hakwan] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. RP Morales, J (reprint author), Columbia Univ, Dept Philosophy, 708 Philosophy Hall,1150 Amsterdam Ave, New York, NY 10027 USA. EM jorgemlg@gmail.com RI de Lange, Floris/D-2860-2009; OI de Lange, Floris/0000-0002-6730-1452; Morales, Jorge/0000-0001-5825-4909 FU Templeton Foundation [6-40689] FX This work is partially supported by a grant from the Templeton Foundation (6-40689). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Ai Koizumi, Megan Peters, and Alex White for comments on an earlier version of this manuscript, and David Heeger for suggesting that we reward the subjects financially to motivate them to behave optimally. NR 43 TC 3 Z9 3 U1 4 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1943-3921 EI 1943-393X J9 ATTEN PERCEPT PSYCHO JI Atten. Percept. Psychophys. PD AUG PY 2015 VL 77 IS 6 BP 2021 EP 2036 DI 10.3758/s13414-015-0897-2 PG 16 WC Psychology; Psychology, Experimental SC Psychology GA CN9CA UT WOS:000358742500018 PM 25836765 ER PT J AU Cicchini, C de Nonno, V Battistelli, C Cozzolino, AM De Santis Puzzonia, M Ciafre, SA Brocker, C Gonzalez, FJ Amicone, L Tripodi, M AF Cicchini, Carla de Nonno, Valeria Battistelli, Cecilia Cozzolino, Angela Maria De Santis Puzzonia, Marco Ciafre, Silvia Anna Brocker, Chad Gonzalez, Frank J. Amicone, Laura Tripodi, Marco TI Epigenetic control of EMT/MET dynamics: HNF4 alpha. impacts DNMT3s through miRs-29 SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Article DE De novo DNA methylation; Hepatocyte; Epithelial-mesenchymal transition; TGF beta; miR-29 ID TO-MESENCHYMAL TRANSITION; NUCLEAR FACTOR 4-ALPHA; HEPATOCELLULAR-CARCINOMA; DNA METHYLTRANSFERASES; DOWN-REGULATION; EXPRESSION; METHYLATION; CANCER; CELL; LIVER AB Background and aims: Epithelial-to-mesenchymal transition (EMT) and the reverse mesenchymal-to-epithelial transition (MET) are manifestations of cellular plasticity that imply a dynamic and profound gene expression reprogramming. While a major epigenetic code controlling the coordinated regulation of a whole transcriptional profile is guaranteed by DNA methylation, DNA methyltransferase (DNMT) activities in EMT/MET dynamics are still largely unexplored. Here, we investigated the molecular mechanisms directly linking HNF4 alpha, the master effector of MET, to the regulation of both de novo of DNMT 3A and 3B. Methods: Correlation among EMT/MET markers, microRNA29 and DNMT3s expression was evaluated by RT-qPCR, Western blotting and immunocytochemical analysis. Functional roles of microRNAs and DNMT3s were tested by anti-miRs, microRNA precursors and chemical inhibitors. ChIP was utilized for investigating HNF4 alpha DNA binding activity. Results: HNF4 alpha silencing was sufficient to induce positive modulation of DNMT3B, in in vitro differentiated hepatocytes as well as in vivo hepatocyte-specific HNF4 alpha knockout mice, and DNMT3A, in vitro, but not DNMT1. In exploring the molecular mechanisms underlying these observations, evidence have been gathered for (i) the inverse correlation between DNMT3 levels and the expression of their regulators miR-29a and miR-29b and (ii) the role of HNF4 alpha as a direct regulator of miR-29a-b transcription. Notably, during TGF beta-induced EMT, DNMT3s' pivotal function has been proved, thus suggesting the need for the repression of these DNMTs in the maintenance of a differentiated phenotype. Conclusions: HNF4 alpha maintains hepatocyte identity by regulating miR-29a and -29b expression, which in turn control epigenetic modifications by limiting DNMT3A and DNMT3B levels. (C) 2015 The Authors. Published by Elsevier B.V. C1 [Cicchini, Carla; de Nonno, Valeria; Battistelli, Cecilia; De Santis Puzzonia, Marco; Amicone, Laura; Tripodi, Marco] Univ Roma La Sapienza, Mol Genet Sect, Dept Cellular Biotechnol & Hematol, Ist Pasteur Fdn Cenci Bolognetti, I-00161 Rome, Italy. [Ciafre, Silvia Anna] Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy. [Brocker, Chad; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cozzolino, Angela Maria; Tripodi, Marco] IRCCS, Natl Inst Infect Dis L Spallanzani, Rome, Italy. RP Cicchini, C (reprint author), Univ Roma La Sapienza, Sez Genet Mol, Dipartimento Biotecnol Cellulari & Ematol, Viale Regina Elena 324, I-00161 Rome, Italy. EM cicchini@bce.uniroma1.it; tripodi@bce.uniroma1.it RI De Santis Puzzonia, Marco/J-3611-2016; Tripodi, Marco/F-1143-2011; OI Tripodi, Marco/0000-0001-6135-971X; De Santis Puzzonia, Marco/0000-0001-5691-1733; ciafre', silvia anna/0000-0001-6467-8396; COZZOLINO, ANGELA MARIA/0000-0002-3981-0639; Amicone, Laura/0000-0002-3487-5740; CICCHINI, Carla/0000-0003-4662-5674 FU Associazione Italiana per la Ricerca sul Cancro [IG 14114]; Ministry for Health of Italy ("Ricerca Corrente"); Ministry of University and Scientific Research of Italy [PRIN 2010LC747T_003] FX Grant Support: Associazione Italiana per la Ricerca sul Cancro (IG 14114); Ministry for Health of Italy ("Ricerca Corrente"); Ministry of University and Scientific Research of Italy (PRIN 2010LC747T_003). NR 34 TC 9 Z9 11 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 EI 0006-3002 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD AUG PY 2015 VL 1849 IS 8 BP 919 EP 929 DI 10.1016/j.bbagrm.2015.05.005 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CO2EN UT WOS:000358969000002 PM 26003733 ER PT J AU Nicol, B Yao, HHC AF Nicol, Barbara Yao, Humphrey H. -C. TI Gonadal Identity in the Absence of Pro-Testis Factor SOX9 and Pro-Ovary Factor Beta-Catenin in Mice SO BIOLOGY OF REPRODUCTION LA English DT Article DE catenin; sex determination; Sox9; Sry; testis ID SEX-DETERMINING REGION; Y-CHROMOSOME; CELL FATE; MOUSE; DIFFERENTIATION; SRY; REVERSAL; GENE; WNT4; SF1 AB Sex-reversal cases in humans and genetic models in mice have revealed that the fate of the bipotential gonad hinges upon the balance between pro-testis SOX9 and pro-ovary beta-catenin pathways. Our central query was: if SOX9 and beta-catenin define the gonad's identity, then what do the gonads become when both factors are absent? To answer this question, we developed mouse models that lack either Sox9, beta-catenin, or both in the somatic cells of the fetal gonads and examined the morphological outcomes and transcriptome profiles. In the absence of Sox9 and beta-catenin, both XX and XY gonads progressively lean toward the testis fate, indicating that expression of certain pro-testis genes requires the repression of the beta-catenin pathway, rather than a direct activation by SOX9. We also observed that XY double knockout gonads were more masculinized than their XX counterpart. To identify the genes responsible for the initial events of masculinization and to determine how the genetic context (XX vs. XY) affects this process, we compared the transcriptomes of Sox9/beta-catenin mutant gonads and found that early molecular changes underlying the XY-specific masculinization involve the expression of Sry and 21 SRY direct target genes, such as Sox8 and Cyp26b1. These results imply that when both Sox9 and beta-catenin are absent, Sry is capable of activating other pro-testis genes and drive testis differentiation. Our findings not only provide insight into the mechanism of sex determination, but also identify candidate genes that are potentially involved in disorders of sex development. C1 [Nicol, Barbara; Yao, Humphrey H. -C.] NIEHS, Reprod & Dev Biol Lab, Res Triangle Pk, NC 27709 USA. RP Yao, HHC (reprint author), NIEHS, Reprod & Dev Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM humphrey.yao@nih.gov RI Yao, Humphrey Hung-Chang/B-4795-2010; OI Yao, Humphrey Hung-Chang/0000-0003-2944-8469; Nicol, Barbara/0000-0002-3434-0658 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ES102965] FX This research was supported by the Intramural Research Program (ES102965) of the NIH, National Institute of Environmental Health Sciences. The raw microarray data are available in GEO (accession no. GSE67463). NR 49 TC 9 Z9 9 U1 0 U2 10 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 EI 1529-7268 J9 BIOL REPROD JI Biol. Reprod. PD AUG 1 PY 2015 VL 93 IS 2 AR 35 DI 10.1095/biolreprod.115.131276 PG 12 WC Reproductive Biology SC Reproductive Biology GA CO8UT UT WOS:000359448300010 PM 26108792 ER PT J AU Kim, Y Maciag, AE Cao, Z Deschamps, JR Saavedra, JE Keefer, LK Holland, RJ AF Kim, Youseung Maciag, Anna E. Cao, Zhao Deschamps, Jeffrey R. Saavedra, Joseph E. Keefer, Larry K. Holland, Ryan J. TI PABA/NO lead optimization: Improved targeting of cytotoxicity to glutathione S-transferase P1-overexpressing cancer cells SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Glutathione S-transferase P1 (GSTP1); Glutathione; Nitric oxide (NO); PABA/NO; Diazeniumdiolate; Arylation; Oxidative stress; Antiproliferative; Cytotoxicity; Apoptosis ID OXIDE-RELEASING PRODRUG; NITRIC-OXIDE; IN-VITRO; JS-K; P-GLYCOPROTEIN; ANTILEUKEMIC ACTIVITY; ANTICANCER LEAD; EXPRESSION; RESISTANCE; LEUKEMIA AB PABA/NO [O-2-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino) diazen-1-ium-1,2-diolate] is a nitric oxide (NO)-releasing arylating agent designed to be selectively activated by reaction with glutathione (GSH) on catalysis by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancer cells. PABA/NO has proven active in several cancer models in vitro and in vivo, but its tendency to be metabolized via a variety of pathways, some that generate inactive metabolites and hydrolysis products, limits its potential as a drug. Here we show that a simple replacement of cyano for nitro at the 4 position to give compound 4b ('p-cyano-PABA/NO') has the dual effect of slowing the undesired side reactions while enhancing the proportion of NO release and arylating activity on catalysis by GSTP1. Compound 4b showed increased resistance to hydrolysis and uncatalyzed reaction with GSH, along with a more favorable product distribution in the presence of GSTP1. It also showed significant proapoptotic activity. The data suggest p-cyano-PABA/NO to be a more promising prodrug than PABA/NO, with better selectivity toward cancer cells. Published by Elsevier Ltd. C1 [Kim, Youseung; Keefer, Larry K.; Holland, Ryan J.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Maciag, Anna E.; Cao, Zhao; Saavedra, Joseph E.] Leidos Biomed Res Inc, Biol Chem Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Deschamps, Jeffrey R.] Naval Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. RP Saavedra, JE (reprint author), Leidos Biomed Res Inc, Biol Chem Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM saavedjo@mail.nih.gov; hollandrj@mail.nih.gov FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; National Institute on Drug Abuse (NIDA) [Y1-DA1101]; Naval Research Laboratory FX This project has been funded with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E, and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.; Crystallographic studies were supported by the National Institute on Drug Abuse (NIDA) under Contract Y1-DA1101 and by the Naval Research Laboratory. NR 27 TC 3 Z9 3 U1 2 U2 12 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 AUG 1 PY 2015 VL 23 IS 15 BP 4980 EP 4988 DI 10.1016/j.bmc.2015.05.020 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA CN4ZV UT WOS:000358440000089 PM 26043946 ER PT J AU Wegbreit, E Weissman, AB Cushman, GK Puzia, ME Kim, KL Leibenluft, E Dickstein, DP AF Wegbreit, Ezra Weissman, Alexandra B. Cushman, Grace K. Puzia, Megan E. Kim, Kerri L. Leibenluft, Ellen Dickstein, Daniel P. TI Facial emotion recognition in childhood-onset bipolar I disorder: an evaluation of developmental differences between youths and adults SO BIPOLAR DISORDERS LA English DT Article DE adolescents; bipolar disorder; child psychiatry; development; emotion; face ID DEPRESSION RATING-SCALE; ANXIETY DISORDERS; LABELING DEFICITS; GLOBAL ASSESSMENT; SUICIDE ATTEMPTS; SPECTRUM DISORDERS; EMPATHIC ABILITIES; BRAIN-DEVELOPMENT; NATIONAL TRENDS; PEDIATRIC MANIA AB ObjectivesBipolar disorder (BD) is a severe mental illness with high healthcare costs and poor outcomes. Increasing numbers of youths are diagnosed with BD, and many adults with BD report that their symptoms started in childhood, suggesting that BD can be a developmental disorder. Studies advancing our understanding of BD have shown alterations in facial emotion recognition both in children and adults with BD compared to healthy comparison (HC) participants, but none have evaluated the development of these deficits. To address this, we examined the effect of age on facial emotion recognition in a sample that included children and adults with confirmed childhood-onset type-I BD, with the adults having been diagnosed and followed since childhood by the Course and Outcome in Bipolar Youth study. MethodsUsing the Diagnostic Analysis of Non-Verbal Accuracy, we compared facial emotion recognition errors among participants with BD (n=66; ages 7-26years) and HC participants (n=87; ages 7-25years). Complementary analyses investigated errors for child and adult faces. ResultsA significant diagnosis-by-age interaction indicated that younger BD participants performed worse than expected relative to HC participants their own age. The deficits occurred both for child and adult faces and were particularly strong for angry child faces, which were most often mistaken as sad. Our results were not influenced by medications, comorbidities/substance use, or mood state/global functioning. ConclusionsYounger individuals with BD are worse than their peers at this important social skill. This deficit may be an important developmentally salient treatment target - that is, for cognitive remediation to improve BD youths' emotion recognition abilities. C1 [Wegbreit, Ezra; Weissman, Alexandra B.; Cushman, Grace K.; Puzia, Megan E.; Kim, Kerri L.; Dickstein, Daniel P.] Brown Univ, Alpert Med Sch, Bradley Hosp, Pediat Mood Imaging & NeuroDev PediMIND Program, East Providence, RI 02915 USA. [Wegbreit, Ezra; Weissman, Alexandra B.; Cushman, Grace K.; Puzia, Megan E.; Kim, Kerri L.; Dickstein, Daniel P.] Brown Univ, Alpert Med Sch, Dept Psychiat & Human Behav, Div Child Psychiat, East Providence, RI 02915 USA. [Leibenluft, Ellen] NIMH, Intramural Res Program, Sect Bipolar Spectrum Disorders, Bethesda, MD 20892 USA. [Kim, Kerri L.] NIMH, Intramural Res Program, Emot & Dev Branch, Bethesda, MD 20892 USA. RP Wegbreit, E (reprint author), Brown Univ, Alpert Med Sch, PediMIND Program, Dept Psychiat & Human Behav,Bradley Hosp, East Providence, RI 02915 USA. EM ezra_wegbreit@brown.edu RI Dickstein, Daniel/L-3210-2016; OI Dickstein, Daniel/0000-0003-1647-5329; Wegbreit, Ezra/0000-0001-5887-1392 FU National Institute of Mental Health [K22MH074945, R01MH087513, R01MH059929] FX We gratefully acknowledge research funding from the National Institute of Mental Health, which supported this work (K22MH074945 and R01MH087513, Principal Investigator: DPD) and supported the Course and Outcome in Bipolar Youth (COBY) study (R01MH059929), the parent study whose Brown University site initially recruited and continues to follow the young adult participants with bipolar disorder. We also would like to thank our research participants and their families for their time and effort, without which this research would not have been possible. NR 84 TC 7 Z9 7 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD AUG PY 2015 VL 17 IS 5 BP 471 EP 485 DI 10.1111/bdi.12312 PG 15 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CO3OK UT WOS:000359067600002 PM 25951752 ER PT J AU Glousker, G Touzot, F Revy, P Tzfati, Y Savage, SA AF Glousker, Galina Touzot, Fabien Revy, Patrick Tzfati, Yehuda Savage, Sharon A. TI Unraveling the pathogenesis of Hoyeraal-Hreidarsson syndrome, a complex telomere biology disorder SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review DE Hoyeraal-Hreidarsson syndrome; dyskeratosis congenita; telomere; immunodeficiency; cerebellar hypoplasia ID LINKED DYSKERATOSIS-CONGENITA; BONE-MARROW FAILURE; ELONGATION HELICASE 1; SMALL NUCLEOLAR RNA; CEREBELLAR HYPOPLASIA; PROGRESSIVE PANCYTOPENIA; REVERSE-TRANSCRIPTASE; COMBINED IMMUNODEFICIENCY; APLASTIC-ANEMIA; PROTEIN TPP1 AB Hoyeraal-Hreidarsson (HH) syndrome is a multisystem genetic disorder characterized by very short telomeres and considered a clinically severe variant of dyskeratosis congenita. The main cause of mortality, usually in early childhood, is bone marrow failure. Mutations in several telomere biology genes have been reported to cause HH in about 60% of the HH patients, but the genetic defects in the rest of the patients are still unknown. Understanding the aetiology of HH and its diverse manifestations is challenging because of the complexity of telomere biology and the multiple telomeric and non-telomeric functions played by telomere-associated proteins in processes such as telomere replication, telomere protection, DNA damage response and ribosome and spliceosome assembly. Here we review the known clinical complications, molecular defects and germline mutations associated with HH, and elucidate possible mechanistic explanations and remaining questions in our understanding of the disease. C1 [Glousker, Galina; Tzfati, Yehuda] Hebrew Univ Jerusalem, Dept Genet, Silberman Inst Life Sci, IL-91904 Jerusalem, Israel. [Touzot, Fabien; Revy, Patrick] Paris Descartes Sorbonne Paris Cite Univ, INSERM, Lab Genome Dynam Immune Syst, UMR 1163, Paris, France. [Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E456,MSC 9772, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Division of Cancer Epidemiology, National Cancer Institute, National Institutes of Health; Israel Science Foundation [1729/13]; Israel Cancer Research Fund; INSERM; Ligue Nationale contre le Cancer (Equipe Labellisee La Ligue); GIS-Institut des maladies rares; ARC; INCa/Canceropole Ile de France; Institut Imagine; European Research Council [249816] FX This work was supported by the intramural research program of the Division of Cancer Epidemiology, National Cancer Institute, National Institutes of Health, by a grant from the Israel Science Foundation (1729/13) and a project grant from the Israel Cancer Research Fund to Y.T., and by institutional grants from INSERM, Ligue Nationale contre le Cancer (Equipe Labellisee La Ligue), GIS-Institut des maladies rares, ARC, INCa/Canceropole Ile de France, Institut Imagine, and the European Research Council [PIDIMMUN grant no. 249816]. P.R. is a scientist from Centre National de la Recherche Scientifique (CNRS). NR 137 TC 9 Z9 9 U1 1 U2 8 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 2015 VL 170 IS 4 BP 457 EP 471 DI 10.1111/bjh.13442 PG 15 WC Hematology SC Hematology GA CO6IH UT WOS:000359259900005 PM 25940403 ER PT J AU Strauss, J Madan, RA Figg, WD AF Strauss, Julius Madan, Ravi A. Figg, William D. TI Evaluating immune responses after sipuleucel-T therapy SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE GU malignancies; immune response; prostate cancer; urology; sipuleucel-T ID RESISTANT PROSTATE-CANCER; COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; SURVIVAL; IMMUNOTHERAPY; PROGNOSIS; TRIALS; CELLS AB Following FDA approval of sipuleucel T in 2010 for metastatic castration resistant prostate cancer (mCRPC), several studies have described the effect of sipuleucel-T on peripheral immune responses. Retrospective associations have also been made with immune responses and survival. A recently published study by Fong et al. was the first to characterize the immune response of sipuleucel-T in the tumor microenvironment. The findings of this study have been hypothesis generating, yet it remains unclear whether the peri-tumor immune response described is predictive of survival. Increasing evidence suggests that radiographic or PSA progression does not accurately reflect survival with sipuleucel-T and other immunotherapies. Finding an immune biomarker which can accurately reflect clinical benefit and validating it prospectively offers the potential for a predictive indicator of response in an area where none currently exists. C1 [Strauss, Julius; Madan, Ravi A.; Figg, William D.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Genitourinary Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 16 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4047 EI 1555-8576 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG PY 2015 VL 16 IS 8 BP 1119 EP 1121 DI 10.1080/15384047.2015.1056417 PG 3 WC Oncology SC Oncology GA CO0LF UT WOS:000358842000001 PM 26054644 ER PT J AU Hoffmann, TJ Van den Eeden, SK Sakoda, LC Jorgenson, E Habel, LA Graff, RE Passarelli, MN Cario, CL Emami, NC Chao, CR Ghai, NR Shan, J Ranatunga, DK Quesenberry, CP Aaronson, D Presti, J Wang, ZM Berndt, SI Chanock, SJ McDonnell, SK French, AJ Schaid, DJ Thibodeau, SN Li, QY Freedman, ML Penney, KL Mucci, LA Haiman, CA Henderson, BE Seminara, D Kvale, MN Kwok, PY Schaefer, C Risch, N Witte, JS AF Hoffmann, Thomas J. Van den Eeden, Stephen K. Sakoda, Lori C. Jorgenson, Eric Habel, Laurel A. Graff, Rebecca E. Passarelli, Michael N. Cario, Clinton L. Emami, Nima C. Chao, Chun R. Ghai, Nirupa R. Shan, Jun Ranatunga, Dilrini K. Quesenberry, Charles P. Aaronson, David Presti, Joseph Wang, Zhaoming Berndt, Sonja I. Chanock, Stephen J. McDonnell, Shannon K. French, Amy J. Schaid, Daniel J. Thibodeau, Stephen N. Li, Qiyuan Freedman, Matthew L. Penney, Kathryn L. Mucci, Lorelei A. Haiman, Christopher A. Henderson, Brian E. Seminara, Daniela Kvale, Mark N. Kwok, Pui-Yan Schaefer, Catherine Risch, Neil Witte, John S. TI A Large Multiethnic Genome-Wide Association Study of Prostate Cancer Identifies Novel Risk Variants and Substantial Ethnic Differences SO CANCER DISCOVERY LA English DT Article ID SUSCEPTIBILITY LOCI; GENOTYPE IMPUTATION; GENETIC EPIDEMIOLOGY; SEQUENCE VARIANTS; AFRICAN ANCESTRY; FAMILY HISTORY; MULTIPLE LOCI; MEN; POPULATION; EXPRESSION AB A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 x 10(-19) (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 x 10(-23)) and SLC22A3 (P = 3.2 x 10(-52)). At the known 19q13.33 locus, rs2659124 (P = 1.3 x 10(-13); OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 x 10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P=0.004). SIGNIFICANCE: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations. (C) 2015 AACR. C1 [Hoffmann, Thomas J.; Graff, Rebecca E.; Passarelli, Michael N.; Cario, Clinton L.; Emami, Nima C.; Risch, Neil; Witte, John S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94158 USA. [Hoffmann, Thomas J.; Kvale, Mark N.; Kwok, Pui-Yan; Risch, Neil; Witte, John S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94158 USA. [Van den Eeden, Stephen K.; Sakoda, Lori C.; Jorgenson, Eric; Habel, Laurel A.; Shan, Jun; Ranatunga, Dilrini K.; Quesenberry, Charles P.; Schaefer, Catherine; Risch, Neil] Kaiser Permanente, Div Res, Oakland, CA 94612 USA. [Van den Eeden, Stephen K.; Witte, John S.] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94158 USA. [Chao, Chun R.; Ghai, Nirupa R.] Kaiser Permanente, Dept Res & Evaluat, Pasadena, CA 94612 USA. [Aaronson, David; Presti, Joseph] Kaiser Oakland Med Ctr, Dept Urol, Oakland, CA USA. [Wang, Zhaoming; Berndt, Sonja I.; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. [McDonnell, Shannon K.; Schaid, Daniel J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [French, Amy J.; Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Li, Qiyuan] Xiamen Univ, Coll Med, Xiamen, Peoples R China. [Freedman, Matthew L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Freedman, Matthew L.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Freedman, Matthew L.] Eli & Edythe L Broad Inst, Cambridge, MA USA. [Penney, Kathryn L.; Mucci, Lorelei A.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Penney, Kathryn L.; Mucci, Lorelei A.] Harvard Univ, Brigham & Womens Hosp, Channing Div Network Med, Dept Med,Med Sch, Boston, MA 02115 USA. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Seminara, Daniela] NCI, NIH, Bethesda, MD 20892 USA. [Witte, John S.] Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA. RP Witte, JS (reprint author), Univ Calif San Francisco, 1450 3rd St, San Francisco, CA 94158 USA. EM Stephen.Vandeneeden@kp.org; wittej@humgen.ucsf.edu FU NIH [CA127298, CA088164, CA112355, AG046616, DC013300, R01 GM107427, CA136578, CA141298, CA131945, CA151254, CA157881, CA63464, CA54281, CA1326792, CA148085, HG004726]; UCSF Goldberg-Benioff Program in Cancer Translational Biology; Prostate Cancer Foundation; Department of Defense [W81XWH-11-1-0261]; California Cancer Research Program [99-86883]; Community Benefit Program, Kaiser Permanente Northern California; National Institute on Aging; National Institute of Mental Health; NIH Common Fund [RC2 AG036607] FX This work was supported by NIH grants CA127298, CA088164, and CA112355 (to J.S. Witte); AG046616 and DC013300 (to T.J. Hoffmann); R01 GM107427 (to M.L. Freedman); CA136578, CA141298, and CA131945 (to K.L. Penney and L.A. Mucci); and CA151254 and CA157881 (to S.N. Thibodeau). This work was also supported by the UCSF Goldberg-Benioff Program in Cancer Translational Biology (to J.S. Witte), Prostate Cancer Foundation Young Investigator Awards (to K.L. Penney and L.A. Mucci), and Department of Defense grant W81XWH-11-1-0261 (to S.N. Thibodeau). The MEC and the genotyping in the African Ancestry Prostate Cancer GWAS Consortium (AAPC) were supported by NIH grants CA63464, CA54281, CA1326792, CA148085, and HG004726, funds from the California Cancer Research Program, grant number 99-86883, and from The Community Benefit Program, Kaiser Permanente Northern California. Support for participant enrollment, survey completion, and biospecimen collection for the RPGEH was provided by the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, and Kaiser Permanente national and regional community benefit programs. Genotyping of the GERA cohort was funded by a grant from the National Institute on Aging, the National Institute of Mental Health, and the NIH Common Fund (RC2 AG036607 to C. Schaefer and N. Risch). PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. NR 61 TC 13 Z9 13 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD AUG PY 2015 VL 5 IS 8 BP 878 EP 891 DI 10.1158/2159-8290.CD-15-0315 PG 14 WC Oncology SC Oncology GA CO7DF UT WOS:000359317700020 PM 26034056 ER PT J AU Albanes, D AF Albanes, Demetrius TI Vitamin D and Cancer: Diversity, Complexity, and Still a Ways to Go SO CANCER PREVENTION RESEARCH LA English DT Article ID D-BINDING PROTEIN; CIRCULATING 25-HYDROXYVITAMIN D; RANDOMIZED CONTROLLED-TRIAL; PROSTATE-CANCER; BREAST-CANCER; PANCREATIC-CANCER; COHORT CONSORTIUM; D SUPPLEMENTATION; CARDIOVASCULAR-DISEASE; PRIMARY PREVENTION AB Vitamin D has taken a center-stage role in our basic and population research quest for the panacea for all human maladies, including cancer, yet sufficient evidence for a beneficial role has existed only for bone health. This Commentary discusses and places into a broader context the report of Chandler and colleagues that found a protective association for higher vitamin D status in colorectal cancer in women, consistent with most other cohort studies but not with limited supplementation trial data. Little human evidence exists for the preventive potential in other malignancies, including breast cancer, with the exception of possible benefit in bladder cancer and an adverse serologic association with prostate cancer (pancreatic cancer risk may be similarly influenced) that is supported by vitamin D genetic data. Current vitamin D trials are examining high-dose supplementation (i.e., 1,600-3,333 IU daily) for effects on multiple outcomes, but they may not have sufficient power to test efficacy in colorectal or other specific malignancies and are unlikely to inform any benefit for higher physiologic levels. A more complete understanding of vitamin D and human carcinogenesis will come from multifaceted lines of research, including elucidation of organ site-specific biologic mechanisms, prospective serologic analyses, testing of vitamin D-related genetic variation, and short-term clinical-metabolic biomarker studies of multidose vitamin D supplementation, including metabolomic profiling of controlled supplementation in these and past or ongoing trials. (C) 2015 AACR. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Albanes, D (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,6E342, Bethesda, MD 20892 USA. EM daa@nih.gov FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS FX This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS. NR 31 TC 1 Z9 1 U1 3 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD AUG PY 2015 VL 8 IS 8 BP 657 EP 661 DI 10.1158/1940-6207.CAPR-15-0207 PG 5 WC Oncology SC Oncology GA CO7DM UT WOS:000359318600001 PM 26220946 ER PT J AU Pan, P Skaer, CW Stirdivant, SM Young, MR Stoner, GD Lechner, JF Huang, YW Wang, LS AF Pan, Pan Skaer, Chad W. Stirdivant, Steven M. Young, Matthew R. Stoner, Gary D. Lechner, John F. Huang, Yi-Wen Wang, Li-Shu TI Beneficial Regulation of Metabolic Profiles by Black Raspberries in Human Colorectal Cancer Patients SO CANCER PREVENTION RESEARCH LA English DT Article ID METABONOMICS; IDENTIFICATION; SYSTEMS; TUMORS; FRUIT AB Dietary intervention of freeze-dried black raspberries (BRBs) in a group of human colorectal cancer patients has demonstrated beneficial effects, including proapoptosis, antiproliferation, and antiangiogenesis. The aim of this study was to investigate BRB-mediated metabolite changes from this same cohort of patients. Twenty-eight colorectal cancer patients were given 60 g BRB powder daily for 1 to 9 weeks. Urine and plasma specimens were collected before and after BRB intervention. A mass spectrometry-based nontargeted metabolomic analysis was conducted on each specimen. A total of more than 400 metabolites were annotated in each specimen. Of these 34 and 6 metabolites were significantly changed by BRBs in urine and plasma, respectively. Increased levels of 4-methylcatechol sulfate in both post-BRB urine and post-BRB plasma were significantly correlated with a higher level of apoptotic marker (TUNEL) in post-BRB tumors. One tricarboxylic acid (TCA) cycle metabolites, cis-aconitate, was increased in post-BRB urine. Furthermore, BRB-derived polyphenols were absorbed and metabolized to various benzoate species, which were significantly increased in post-BRB specimens. Increased benzoate levels were positively correlated with enhanced levels of amino acid metabolite. These results suggest that BRBs induce significant metabolic changes and affect energy generating pathways. This study supports the hypothesis that BRBs might be beneficial to colorectal cancer patients through the regulation of multiple metabolites. (C) 2015 AACR. C1 [Pan, Pan; Skaer, Chad W.; Stoner, Gary D.; Lechner, John F.; Wang, Li-Shu] Med Coll Wisconsin, Dept Med, Div Hematol & Oncol, Milwaukee, WI 53226 USA. [Stirdivant, Steven M.] Metabolon Inc, Clin Res & Dev, Durham, NC USA. [Young, Matthew R.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21701 USA. [Huang, Yi-Wen] Med Coll Wisconsin, Dept Obstet & Gynecol, Milwaukee, WI 53226 USA. RP Wang, LS (reprint author), Med Coll Wisconsin, Room C4930,8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM liswang@mcw.edu FU NIH [5 R01 CA148818 04]; American Cancer Society [RSG-13-138-01-CNE] FX This work was supported by NIH grant 5 R01 CA148818 04 and American Cancer Society, RSG-13-138-01-CNE (to L.-S. Wang). NR 29 TC 8 Z9 8 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD AUG PY 2015 VL 8 IS 8 BP 743 EP 750 DI 10.1158/1940-6207.CAPR-15-0065 PG 8 WC Oncology SC Oncology GA CO7DM UT WOS:000359318600011 PM 26054356 ER PT J AU Chang, YS Chen, WY Yin, JJ Sheppard-Tillman, H Huang, JT Liu, YN AF Chang, Yung-Sheng Chen, Wei-Yu Yin, Juan Juan Sheppard-Tillman, Heather Huang, Jiaoti Liu, Yen-Nien TI EGF Receptor Promotes Prostate Cancer Bone Metastasis by Downregulating miR-1 and Activating TWIST1 SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; TRANSCRIPTION FACTOR; UP-REGULATION; EXPRESSION; MICRORNAS; PATHWAY; PROGRESSION; TARGET; CELLS AB Dysregulation of the EGFR signaling axis enhances bone metastases in many solid cancers. However, the relevant downstream effector signals in this axis are unclear. miR-1 was recently shown to function as a tumor suppressor in prostate cancer cells, where its expression correlated with reduced metastatic potential. In this study, we demonstrated a role for EGFR translocation in regulating transcription of miR-1-1, which directly targets expression of TWIST1. Consistent with these findings, we observed decreased miR-1 levels that correlated with enhanced expression of activated EGFR and TWIST1 in a cohort of human prostate cancer specimens and additional datasets. Our findings support a model in which nuclear EGFR acts as a transcriptional repressor to constrain the tumor-suppressive role of miR-1 and sustain oncogenic activation of TWIST1, thereby leading to accelerated bone metastasis. (C) 2015 AACR. C1 [Chang, Yung-Sheng; Liu, Yen-Nien] Taipei Med Univ, Coll Med Sci & Technol, Grad Inst Canc Biol & Drug Discovery, Taipei 11031, Taiwan. [Chen, Wei-Yu] Taipei Med Univ, Wan Fang Hosp, Dept Pathol, Taipei 11031, Taiwan. [Chen, Wei-Yu] Taipei Med Univ, Coll Med, Sch Med, Dept Pathol, Taipei 11031, Taiwan. [Yin, Juan Juan; Sheppard-Tillman, Heather] NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. [Huang, Jiaoti] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA USA. RP Liu, YN (reprint author), Taipei Med Univ, 250 Wu Hsing St, Taipei 11031, Taiwan. EM liuy@tmu.edu.tw FU Ministry of Science and Technology [MOST103-2314-B-038-051]; National Health Research Institutes of Taiwan [NHRI-EX104-10308BC] FX This work was jointly supported by grants from the Ministry of Science and Technology (MOST103-2314-B-038-051) and the National Health Research Institutes (NHRI-EX104-10308BC) of Taiwan. NR 37 TC 18 Z9 18 U1 2 U2 7 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 2015 VL 75 IS 15 BP 3077 EP 3086 DI 10.1158/0008-5472.CAN-14-3380 PG 10 WC Oncology SC Oncology GA CO7EU UT WOS:000359323200012 PM 26071255 ER PT J AU Russell, MR Penikis, A Oldridge, DA Alvarez-Dominguez, JR McDaniel, L Diamond, M Padovan, O Raman, P Li, YM Wei, JS Zhang, SL Gnanchandran, J Seeger, R Asgharzadeh, S Khan, J Diskin, SJ Maris, JM Cole, KA AF Russell, Mike R. Penikis, Annalise Oldridge, Derek A. Alvarez-Dominguez, Juan R. McDaniel, Lee Diamond, Maura Padovan, Olivia Raman, Pichai Li, Yimei Wei, Jun S. Zhang, Shile Gnanchandran, Janahan Seeger, Robert Asgharzadeh, Shahab Khan, Javed Diskin, Sharon J. Maris, John M. Cole, Kristina A. TI CASC15-S Is a Tumor Suppressor lncRNA at the 6p22 Neuroblastoma Susceptibility Locus SO CANCER RESEARCH LA English DT Article ID LONG NONCODING RNAS; HIGH-RISK NEUROBLASTOMA; DEVELOPMENTAL BIOLOGY; EPIGENETIC REGULATION; CANCER; GENOME; ASSOCIATION; EXPRESSION; CELLS; BARD1 AB Chromosome 6p22 was identified recently as a neuroblastoma susceptibility locus, but its mechanistic contributions to tumorigenesis are as yet undefined. Here we report that the most highly significant single-nucleotide polymorphism (SNP) associations reside within CASC15, a long noncoding RNA that we define as a tumor suppressor at 6p22. Low-level expression of a short CASC15 isoform (CASC15-S) associated highly with advanced neuroblastoma and poor patient survival. In human neuroblastoma cells, attenuating CASC15-S increased cellular growth and migratory capacity. Gene expression analysis revealed downregulation of neuroblastoma-specific markers in cells with attenuated CASC15-S, with concomitant increases in cell adhesion and extracellular matrix transcripts. Altogether, our results point to CASC15-S as a mediator of neural growth and differentiation, which impacts neuroblastoma initiation and progression. (C) 2015 AACR. C1 [Russell, Mike R.; Penikis, Annalise; Oldridge, Derek A.; McDaniel, Lee; Diamond, Maura; Raman, Pichai; Li, Yimei; Diskin, Sharon J.; Maris, John M.; Cole, Kristina A.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Alvarez-Dominguez, Juan R.] MIT, Whitehead Inst Biomed Res, Cambridge, MA USA. [Alvarez-Dominguez, Juan R.] MIT, Dept Biol, Cambridge, MA USA. [Padovan, Olivia] Univ Penn, Dept Phys & Astron, Philadelphia, PA 19104 USA. [Raman, Pichai] Childrens Hosp Philadelphia, Ctr Biomed Informat, Philadelphia, PA 19104 USA. [Wei, Jun S.; Zhang, Shile; Khan, Javed] NCI, Oncogen Sect, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Gnanchandran, Janahan; Seeger, Robert; Asgharzadeh, Shahab] Childrens Hosp Philadelphia, Div Hematol Oncol, Dept Pediat, Philadelphia, PA 19104 USA. [Gnanchandran, Janahan; Seeger, Robert; Asgharzadeh, Shahab] Univ So Calif, Saban Res Inst, Los Angeles, CA USA. [Diskin, Sharon J.; Maris, John M.; Cole, Kristina A.] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Diskin, Sharon J.; Maris, John M.; Cole, Kristina A.] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. RP Cole, KA (reprint author), Childrens Hosp Philadelphia, 3501 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM colek@email.chop.edu RI Cole, Kristina/M-3922-2015 FU Alex's Lemonade Stand Foundation; [K08CA136979] FX This work was supported by grant K08CA136979 (K.A. Cole) and Alex's Lemonade Stand Foundation (K.A. Cole and M.R. Russell). NR 48 TC 12 Z9 12 U1 0 U2 13 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 2015 VL 75 IS 15 BP 3155 EP 3166 DI 10.1158/0008-5472.CAN-14-3613 PG 12 WC Oncology SC Oncology GA CO7EU UT WOS:000359323200020 PM 26100672 ER PT J AU Torabi-Parizi, P Davey, RT Suffredini, AF Chertow, DS AF Torabi-Parizi, Parizad Davey, Richard T., Jr. Suffredini, Anthony F. Chertow, Daniel S. TI Caring for Critically Ill Patients Infected With the Ebola Virus Logistic and Human Challenges Response SO CHEST LA English DT Letter C1 [Torabi-Parizi, Parizad; Suffredini, Anthony F.; Chertow, Daniel S.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Davey, Richard T., Jr.] NIAID, Clin Res Sect, Immunoregulat Lab, NIH, Bethesda, MD USA. RP Torabi-Parizi, P (reprint author), NIH, Dept Crit Care Med, 10 Ctr Dr,2C145, Bethesda, MD 20892 USA. EM torabiparizip@cc.nih.gov NR 1 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 2015 VL 148 IS 2 BP E65 EP E65 DI 10.1378/chest.15-0986 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CO2SA UT WOS:000359005700014 PM 26238847 ER PT J AU Remaley, AT AF Remaley, Alan T. TI A Woman with Primary Biliary Cirrhosis and Hyponatremia Comment SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NIH, Bldg 10,Rm 2C-433,10 Ctr Dr,MSC 1508, Bethesda, MD 20892 USA. EM aremaley1@cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD AUG PY 2015 VL 61 IS 8 BP 1032 EP 1032 DI 10.1373/clinchem.2014.236851 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CO0BO UT WOS:000358815300008 PM 26220584 ER PT J AU Korzun, WJ Nilsson, G Bachmann, LM Myers, GL Sakurabayashi, I Nakajima, K Nakamura, M Shamburek, RD Remaley, AT Miller, WG AF Korzun, William J. Nilsson, Goeran Bachmann, Lorin M. Myers, Gary L. Sakurabayashi, Ikunosuke Nakajima, Katsuyuki Nakamura, Masakazu Shamburek, Robert D. Remaley, Alan T. Miller, W. Greg TI Difference in Bias Approach for Commutability Assessment: Application to Frozen Pools of Human Serum Measured by 8 Direct Methods for HDL and LDL Cholesterol SO CLINICAL CHEMISTRY LA English DT Article AB BACKGROUND: We used a difference in bias approach to evaluate the commutability of 4 frozen serum pools for 8 direct methods for measurement of HDL and LDL cholesterol (HDLC and LDLC). METHODS: Freshly collected nonfrozen sera from 138 diseased and 37 nondiseased patients and 4 frozen pools from the CDC Lipid Standardization Program were measured by direct methods and by the beta-quantification reference measurement procedure of the CDC. We used an error components model to estimate the difference in the bias component of error plus its uncertainty for frozen pools vs patient samples between the direct method and the reference procedure. Frozen pools with bias differences less than a critical value determined by either medical requirements for bias or the random error components of the measurement procedures were considered commutable. RESULTS: On the basis of medical requirement criteria, 1 of the 4 frozen pools was commutable for most of the HDLC methods for both diseased and nondiseased patients, and none was commutable for LDLC methods. On the basis of random error criteria, all of the frozen pools were generally commutable for all of the HDLC methods for both diseased and nondiseased patients, and 1 of the 4 frozen pools was generally commutable for most of the LDLC methods for both diseased and nondiseased patients. CONCLUSIONS: Commutability was assessed as the closeness of agreement of the difference in bias between a reference material and a set of patient samples. Criteria for commutability could be based on fixed medical requirements for bias or on random error components. (C) 2015 American Association for Clinical Chemistry C1 [Korzun, William J.; Bachmann, Lorin M.; Miller, W. Greg] Virginia Commonwealth Univ, Richmond, VA USA. [Myers, Gary L.] Amer Assoc Clin Chem, Washington, DC USA. [Sakurabayashi, Ikunosuke] Jichi Med Univ, Shimotsuke, Tochigi, Japan. [Nakajima, Katsuyuki] Otsuka Pharmaceut Co Ltd, Tokyo, Japan. [Nakamura, Masakazu] Osaka Med Ctr Hlth Sci & Promot, Osaka, Japan. [Shamburek, Robert D.; Remaley, Alan T.] NIH, Bethesda, MD 20892 USA. RP Miller, WG (reprint author), POB 980286, Richmond, VA 23298 USA. EM gmiller@vcu.edu NR 9 TC 4 Z9 4 U1 1 U2 7 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD AUG PY 2015 VL 61 IS 8 BP 1107 EP 1113 DI 10.1373/clinchem.2015.240861 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CO0BO UT WOS:000358815300015 PM 26071490 ER PT J AU Davis, M Kopp, JB AF Davis, Michael Kopp, Jeffrey B. TI Preparing for Disasters for Patients on Dialysis SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID HURRICANE SANDY; KATRINA; CARE C1 [Davis, Michael; Kopp, Jeffrey B.] NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD USA. RP Kopp, JB (reprint author), NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jbkopp@nih.gov FU Intramural NIH HHS NR 10 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD AUG PY 2015 VL 10 IS 8 BP 1316 EP 1317 DI 10.2215/CJN.07340715 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA CO5AU UT WOS:000359172800003 PM 26220815 ER PT J AU Drawz, PE Archdeacon, P McDonald, CJ Powe, NR Smith, KA Norton, J Williams, DE Patel, UD Narva, A AF Drawz, Paul E. Archdeacon, Patrick McDonald, Clement J. Powe, Neil R. Smith, Kimberly A. Norton, Jenna Williams, Desmond E. Patel, Uptal D. Narva, Andrew TI CKD as a Model for Improving Chronic Disease Care through Electronic Health Records SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; INCIDENT HEMODIALYSIS-PATIENTS; INFORMATION-TECHNOLOGY; CONTROLLED-TRIAL; AMBULATORY-CARE; CLINICAL-TRIALS; CHRONIC ILLNESS; BLOOD-PRESSURE; UNITED-STATES; MORTALITY AB Electronic health records have the potential to improve the care of patients with chronic medical conditions. CKD provides a unique opportunity to show this potential: the disease is common in the United States, there is significant room to improve CKD detection and management, CKD and its related conditions are defined primarily by objective laboratory data, CKD care requires collaboration by a diverse team of health care professionals, and improved access to CKD-related data would enable identification of a group of patients at high risk for multiple adverse outcomes. However, to realize the potential for improvement in CKD-related care, electronic health records will need to provide optimal functionality for providers and patients and interoperability across multiple health care settings. The goal of the National Kidney Disease Education Program Health Information Technology Working Group is to enable and support the widespread interoperability of data related to kidney health among health care software applications to optimize CKD detection and management. Over the course of the last 2 years, group members met to identify general strategies for using electronic health records to improve care for patients with CKD. This paper discusses these strategies and provides general goals for appropriate incorporation of CKD-related data into electronic health records and corresponding design features that may facilitate (1) optimal care of individual patients with CKD through improved access to clinical information and decision support, (2) clinical quality improvement through enhanced population management capabilities, (3) CKD surveillance to improve public health through wider availability of population-level CKD data, and (4) research to improve CKD management practices through efficiencies in study recruitment and data collection. Although these strategies may be most effectively applied in the setting of CKD, because it is primarily defined by laboratory abnormalities and therefore, an ideal computable electronic health record phenotype, they may also apply to other chronic diseases. C1 [Drawz, Paul E.] Univ Minnesota, Div Renal Dis & Hypertens, Minneapolis, MN USA. [Archdeacon, Patrick] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [McDonald, Clement J.] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. [Powe, Neil R.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Smith, Kimberly A.] Ctr Medicare & Medicaid Serv, Ctr Clin Stand & Qual, Baltimore, MD USA. [Norton, Jenna; Narva, Andrew] NIDDK, Natl Kidney Dis Educ Program, Bethesda, MD 20892 USA. [Williams, Desmond E.] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Patel, Uptal D.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. RP Narva, A (reprint author), NIDDK, Natl Kidney Dis Educ Program, NIH, Bldg 31,Room 9A27 MSC 2560,31 Ctr Dr, Bethesda, MD 20892 USA. EM narvaa@niddk.nih.gov FU National Institutes of Health (NIH) [R01-DK093938, R34-DK102166]; NKDEP HIT Intern FX U.D.P. was supported by National Institutes of Health (NIH) Grants R01-DK093938 and R34-DK102166.; Thanks for support from the NKDEP HIT Intern, Jessica Pereira. NR 56 TC 1 Z9 1 U1 1 U2 7 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD AUG PY 2015 VL 10 IS 8 BP 1488 EP 1499 DI 10.2215/CJN.00940115 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA CO5AU UT WOS:000359172800025 PM 26111857 ER PT J AU Ernst, M Luciana, M AF Ernst, Monique Luciana, Monica TI Neuroimaging of the dopamine/reward system in adolescent drug use SO CNS SPECTRUMS LA English DT Review DE adolescence; substance abuse; marijuana; striatum; dopamine; neuroimaging ID D-2/D-3 RECEPTOR AVAILABILITY; POSITRON-EMISSION-TOMOGRAPHY; VENTRAL TEGMENTAL AREA; PREFRONTAL CORTEX NEURONS; YOUTH TREATMENT CYT; NUCLEUS-ACCUMBENS; CANNABIS USERS; POSTNATAL-DEVELOPMENT; MARIJUANA USE; INDIVIDUAL-DIFFERENCES AB Adolescence is characterized by heightened risk-taking, including substance misuse. These behavioral patterns are influenced by ontogenic changes in neurotransmitter systems, particularly the dopamine system, which is fundamentally involved in the neural coding of reward and motivated approach behavior. During adolescence, this system evidences a peak in activity. At the same time, the dopamine (DA) system is neuroplastically altered by substance abuse, impacting subsequent function. Here, we describe properties of the dopamine system that change with typical adolescent development and that are altered with substance abuse. Much of this work has been gleaned from animal models due to limitations in measuring dopamine in pediatric samples. Structural and functional neuroimaging techniques have been used to examine structures that are heavily DA-innervated; they measure morphological and functional changes with age and with drug exposure. Presenting marijuana abuse as an exemplar, we consider recent findings that support an adolescent peak in DA-driven reward-seeking behavior and related deviations in motivational systems that are associated with marijuana abuse/dependence. Clinicians are advised that (1) chronic adolescent marijuana use may lead to deficiencies in incentive motivation, (2) that this state is due to marijuana's interactions with the developing DA system, and (3) that treatment strategies should be directed to remediating resultant deficiencies in goal-directed activity. C1 [Ernst, Monique] NIMH, Neurodev Reward Syst Program, Bethesda, MD 20892 USA. [Luciana, Monica] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. RP Ernst, M (reprint author), NIMH, Neurodev Reward Syst, Sect Neurobiol Fear & Anxiety NFA, Emot Dev & Affect Neurosci Branch EDAN,NIH, 15K North Dr, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism [AA020033] FX Monique Ernst does not have anything to disclose. Monica Luciana has the following disclosure: National Institute on Alcohol Abuse and Alcoholism, grant recipient, Grant AA020033. NR 134 TC 2 Z9 2 U1 4 U2 14 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1092-8529 EI 2165-6509 J9 CNS SPECTRUMS JI CNS Spectr. PD AUG PY 2015 VL 20 IS 4 BP 427 EP 441 DI 10.1017/S1092852915000395 PG 15 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CO2TA UT WOS:000359008300011 PM 26095977 ER PT J AU Ordonez, AE Sastry, NV Gogtay, N AF Ordonez, Anna E. Sastry, Nevin V. Gogtay, Nitin TI Functional and clinical insights from neuroimaging studies in childhood-onset schizophrenia SO CNS SPECTRUMS LA English DT Review DE Childhood onset schizophrenia; neurodevelopment; neuroimaging; review; schizophrenia ID PROGRESSIVE BRAIN CHANGES; GRAY-MATTER LOSS; 1ST-EPISODE SCHIZOPHRENIA; NONPSYCHOTIC SIBLINGS; CORTICAL THICKNESS; HEALTHY SIBLINGS; TEMPORAL-LOBE; NEURODEVELOPMENTAL MODEL; COGNITIVE DYSMETRIA; SPECTRUM DISORDERS AB Childhood-onset schizophrenia is a rare pediatric onset psychiatric disorder continuous with and typically more severe than its adult counterpart. Neuroimaging research conducted on this population has revealed similarly severe neural abnormalities. When taken as a whole, neuroimaging research in this population shows generally decreased cortical gray matter coupled with white matter connectivity abnormalities, suggesting an anatomical basis for deficits in executive function. Subcortical abnormalities are pronounced in limbic structures, where volumetric deficits are likely related to social skill deficits, and cerebellar deficits that have been correlated to cognitive abnormalities. Structures relevant to motor processing also show a significant alteration, with volumetric increase in basal ganglia structures likely due to antipsychotic administration. Neuroimaging of this disorder shows an important clinical image of exaggerated cortical loss, altered white matter connectivity, and differences in structural development of subcortical areas during the course of development and provides important background to the disease state. C1 [Ordonez, Anna E.; Sastry, Nevin V.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Gogtay, Nitin] NIMH, Off Clin Res, NIH, Bethesda, MD 20892 USA. RP Ordonez, AE (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Rm 3N202,10 Ctr Dr,MSC-1600, Bethesda, MD 20892 USA. EM annaordonez@mail.nih.gov NR 104 TC 0 Z9 0 U1 4 U2 14 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1092-8529 EI 2165-6509 J9 CNS SPECTRUMS JI CNS Spectr. PD AUG PY 2015 VL 20 IS 4 BP 442 EP 450 DI 10.1017/S1092852915000437 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CO2TA UT WOS:000359008300012 PM 26234702 ER PT J AU Fessler, MB AF Fessler, Michael B. TI Regulation of Adaptive Immunity in Health and Disease by Cholesterol Metabolism SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review DE Cholesterol; Lipoprotein; T cell; Dendritic cell; Asthma; Statins ID LIVER-X-RECEPTOR; T-CELL-ACTIVATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; HIGH-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-A-I; REMITTING MULTIPLE-SCLEROSIS; EMERGENCY-DEPARTMENT VISITS; LIPID RAFTS; DENDRITIC CELLS; ANTIGEN PRESENTATION AB Four decades ago, it was observed that stimulation of T cells induces rapid changes in cellular cholesterol that are required before proliferation can commence. Investigators returning to this phenomenon have finally revealed its molecular underpinnings. Cholesterol trafficking and its dysregulation are now also recognized to strongly influence dendritic cell function, T cell polarization, and antibody responses. In this review, the state of the literature is reviewed on how cholesterol and its trafficking regulate the cells of the adaptive immune response and in vivo disease phenotypes of dysregulated adaptive immunity, including allergy, asthma, and autoimmune disease. Emerging evidence supporting a potential role for statins and other lipid-targeted therapies in the treatment of these diseases is presented. Just as vascular biologists have embraced immunity in the pathogenesis and treatment of atherosclerosis, so should basic and clinical immunologists in allergy, pulmonology, and other disciplines seek to encompass a basic understanding of lipid science. C1 NIEHS, Immun Inflammat & Dis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Fessler, MB (reprint author), NIEHS, Immun Inflammat & Dis Lab, NIH, 111 TW Alexander Dr,Maildrop D2-01,POB 12233, Res Triangle Pk, NC 27709 USA. EM fesslerm@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES102005] FX The author thanks Dr. Sue Edelstein for assistance with figure production. This work was supported by the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES102005). NR 164 TC 8 Z9 8 U1 0 U2 27 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 EI 1534-6315 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD AUG PY 2015 VL 15 IS 8 AR 48 DI 10.1007/s11882-015-0548-7 PG 16 WC Allergy; Immunology SC Allergy; Immunology GA CN9PC UT WOS:000358780300004 PM 26149587 ER PT J AU Bernhardt, ML Lowther, KM Padilla-Banks, E McDonough, CE Lee, KN Evsikov, AV Uliasz, TF Chidiac, P Williams, CJ Mehlmann, LM AF Bernhardt, Miranda L. Lowther, Katie M. Padilla-Banks, Elizabeth McDonough, Caitlin E. Lee, Katherine N. Evsikov, Alexei V. Uliasz, Tracy F. Chidiac, Peter Williams, Carmen J. Mehlmann, Lisa M. TI Regulator of G-protein signaling 2 (RGS2) suppresses premature calcium release in mouse eggs SO DEVELOPMENT LA English DT Article DE RGS2; G(q); Oocyte; Meiotic maturation; Calcium; Egg activation ID INDUCED CA2+ RELEASE; MEIOTIC MATURATION; INOSITOL TRISPHOSPHATE; MUSCARINIC RECEPTOR; MAMMALIAN OOCYTES; ACETYLCHOLINE-RECEPTORS; ENDOPLASMIC-RETICULUM; EMBRYO DEVELOPMENT; ADENYLYL-CYCLASE; ACTIVATION AB During oocyte maturation, capacity and sensitivity of Ca2+ signaling machinery increases dramatically, preparing the metaphase II (MII)-arrested egg for fertilization. Upon sperm-egg fusion, Ca2+ release from IP3-sensitive endoplasmic reticulum stores results in cytoplasmic Ca2+ oscillations that drive egg activation and initiate early embryo development. Premature Ca2+ release can cause parthenogenetic activation prior to fertilization; thus, preventing inappropriate Ca2+ signaling is crucial for ensuring robust MII arrest. Here, we show that regulator of G-protein signaling 2 (RGS2) suppresses Ca2+ release in MII eggs. Rgs2 mRNA was recruited for translation during oocyte maturation, resulting in similar to 20-fold more RGS2 protein in MII eggs than in fully grown immature oocytes. Rgs2-siRNA-injected oocytes matured to MII; however, they had increased sensitivity to low pH and acetylcholine (ACh), which caused inappropriate Ca2+ release and premature egg activation. When matured in vitro, RGS2-depleted eggs underwent spontaneous Ca2+ increases that were sufficient to cause premature zona pellucida conversion. Rgs2(-/-) females had reduced litter sizes, and their eggs had increased sensitivity to low pH and ACh. Rgs2(-/-) eggs also underwent premature zona pellucida conversion in vivo. These findings indicate that RGS2 functions as a brake to suppress premature Ca2+ release in eggs that are poised on the brink of development. C1 [Bernhardt, Miranda L.; Padilla-Banks, Elizabeth; McDonough, Caitlin E.; Williams, Carmen J.] NIEHS, Reprod & Dev Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Lowther, Katie M.; Uliasz, Tracy F.; Mehlmann, Lisa M.] UConn Hlth, Dept Cell Biol, Farmington, CT 06030 USA. [Lee, Katherine N.; Chidiac, Peter] Univ Western Ontario, Dept Physiol & Pharmacol, Schulich Sch Med & Dent, London, ON N6A 5C1, Canada. [Evsikov, Alexei V.] Univ S Florida, Dept Mol Med, Tampa, FL 33612 USA. RP Williams, CJ (reprint author), NIEHS, Reprod & Dev Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM williamsc5@niehs.nih.gov; lmehlman@uchc.edu RI Chidiac, Peter/L-5906-2015; OI Bernhardt, Miranda/0000-0001-5424-5685 FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Environmental Health Sciences [Z01ES102985]; NIH [HD056366]; University of Connecticut Health Center Research Advisory Council; Canadian Institutes of Health Research FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences [Z01ES102985 to C.J.W.], NIH grant HD056366 and the University of Connecticut Health Center Research Advisory Council (to L.M.M.), and a grant from the Canadian Institutes of Health Research (to P.C.). Deposited in PMC for release after 12 months. NR 54 TC 2 Z9 2 U1 2 U2 11 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD AUG 1 PY 2015 VL 142 IS 15 BP 2633 EP U167 DI 10.1242/dev.121707 PG 17 WC Developmental Biology SC Developmental Biology GA CO1VF UT WOS:000358943200010 PM 26160904 ER PT J AU McCaffery, JM Anderson, A Bantle, JP Berkowitz, RI Bray, GA Cheskin, L Clark, JM Curtis, JM Delahanty, LM Evans, M Foreyt, JP Glasser, S Gregg, EW Hanson, RL Hazuda, HP Hill, JO Horton, ES Huggins, GS Jakicic, JM Jeffery, RW Johnson, KC Kahn, SE Kelley, DE Kitabchi, AE Knowler, WC Lewis, CE Montez, MG Kure, A Nathan, DM Nyenwe, E Pajewski, NM Papandonatos, GD Patricio, J Peter, I Peters, A Pi-Sunyer, X Pownall, H Wadden, TA Wagenknecht, LE Wing, RR Wyatt, H AF McCaffery, Jeanne M. Anderson, Andrea Bantle, John P. Berkowitz, Robert I. Bray, George A. Cheskin, Lawrence Clark, Jeanne M. Curtis, Jeffrey M. Delahanty, Linda M. Evans, Mary Foreyt, John P. Glasser, Stephen Gregg, Edward W. Hanson, Robert L. Hazuda, Helen P. Hill, James O. Horton, Edward S. Huggins, Gordon S. Jakicic, John M. Jeffery, Robert W. Johnson, Karen C. Kahn, Steven E. Kelley, David E. Kitabchi, Abbas E. Knowler, William C. Lewis, Cora E. Montez, Maria G. Kure, Anne Nathan, David M. Nyenwe, Ebenezer Pajewski, Nicholas M. Papandonatos, George D. Patricio, Jennifer Peter, Inga Peters, Anne Pi-Sunyer, Xavier Pownall, Henry Wadden, Thomas A. Wagenknecht, Lynne E. Wing, Rena R. Wyatt, Holly CA Look AHEAD Res Grp TI Prospective association of a genetic risk score and lifestyle intervention with cardiovascular morbidity and mortality among individuals with type 2 diabetes: the Look AHEAD randomised controlled trial SO DIABETOLOGIA LA English DT Article DE Cardiovascular disease; Genetics; Lifestyle intervention; Myocardial infarction; Obesity; Stroke; Type 2 diabetes; Weight loss ID CORONARY-HEART-DISEASE; UNRELATED INDIVIDUALS; CLINICAL-TRIAL; WEIGHT-LOSS; WIDE ASSOCIATION; HEALTH; PREDICTION; ATHEROSCLEROSIS; INFERENCE; OBESITY AB Aims/hypothesis Both obesity and genetics contribute to cardiovascular disease (CVD). We examined whether a genetic risk score (GRS) prospectively predicted cardiovascular morbidity andmortality among overweight/obese individuals with type 2 diabetes and whether behavioural weight loss could diminish this association. Methods Look AHEAD (Action for Health in Diabetes) is a randomised controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes among overweight/obese individuals with type 2 diabetes. Of the participants, 4,016 provided consent for genetic analyses and had DNA samples passing quality control procedures. These secondary data analyses focused on whether a GRS derived from 153 single nucleotide polymorphisms (SNPs) associated with coronary artery disease in the most recent genome-wide association study predicted cardiovascular morbidity and mortality over a median of 9.6 years of follow-up, and whether ILI would diminish this association. Results The GRS significantly predicted the primary composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for angina in the full sample (HR, 95% CI per 1 SD increase in GRS: 1.19 [1.10, 1.28]) and among individuals with no known history of CVD at baseline (HR 1.18 [95% CI 1.07, 1.30]). In no case did ILI significantly alter this association. Conclusions/interpretation A GRS comprised of SNPs significantly predicts cardiovascular morbidity and mortality over 9.6 years of follow-up in Look AHEAD. Lifestyle intervention did not alter the genetic association. C1 [McCaffery, Jeanne M.; Wing, Rena R.] Brown Univ, Alpert Sch Med, Miriam Hosp, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Anderson, Andrea; Pajewski, Nicholas M.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Bantle, John P.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Berkowitz, Robert I.; Wadden, Thomas A.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Bray, George A.] Louisiana State Univ, Pennington Biomed Res Ctr, Dept Clin Obes, Baton Rouge, LA 70808 USA. [Cheskin, Lawrence] Johns Hopkins, Johns Hopkins Bloomberg Sch Publ Hlth, Global Obes Prevent Ctr, Hlth Behav & Soc, Baltimore, MD USA. [Clark, Jeanne M.] Johns Hopkins Univ, Dept Med Gen Internal Med & Epidemiol, Baltimore, MD USA. [Curtis, Jeffrey M.] St Josephs Hosp, Dept Family Med, Phoenix, AZ USA. [Curtis, Jeffrey M.] NIDDK, Southwest Amer Indian Ctr, NIH, Phoenix, AZ USA. [Delahanty, Linda M.] Massachusetts Gen Hosp, Dept Med, Ctr Diabet, Boston, MA 02114 USA. [Delahanty, Linda M.; Nathan, David M.] Harvard Univ, Sch Med, Boston, MA USA. [Evans, Mary] NIDDK, Dept Digest Dis & Nutr, Bethesda, MD 20892 USA. [Foreyt, John P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Glasser, Stephen] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Gregg, Edward W.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Hanson, Robert L.] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Hazuda, Helen P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Nephrol, San Antonio, TX 78229 USA. [Hill, James O.] Univ Colorado, Anschutz Hlth & Wellness Ctr, Aurora, CO USA. [Horton, Edward S.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Horton, Edward S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Huggins, Gordon S.] Tufts Med Ctr, MCRI Ctr Translat Genom, Boston, MA USA. [Jakicic, John M.] Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA USA. [Jeffery, Robert W.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Kahn, Steven E.; Kure, Anne] Univ Washington, Seattle, WA 98195 USA. [Kelley, David E.] Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA USA. [Kitabchi, Abbas E.] Univ Tennessee, Ctr Hlth Sci, Dept Med, Memphis, TN 38163 USA. [Knowler, William C.] NIDDK, Phoenix, AZ USA. [Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Montez, Maria G.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Nephrol, San Antonio, TX 78229 USA. [Kure, Anne] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Nathan, David M.] Massachusetts Gen Hosp, Dept Med, Diabet Unit, Ctr Diabet, Boston, MA 02114 USA. [Nyenwe, Ebenezer] Univ Tennessee, Ctr Hlth Sci, Div Endocrinol Diabet & Metab, Memphis, TN 38163 USA. [Papandonatos, George D.] Brown Univ, Sch Publ Hlth, Dept Biostat, Providence, RI 02912 USA. [Patricio, Jennifer; Pi-Sunyer, Xavier] Columbia Univ, St Lukes Roosevelt Hosp Ctr, New York Obes Res Ctr, New York, NY USA. [Peter, Inga] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Peters, Anne] Roybal Comprehens Hlth Ctr, Los Angeles, CA USA. [Pownall, Henry] Methodist Hosp, Res Inst, Dept Cardiol, Houston, TX 77030 USA. [Wagenknecht, Lynne E.] Wake Forest Sch Med, Dept Publ Hlth Serv, Winston Salem, NC USA. [Wyatt, Holly] Univ Colorado, Anschutz Hlth & Wellness Ctr, Aurora, CO USA. RP McCaffery, JM (reprint author), Miriam Hosp, Weight Control & Diabet Res Ctr, 196 Richmond St, Providence, RI 02903 USA. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases [DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, DK56992]; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; NIH Office of Research on Women's Health; Centers for Disease Control and Prevention; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Johns Hopkins Medical Institutions Bayview General Clinical Research Center [M01RR02719]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center; Massachusetts Institute of Technology General Clinical Research Center [M01RR01066]; University of Colorado Health Sciences Center General Cl inical Research Center [M01RR00051]; Clinical Nutrition Research Unit [P30 DK48520]; University of Tennessee at Memphis General Clinical Research Center [M01RR0021140]; University of Pittsburgh General Clinical Research Center (GCRC) [M01RR000056]; Clinical Translational Research Center (CTRC) - Clinical and Translational Science Award [UL1 RR 024153]; NIH grant [DK 046204]; VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; Frederic C. Bartter General Clinical Research Center [M01RR01346] FX Funded by the National Institutes of Health through cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases: DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135 and DK56992. Additional funding was provided by the National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; NIH Office of Research on Women's Health; and the Centers for Disease Control and Prevention. 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 (I.H.S.) provided personnel, medical oversight and use of facilities. The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the I.H.S. or other funding sources.; Additional support was received from The Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01RR02719); the Massachusetts General Hospital Mallinckrodt General Clinical Research Center and the Massachusetts Institute of Technology General Clinical Research Center (M01RR01066); the University of Colorado Health Sciences Center General Cl inical Research Center (M01RR00051) and Clinical Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR0021140); the University of Pittsburgh General Clinical Research Center (GCRC) (M01RR000056); the Clinical Translational Research Center (CTRC) funded by the Clinical and Translational Science Award (UL1 RR 024153) and NIH grant (DK 046204); the VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; and the Frederic C. Bartter General Clinical Research Center (M01RR01346). NR 35 TC 1 Z9 1 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2015 VL 58 IS 8 BP 1803 EP 1813 DI 10.1007/s00125-015-3610-z PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CO0XN UT WOS:000358877300020 ER PT J AU Bardo, MT Compton, WM AF Bardo, Michael. T. Compton, Wilson. M. TI Does physical activity protect against drug abuse vulnerability? SO DRUG AND ALCOHOL DEPENDENCE LA English DT Review DE Physical activity; Exercise; Drug abuse; Drug reward; Impulsivity; Stress ID CONDITIONED PLACE PREFERENCE; MEDIAL PREFRONTAL CORTEX; SUBSTANCE USE DISORDERS; POSITRON-EMISSION-TOMOGRAPHY; MODERATE-INTENSITY EXERCISE; RANDOMIZED CONTROLLED-TRIAL; CUE-INDUCED REINSTATEMENT; ALTERS BRAIN ACTIVATION; RUNNING-WHEEL EXERCISE; SMOKING-CESSATION AB Background: The current review examined recent literature to determine our state of knowledge about the potential ability of physical activity serve as a protectant against drug abuse vulnerability. Methods: Both preclinical and clinical studies were examined using either associational or random assignment study designs. In addition to examining drug use as an outcome variable, the potential neural mediators linking physical activity and drug abuse vulnerability were examined. Conclusions: Several important conclusions may be drawn. First, the preclinical evidence is solid in showing that physical activity in various forms is able to serve as both a preventive and treatment intervention that reduces drug use, although voluntary alcohol drinking appears to be an exception to this conclusion. Second, the clinical evidence provides some evidence, albeit mixed, to suggest a beneficial effect of physical activity on tobacco dependent individuals. In contrast, there exists only circumstantial evidence that physical activity may reduce use of drugs other than nicotine, and there is essentially no solid information from random control studies to know if physical activity may prevent initiation of problem use. Finally, both preclinical and clinical evidence shows that various brain systems are altered by physical activity, with the medial prefrontal cortex (mPFC) serving as one potential node that may mediate the putative link between physical activity and drug abuse vulnerability. It is concluded that novel neuro-behavioral approaches taking advantage of novel techniques for assessing the physiological impact of physical activity are needed and can be used to inform the longitudinal random control studies that will answer definitively the question posed. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Bardo, Michael. T.] Univ Kentucky, Dept Psychol, Lexington, KY 40536 USA. [Bardo, Michael. T.] Univ Kentucky, Ctr Drug Abuse Res Translat, Lexington, KY 40536 USA. [Compton, Wilson. M.] NIDA, Bethesda, MD 20892 USA. RP Bardo, MT (reprint author), Univ Kentucky, Dept Psychol, Lexington, KY 40536 USA. EM mbardo@uky.edu NR 170 TC 9 Z9 9 U1 4 U2 36 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD AUG 1 PY 2015 VL 153 BP 3 EP 13 DI 10.1016/j.drugalcdep.2015.05.037 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CO5AP UT WOS:000359172300003 PM 26091750 ER PT J AU de Alexandre, RB Horvath, AD Szarek, E Manning, AD Leal, LF Kardauke, F Epstein, JA Carraro, DM Soares, FA Apanasovich, TV Stratakis, CA Faucz, FR AF de Alexandre, Rodrigo B. Horvath, Anelia D. Szarek, Eva Manning, Allison D. Leal, Leticia F. Kardauke, Fabio Epstein, Jonathan A. Carraro, Dirce M. Soares, Fernando A. Apanasovich, Tatiyana V. Stratakis, Constantine A. Faucz, Fabio R. TI Phosphodiesterase sequence variants may predispose to prostate cancer SO ENDOCRINE-RELATED CANCER LA English DT Article DE prostate cancer; PCa; phosphodiesterases; PDE family; CREB; pCREB; cAMP; cGMP ID PROTEIN-KINASE-A; CAMP-SPECIFIC PHOSPHODIESTERASE; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; ERECTILE DYSFUNCTION; GENE-EXPRESSION; ADRENAL-CORTEX; 11A PDE11A; ADRENOCORTICAL HYPERPLASIA; ANDROGEN RECEPTOR; INHIBITS GROWTH AB We hypothesized that mutations that inactivate phosphodiesterase (PDE) activity and lead to increased cAMP and cyclic guanosine monophosphate levels may be associated with prostate cancer (PCa). We sequenced the entire PDE coding sequences in the DNA of 16 biopsy samples from PCa patients. Novel mutations were confirmed in the somatic or germline state by Sanger sequencing. Data were then compared to the 1000 Genome Project. PDE, CREB and pCREB protein expression was also studied in all samples, in both normal and abnormal tissue, by immunofluorescence. We identified three previously described PDE sequence variants that were significantly more frequent in PCa. Four novel sequence variations, one each in the PDE4B, PDE6C, PDE7B and PDE10A genes, respectively, were also found in the PCa samples. Interestingly, PDE10A and PDE4B novel variants that were present in 19 and 6% of the patients were found in the tumor tissue only. In patients carrying PDE defects, there was pCREB accumulation (P < 0.001), and an increase of the pCREB: CREB ratio (patients 0.97 +/- 0.03; controls 0.52 +/- 0.03; P-value <0.001) by immunohistochemical analysis. We conclude that PDE sequence variants may play a role in the predisposition and/or progression to PCa at the germline and/or somatic state respectively. C1 [de Alexandre, Rodrigo B.; Horvath, Anelia D.; Szarek, Eva; Manning, Allison D.; Leal, Leticia F.; Epstein, Jonathan A.; Stratakis, Constantine A.; Faucz, Fabio R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD 20892 USA. [de Alexandre, Rodrigo B.; Horvath, Anelia D.; Szarek, Eva; Manning, Allison D.; Leal, Leticia F.; Epstein, Jonathan A.; Stratakis, Constantine A.; Faucz, Fabio R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD 20892 USA. [de Alexandre, Rodrigo B.; Kardauke, Fabio; Faucz, Fabio R.] Pontificia Univ Catolica Parana PUCPR, Sch Hlth & Biosci, BR-80215901 Curitiba, Parana, Brazil. [Horvath, Anelia D.] George Washington Univ, Dept Physiol & Pharmacol, Washington, DC 20037 USA. [Carraro, Dirce M.] AC Camargo Canc Ctr, CIPE, Lab Genom & Mol Biol, BR-01509010 Sao Paulo, SP, Brazil. [Soares, Fernando A.] AC Camargo Canc Ctr, Dept Pathol, BR-01509010 Sao Paulo, SP, Brazil. [Apanasovich, Tatiyana V.] George Washington Univ, Dept Stat, Washington, DC 20037 USA. RP Faucz, FR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD 20892 USA. EM fabio.faucz@nih.gov RI de Alexandre, Rodrigo/H-9489-2013; carraro, dirce/C-9179-2009; OI de Alexandre, Rodrigo/0000-0002-1253-7716; carraro, dirce/0000-0001-5667-1418; Soares, Fernando Augusto/0000-0003-1647-7842 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural National Institutes of Health Project [Z01-HD-000642-04]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [311166/2011-3 - PQ-2]; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) [5406/10-2 - 2011] FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural National Institutes of Health Project Z01-HD-000642-04 (to C A S). In part, by a grant from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Process: 311166/2011-3 - PQ-2 (to F R F). And, in part, by a grant from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Process: 5406/10-2 - 2011 (to R B A). NR 86 TC 2 Z9 2 U1 2 U2 4 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD AUG PY 2015 VL 22 IS 4 BP 519 EP 530 DI 10.1530/ERC-15-0134 PG 12 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA CO2RK UT WOS:000359004100004 PM 25979379 ER PT J AU Sambataro, F Podell, JE Murty, VP Das, S Kolachana, B Goldberg, TE Weinberger, DR Mattay, VS AF Sambataro, Fabio Podell, Jamie E. Murty, Vishnu P. Das, Saumitra Kolachana, Bhaskar Goldberg, Terry E. Weinberger, Daniel R. Mattay, Venkata S. TI A variable number of tandem repeats in the 3 '-untranslated region of the dopamine transporter modulates striatal function during working memory updating across the adult age span SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE aging; dopamine; functional magnetic resonance imaging; SLC6A3; working memory ID MEDIAL TEMPORAL-LOBE; BASAL GANGLIA; PREFRONTAL CORTEX; COGNITION; HUMANS; CONNECTIVITY; PERFORMANCE; RECEPTOR AB Dopamine modulation of striatal function is critical for executive functions such as working memory (WM) updating. The dopamine transporter (DAT) regulates striatal dopamine signaling via synaptic reuptake. A variable number of tandem repeats in the 3-untranslated region of SLC6A3 (DAT1-3-UTR-VNTR) is associated with DAT expression, such that 9-repeat allele carriers tend to express lower levels (associated with higher extracellular dopamine concentrations) than 10-repeat homozygotes. Aging is also associated with decline of the dopamine system. The goal of the present study was to investigate the effects of aging and DAT1-3-UTR-VNTR on the neural activity and functional connectivity of the striatum during WM updating. Our results showed both an age-related decrease in striatal activity and an effect of DAT1-3-UTR-VNTR. Ten-repeat homozygotes showed reduced striatal activity and increased striatal-hippocampal connectivity during WM updating relative to the 9-repeat carriers. There was no age by DAT1-3-UTR-VNTR interaction. These results suggest that, whereas striatal function during WM updating is modulated by both age and genetically determined DAT levels, the rate of the age-related decline in striatal function is similar across both DAT1-3-UTR-VNTR genotype groups. They further suggest that, because of the baseline difference in striatal function based on DAT1-3-UTR-VNTR polymorphism, 10-repeat homozygotes, who have lower levels of striatal function throughout the adult life span, may reach a threshold of decreased striatal function and manifest impairments in cognitive processes mediated by the striatum earlier in life than the 9-repeat carriers. Our data suggest that age and DAT1-3-UTR-VNTR polymorphism independently modulate striatal function. C1 [Sambataro, Fabio] Hoffmann La Roche AG, pRED, NORD DTA, Basel, Switzerland. [Sambataro, Fabio; Podell, Jamie E.; Murty, Vishnu P.; Das, Saumitra; Kolachana, Bhaskar; Weinberger, Daniel R.; Mattay, Venkata S.] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, Intramural Res Program,NIH, Bethesda, MD 20892 USA. [Goldberg, Terry E.] Litwin Zucker Alzheimers Dis Res Ctr, Feinstein Inst, Manhasset, NY USA. [Weinberger, Daniel R.; Mattay, Venkata S.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weinberger, Daniel R.; Mattay, Venkata S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Weinberger, Daniel R.; Mattay, Venkata S.] Johns Hopkins Univ, Sch Med, Lieber Inst Brain Dev, Baltimore, MD USA. RP Mattay, VS (reprint author), Lieber Inst Brain Dev, Johns Hopkins Med Campus,855 North Wolfe St, Baltimore, MD 21205 USA. EM Anand.Mattay@libd.org OI Sambataro , Fabio/0000-0003-2102-416X NR 38 TC 2 Z9 2 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD AUG PY 2015 VL 42 IS 3 BP 1912 EP 1918 DI 10.1111/ejn.12956 PG 7 WC Neurosciences SC Neurosciences & Neurology GA CO1XF UT WOS:000358948800005 PM 25997640 ER PT J AU De Castro, M Biesecker, LG AF De Castro, Mauricio Biesecker, Leslie G. TI Next-generation sequencing to estimate the prevalence of a great unknown: McArdle disease Response SO GENETICS IN MEDICINE LA English DT Letter ID CYSTIC-FIBROSIS C1 [De Castro, Mauricio] NHGRI, Med Genet, NIH, Bethesda, MD 20892 USA. [Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Betheseda, MD USA. RP De Castro, M (reprint author), NHGRI, Med Genet, NIH, Bethesda, MD 20892 USA. EM mauricio.decastro-pretelt@nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD AUG PY 2015 VL 17 IS 8 BP 680 EP 681 DI 10.1038/gim.2015.80 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA CO1ZY UT WOS:000358956200012 PM 26240974 ER PT J AU Sen, ND Zhou, FJ Ingolia, NT Hinnebusch, AG AF Sen, Neelam Dabas Zhou, Fujun Ingolia, Nicholas T. Hinnebusch, Alan G. TI Genome-wide analysis of translational efficiency reveals distinct but overlapping functions of yeast DEAD-box RNA helicases Ded1 and eIF4A SO GENOME RESEARCH LA English DT Article ID REOVIRUS MESSENGER-RNA; SMALL SIZE CLASS; SACCHAROMYCES-CEREVISIAE; INITIATION-FACTORS; POSTTRANSCRIPTIONAL REGULATION; DEPENDENT TRANSLATION; SECONDARY STRUCTURE; PROTEIN DHX29; RIBOSOMES; REQUIREMENT AB DEAD-box RNA helicases eIF4A and Ded1 are believed to promote translation initiation by resolving mRNA secondary structures that impede ribosome attachment at the mRNA 5' end or subsequent scanning of the 5' UTR, but whether they perform unique or overlapping functions in vivo is poorly understood. We compared the effects of mutations in Ded1 or eIF4A on global translational efficiencies (TEs) in budding yeast Saccharomyces cerevisiae by ribosome footprint profiling. Despite similar reductions in bulk translation, inactivation of a cold-sensitive Ded1 mutant substantially reduced the TEs of > 600 mRNAs, whereas inactivation of a temperature-sensitive eIF4A variant encoded by tifl-A79V (in a strain lacking the ortholog TIF2) yielded < 40 similarly impaired mRNAs. The broader requirement for Ded1 did not reflect more pervasive secondary structures at low temperature, as inactivation of temperature-sensitive and cold-sensitive ded1 mutants gave highly correlated results. Interestingly, Ded1-dependent mRNAs exhibit greater than average 5' UTR length and propensity for secondary structure, implicating Ded1 in scanning through structured 5' UTRs. Reporter assays confirmed that cap-distal stem-loop insertions increase dependence on Ded1 but not eIF4A for efficient translation. While only a small fraction of mRNAs shows a heightened requirement for eIF4A, dependence on eIF4A is correlated with requirements for Ded1 and 5' UTR features characteristic of Ded1-dependent mRNAs. Our findings suggest that Ded1 is critically required to promote scanning through secondary structures within 5' UTRs, and while eIF4A cooperates with Ded1 in this function, it also promotes a step of initiation common to virtually all yeast mRNAs. C1 [Sen, Neelam Dabas; Zhou, Fujun; Hinnebusch, Alan G.] Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Ingolia, Nicholas T.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. RP Ingolia, NT (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. EM nick@ingolia.org; ahinnebusch@nih.gov FU Searle Scholars Program [11-SSP-229]; NIEHS grant [R21 ES22575-01]; Intramural Research Program of the National Institutes of Health FX We thank members of our laboratories and the Dever and Lorsch groups for many helpful suggestions, Sumit Sen, James Iben, and Tingfen Yan for help with bioinformatics, and Patrick Linder, Roy Parker, Susan Wente, and Charlie Boone for generous gifts of strains or plasmids. N.T.I. was supported by the Searle Scholars Program (11-SSP-229) and NIEHS grant R21 ES22575-01. This work was supported in part by the Intramural Research Program of the National Institutes of Health. NR 34 TC 16 Z9 16 U1 2 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD AUG PY 2015 VL 25 IS 8 BP 1196 EP 1205 DI 10.1101/gr.191601.115 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA CO2AL UT WOS:000358957500011 PM 26122911 ER PT J AU Li, S Yao, JH Navab, N AF Li, Shuo Yao, Jianhua Navab, Nassir TI Special Issue on Spine Imaging, Image-Based Modeling, and Image Guided Intervention SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Editorial Material C1 [Li, Shuo] Univ Western Ontario, London, ON N6A 4V2, Canada. [Li, Shuo] Digital Imaging Grp London, London, ON N6A 4V2, Canada. [Yao, Jianhua] NIH, Dept Radiol, Bethesda, MD 20892 USA. [Yao, Jianhua] NIH, Imaging Sci Clin Ctr, Bethesda, MD 20892 USA. [Navab, Nassir] Tech Univ Munich, D-85748 Munich, Germany. RP Li, S (reprint author), Univ Western Ontario, London, ON N6A 4V2, Canada. NR 12 TC 0 Z9 0 U1 5 U2 7 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD AUG PY 2015 VL 34 IS 8 SI SI BP 1625 EP 1626 DI 10.1109/TMI.2015.2456376 PG 2 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA CO1DO UT WOS:000358893300001 PM 26465019 ER PT J AU Wang, Q Lu, L Wu, DJ El-Zehiry, N Zheng, YF Shen, DG Zhou, KS AF Wang, Qian Lu, Le Wu, Dijia El-Zehiry, Noha Zheng, Yefeng Shen, Dinggang Zhou, Kevin S. TI Automatic Segmentation of Spinal Canals in CT Images via Iterative Topology Refinement SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Image landmark detection; image segmentation; random walk; spinal canal; topology ID MAGNETIC-RESONANCE IMAGES; GRADIENT VECTOR FLOW; SEMIAUTOMATIC SEGMENTATION; DEFORMABLE-MODEL; CORD; REGISTRATION; CLASSIFICATION; EXTRACTION; BONE; CUTS AB Accurate segmentation of the spinal canals in computed tomography (CT) images is an important task in many related studies. In this paper, we propose an automatic segmentation method and apply it to our highly challenging image cohort that is acquired from multiple clinical sites and from the CT channel of the PET-CT scans. To this end, we adapt the interactive random-walk solvers to be a fully automatic cascaded pipeline. The automatic segmentation pipeline is initialized with robust voxelwise classification using Haar-like features and probabilistic boosting tree. Then, the topology of the spinal canal is extracted from the tentative segmentation and further refined for the subsequent random-walk solver. In particular, the refined topology leads to improved seeding voxels or boundary conditions, which allow the subsequent random-walk solver to improve the segmentation result. Therefore, by iteratively refining the spinal canal topology and cascading the random-walk solvers, satisfactory segmentation results can be acquired within only a few iterations, even for cases with scoliosis, bone fractures and lesions. Our experiments validate the capability of the proposed method with promising segmentation performance, even though the resolution and the contrast of our dataset with 110 patient cases (90 for testing and 20 for training) are low and various bone pathologies occur frequently. C1 [Wang, Qian] Shanghai Jiao Tong Univ, Sch Biomed Engn, Med X Res Inst, Shanghai 200240, Peoples R China. [Lu, Le] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Wu, Dijia] Google, Seattle, WA 98103 USA. [El-Zehiry, Noha; Zheng, Yefeng; Zhou, Kevin S.] Siemens Corp Res, Princeton, NJ 08540 USA. [Shen, Dinggang] Univ N Carolina, Dept Radiol, Chapel Hill, NC 27510 USA. [Shen, Dinggang] Univ N Carolina, BRIC, Chapel Hill, NC 27510 USA. RP Shen, DG (reprint author), Univ N Carolina, Dept Radiol, Chapel Hill, NC 27510 USA. EM wang.qian@sjtu.edu.cn; le.lu@nih.gov; dijia@google.com; noha.el-zehiry@siemens.com; yefeng.zheng@siemens.com; dgshen@med.unc.edu; shaohua.zhou@siemens.com OI Wang, Qian/0000-0002-3490-3836 FU National Natural Science Foundation of China (NSFC) [61401271, 61473190, 81471733]; National Institute of Health of United States (NIH) [CA140413] FX Manuscript received April 07, 2015; revised May 14, 2015; accepted May 16, 2015. Date of publication May 25, 2015; date of current version July 29, 2015. This work was supported in part by the National Natural Science Foundation of China (NSFC) Grants (61401271, 61473190, 81471733), and the National Institute of Health of United States (NIH) Grant (CA140413). Asterisk indicates corresponding author. NR 37 TC 2 Z9 2 U1 3 U2 14 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD AUG PY 2015 VL 34 IS 8 SI SI BP 1694 EP 1704 DI 10.1109/TMI.2015.2436693 PG 11 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA CO1DO UT WOS:000358893300007 PM 26241768 ER PT J AU Neller, MA Ladell, K McLaren, JE Matthews, KK Gostick, E Pentier, JM Dolton, G Schauenburg, AJA Koning, D Costa, AICAF Watkins, TS Venturi, V Smith, C Khanna, R Miners, K Clement, M Wooldridge, L Cole, DK van Baarle, D Sewell, AK Burrows, SR Price, DA Miles, JJ AF Neller, Michelle A. Ladell, Kristin McLaren, James E. Matthews, Katherine K. Gostick, Emma Pentier, Johanne M. Dolton, Garry Schauenburg, Andrea J. A. Koning, Dan Costa, Ana Isabel C. A. Fontaine Watkins, Thomas S. Venturi, Vanessa Smith, Corey Khanna, Rajiv Miners, Kelly Clement, Mathew Wooldridge, Linda Cole, David K. van Baarle, Debbie Sewell, Andrew K. Burrows, Scott R. Price, David A. Miles, John J. TI Naive CD8(+) T-cell precursors display structured TCR repertoires and composite antigen-driven selection dynamics SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Article ID RECEPTOR RECOGNITION; RESPONSE MAGNITUDE; MOLECULAR-BASIS; HIGH-FREQUENCY; SIV INFECTION; PHENOTYPE; IMMUNODOMINANCE; EPITOPE; HUMANS; CLONOTYPES AB Basic parameters of the naive antigen (Ag)-specific T-cell repertoire in humans remain poorly defined. Systematic characterization of this 'ground state' immunity in comparison with memory will allow a better understanding of clonal selection during immune challenge. Here, we used high-definition cell isolation from umbilical cord blood samples to establish the baseline frequency, phenotype and T-cell antigen receptor (TCR) repertoire of CD8(+) T-cell precursor populations specific for a range of viral and self-derived Ags. Across the board, these precursor populations were phenotypically naive and occurred with hierarchical frequencies clustered by Ag specificity. The corresponding patterns of TCR architecture were highly ordered and displayed partial overlap with adult memory, indicating biased structuring of the T-cell repertoire during Ag-driven selection. Collectively, these results provide new insights into the complex nature and dynamics of the naive T-cell compartment. C1 [Neller, Michelle A.; Matthews, Katherine K.; Watkins, Thomas S.; Smith, Corey; Khanna, Rajiv; Burrows, Scott R.; Miles, John J.] Queensland Inst Med Res, Cellular Immunol Lab, Human Immun Lab, Brisbane, Qld 4006, Australia. [Neller, Michelle A.; Matthews, Katherine K.; Watkins, Thomas S.; Smith, Corey; Khanna, Rajiv; Burrows, Scott R.; Miles, John J.] Queensland Inst Med Res, Tumour Immunol Lab, Brisbane, Qld 4006, Australia. [Ladell, Kristin; McLaren, James E.; Gostick, Emma; Pentier, Johanne M.; Dolton, Garry; Schauenburg, Andrea J. A.; Miners, Kelly; Clement, Mathew; Wooldridge, Linda; Cole, David K.; Sewell, Andrew K.; Price, David A.; Miles, John J.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Koning, Dan; Costa, Ana Isabel C. A. Fontaine; van Baarle, Debbie] Univ Med Ctr Utrecht, Dept Immunol, Utrecht, Netherlands. [Venturi, Vanessa] Univ New S Wales, Ctr Vasc Res, Computat Biol Unit, Kensington, NSW 2033, Australia. [Burrows, Scott R.; Miles, John J.] Univ Queensland, Sch Med, Brisbane, Qld, Australia. [Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Price, DA (reprint author), Cardiff Univ, Sch Med, Inst Infect & Immun, Henry Wellcome Bldg,Heath Pk, Cardiff CF14 4XN, S Glam, Wales. EM dprice1@mail.nih.gov; john.miles@qimr.edu.au RI Ladell, Kristin/C-8301-2013; Price, David/C-7876-2013; OI Ladell, Kristin/0000-0002-9856-2938; Price, David/0000-0001-9416-2737; Sewell, Andrew/0000-0003-3194-3135 FU NHMRC [APP613664]; Biotechnology and Biological Sciences Research Council [BB/H001085/1] FX LW is a Wellcome Trust Intermediate Clinical Fellow, DKC is a Wellcome Trust Career Development Fellow, SRB is a National Health and Medical Research Council (NHMRC) Principal Fellow, DAP is a Wellcome Trust Senior Investigator and JJM is an NHMRC Career Development Fellow. We thank Immudex for providing fluorochrome-conjugated dextramer backbones, Katie Butler and Franco Tavarozzi for tissue typing and The Anthony Nolan Trust for providing UCB samples. This work was supported by the NHMRC (grant APP613664) and the Biotechnology and Biological Sciences Research Council (grant BB/H001085/1). NR 41 TC 9 Z9 9 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 EI 1440-1711 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD AUG PY 2015 VL 93 IS 7 BP 625 EP 633 DI 10.1038/icb.2015.17 PG 9 WC Cell Biology; Immunology SC Cell Biology; Immunology GA CO8MX UT WOS:000359424600005 PM 25801351 ER PT J AU Wheatley, LM Plaut, M Schwaninger, JM Banerji, A Castells, M Finkelman, FD Gleich, GJ Guttman-Yassky, E Mallal, SAK Naisbitt, DJ Ostrov, DA Phillips, EJ Pichler, WJ Platts-Mills, TAE Roujeau, JC Schwartz, LB Trepanier, LA AF Wheatley, Lisa M. Plaut, Marshall Schwaninger, Julie M. Banerji, Aleena Castells, Mariana Finkelman, Fred D. Gleich, Gerald J. Guttman-Yassky, Emma Mallal, Simon A. K. Naisbitt, Dean J. Ostrov, David A. Phillips, Elizabeth J. Pichler, Werner J. Platts-Mills, Thomas A. E. Roujeau, Jean-Claude Schwartz, Lawrence B. Trepanier, Lauren A. TI Report from the National Institute of Allergy and Infectious Diseases workshop on drug allergy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Drug allergy; drug hypersensitivity; desensitization; pharmacogenomics; Stevens-Johnson syndrome; toxic epidermal necrolysis; hapten hypothesis; altered peptide repertoire hypothesis; pharmacologic interaction with immune receptor hypothesis ID TOXIC EPIDERMAL NECROLYSIS; STEVENS-JOHNSON-SYNDROME; BETA-LACTAM ANTIBIOTICS; INDUCED LIVER-INJURY; RED MEAT ALLERGY; HYPERSENSITIVITY REACTIONS; CYSTIC-FIBROSIS; PENICILLIN ALLERGY; PEPTIDE REPERTOIRE; CROSS-REACTIVITY AB Allergic reactions to drugs are a serious public health concern. In 2013, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop on drug allergy. International experts in the field of drug allergy with backgrounds in allergy, immunology, infectious diseases, dermatology, clinical pharmacology, and pharmacogenomics discussed the current state of drug allergy research. These experts were joined by representatives from several National Institutes of Health institutes and the US Food and Drug Administration. The participants identified important advances that make new research directions feasible and made suggestions for research priorities and for development of infrastructure to advance our knowledge of the mechanisms, diagnosis, management, and prevention of drug allergy. The workshop summary and recommendations are presented herein. C1 [Wheatley, Lisa M.; Plaut, Marshall; Schwaninger, Julie M.] NIAID, Div Allergy Immunol & Transplantat, NIH, Rockville, MD 20852 USA. [Banerji, Aleena] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Castells, Mariana] Brigham & Womens Hosp, Dept Med, Div Rheumatol Immunol & Allergy, Drug Hypersensit & Desensitizat Ctr, Boston, MA 02115 USA. [Finkelman, Fred D.] Univ Cincinnati, Div Allergy Immunol & Rheumatol, Dept Internal Med, Coll Med,Dept Med,Cincinnati Vet Affairs Med Ctr, Cincinnati, OH 45221 USA. [Finkelman, Fred D.] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA. [Gleich, Gerald J.] Univ Utah, Dept Dermatol, Salt Lake City, UT USA. [Gleich, Gerald J.] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA. [Guttman-Yassky, Emma] Mt Sinai Med Ctr, Dept Dermatol, New York, NY 10029 USA. [Guttman-Yassky, Emma] Mt Sinai Med Ctr, Inst Immunol, Icahn Sch Med, New York, NY 10029 USA. [Mallal, Simon A. K.] Vanderbilt Univ, Sch Med, Dept Med, Ctr Translat Immunol & Infect Dis, Nashville, TN 37212 USA. [Mallal, Simon A. K.; Phillips, Elizabeth J.] Murdoch Univ, Inst Immunol & Infect Dis, Murdoch, WA 6150, Australia. [Naisbitt, Dean J.] Univ Liverpool, Dept Pharmacol, MRC, Ctr Drug Safety Sci, Liverpool L69 3BX, Merseyside, England. [Ostrov, David A.] Univ Florida, Coll Med, Div Expt Pathol, Dept Pathol Immunol & Lab Med, Gainesville, FL USA. [Phillips, Elizabeth J.] Vanderbilt Univ, Med Ctr, Dept Med, Div Infect Dis, Nashville, TN USA. [Pichler, Werner J.] ADR AC GMBH, CH-3008 Bern, Switzerland. [Platts-Mills, Thomas A. E.] Univ Virginia, Dept Med, Asthma & Allerg Dis Ctr, Charlottesville, VA USA. [Roujeau, Jean-Claude] Univ Paris Est Creteil, F-94010 Creteil, France. [Schwartz, Lawrence B.] Virginia Commonwealth Univ, Dept Internal Med, Div Rheumatol Allergy & Immunol, Richmond, VA 23284 USA. [Trepanier, Lauren A.] Univ Wisconsin Madison, Sch Vet Med, Dept Med Sci, Madison, WI USA. RP Wheatley, LM (reprint author), NIAID, NIH, Div Allergy Immunol & Transplantat, Rockville, MD 20852 USA. EM lisa.wheatley@nih.gov FU Merck; Sanofi; National Institutes of Health (NIH) Desensitization; National Institute of Allergy and Infectious Diseases (NIAID); GlaxoSmithKline; Regeneron; Celgene; BMS; Janssen; NHMRC Australia; NIH; UpToDate; Roche; Lilly; Boehringer Ingelheim; AiCuris; Menarini; NIAID; AB Science; Novartis; OM-Pharma; Science Technologie; Astellas pharma; Sanofi Aventis; Dyax; ViroPharma; HELIX; CSL Behring FX M. Castells has received consultancy fees from Merck and Sanofi, is employed by BWH, has received research support from National Institutes of Health (NIH) Desensitization (pending), has received royalties from UpToDate, and has received travel support from the American Academy of Allergy, Asthma & Immunology (AAAAI) as a member of the Board of Directors. F. D. Finkelman has received travel support and research support from the National Institute of Allergy and Infectious Diseases (NIAID) and has a relevant patent pending with the University of Cincinnati. G. J. Gleich has received travel support from the University of Utah, has received consultancy fees from GlaxoSmithKline, and has provided expert testimony for plaintiffs' attorneys. E. Guttman-Yassky is a board member for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, Medimmune, Celgene, Anacor, and Leo Pharma; has received consultancy fees from Regeneron, Sanofi Aventis, Medimmune, Celgene, Stiefel/GlaxoSmithKline, Celsus, BMS, Amgen, and Drais; and has received research support from Regeneron, Celgene, BMS, and Janssen. S. A. K. Mallal has equity in IIID Ltd, which has a patent for HLA-B*5701 screening for abacavir hypersensitivity. D. J. Naisbitt, D. A. Ostrov, and L. A. Trepanier have received travel support from the NIH/NIAID. E. J. Phillips has received research support from NHMRC Australia and from the NIH, has received personal fees from UpToDate, and is a codirector of the company that holds the patent for HLA-B*57:01 testing for abacavir HSR; honoraria were paid to her institution by Merck Pty Ltd and ViiV. W.J. Pichler has received consultancy fees from Roche, Lilly, Boehringer Ingelheim, AiCuris, and Menarini. T. A. E. Platts-Mills has received research support from the NIAID and has received consultancy fees and travel support from Thermo Fisher/Phadia. J.-C. Roujeau has received travel support from the NIH/NIAID; is a board member for Pfizer, Menarini, Vertex, Servier, OM Pharma, and Boehringer-Ingelheim; has received consultancy fees from AB Science; has provided expert testimony for McNeil consumers (a branch of J & J); has received research support from GlaxoSmithKline, Novartis, Boehringer Ingelheim, OM-Pharma, Science & Technologie, Astellas pharma, Menarini; has received lecture fees from Menarini; and has received payment for development of educational presentations from Janssen. L. B. Schwartz has received travel support from the NIH/NIAID; has received consultancy fees from Sanofi Aventis, Dyax, ViroPharma, and HELIX; has received research support from CSL Behring and Dyax; has received royalties from VCU Tech Transfer; and is an Associate Editor of and has received an honorarium from the Journal of Clinical Immunology. The rest of the authors declare that they have no relevant conflicts of interest. NR 78 TC 6 Z9 6 U1 0 U2 10 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 2015 VL 136 IS 2 BP 262 EP + DI 10.1016/j.jaci.2015.05.027 PG 12 WC Allergy; Immunology SC Allergy; Immunology GA CO2RS UT WOS:000359004900006 PM 26254053 ER PT J AU Engelhardt, KR Gertz, ME Keles, S Schaffer, AA Sigmund, EC Glocker, C Saghafi, S Pourpak, Z Ceja, R Sassi, A Graham, LE Massaad, MJ Mellouli, F Ben-Mustapha, I Khemiri, M Kilic, SS Etzioni, A Freeman, AF Thiel, J Schulze, I Al-Herz, W Metin, A Sanal, O Tezcan, I Yeganeh, M Niehues, T Dueckers, G Weinspach, S Patiroglu, T Unal, E Dasouki, M Yilmaz, M Genel, F Aytekin, C Kutukculer, N Somer, A Kilic, M Reisli, I Camcioglu, Y Gennery, AR Cant, AJ Jones, A Gaspar, BH Arkwright, PD Pietrogrande, MC Baz, Z Al-Tamemi, S Lougaris, V Lefranc, G Megarbane, A Boutros, J Galal, N Bejaoui, M Barbouche, MR Geha, RS Chatila, TA Grimbacher, B AF Engelhardt, Karin R. Gertz, Michael E. Keles, Sevgi Schaeffer, Alejandro A. Sigmund, Elena C. Glocker, Cristina Saghafi, Shiva Pourpak, Zahra Ceja, Ruben Sassi, Atfa Graham, Laura E. Massaad, Michel J. Mellouli, Fethi Ben-Mustapha, Imen Khemiri, Monia Kilic, Sara Sebnem Etzioni, Amos Freeman, Alexandra F. Thiel, Jens Schulze, Ilka Al-Herz, Waleed Metin, Ayse Sanal, Oezden Tezcan, Ilhan Yeganeh, Mehdi Niehues, Tim Dueckers, Gregor Weinspach, Sebastian Patiroglu, Turkan Unal, Ekrem Dasouki, Majed Yilmaz, Mustafa Genel, Ferah Aytekin, Caner Kutukculer, Necil Somer, Ayper Kilic, Mehmet Reisli, Ismail Camcioglu, Yildiz Gennery, Andrew R. Cant, Andrew J. Jones, Alison Gaspar, Bobby H. Arkwright, Peter D. Pietrogrande, Maria C. Baz, Zeina Al-Tamemi, Salem Lougaris, Vassilios Lefranc, Gerard Megarbane, Andre Boutros, Jeannette Galal, Nermeen Bejaoui, Mohamed Barbouche, Mohamed-Ridha Geha, Raif S. Chatila, Talal A. Grimbacher, Bodo TI The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Primary combined immunodeficiency; hyper-IgE syndrome; autosomal recessive hyper-IgE syndrome; dedicator of cytokinesis 8; signal transducer and activator of transcription 3; Molluscum contagiosum ID HYPER-IGE SYNDROME; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; DOCK8 DEFICIENCY; MUTATIONS; IMMUNODEFICIENCY; STAT3; GLYCOSYLATION; DISORDER; SURVIVAL AB Background: Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. Objectives: We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. Methods: Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. Results: DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/mu L (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. Conclusions: DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures. C1 [Engelhardt, Karin R.; Graham, Laura E.; Grimbacher, Bodo] Royal Free Hosp, Dept Immunol & Mol Pathol, London, England. [Engelhardt, Karin R.; Graham, Laura E.; Grimbacher, Bodo] UCL, London WC1E 6BT, England. [Engelhardt, Karin R.; Sigmund, Elena C.; Glocker, Cristina; Thiel, Jens; Schulze, Ilka; Grimbacher, Bodo] Univ Med Ctr Freiburg, CCI, Freiburg, Germany. [Engelhardt, Karin R.; Gennery, Andrew R.; Cant, Andrew J.] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Gertz, Michael E.; Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Keles, Sevgi; Ceja, Ruben; Chatila, Talal A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Div Immunol Allergy & Rheumatol, Los Angeles, CA 90095 USA. [Keles, Sevgi; Reisli, Ismail] Konya Necmettin Erbakan Univ, Div Pediat Allergy & Immunol, Konya, Turkey. [Keles, Sevgi; Ceja, Ruben; Massaad, Michel J.; Geha, Raif S.; Chatila, Talal A.] Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Saghafi, Shiva; Pourpak, Zahra] Univ Tehran Med Sci, Childrens Med Ctr, Immunol Asthma & Allergy Res Inst, Tehran, Iran. [Yeganeh, Mehdi] Univ Tehran Med Sci, Childrens Med Ctr, Immunol Asthma & Allergy Res Inst, Tehran, Iran. [Sassi, Atfa; Ben-Mustapha, Imen; Barbouche, Mohamed-Ridha] Pasteur Inst Tunis, Lab Immunol Vaccinol & Mol Genet, Tunis, Tunisia. [Sassi, Atfa; Ben-Mustapha, Imen; Barbouche, Mohamed-Ridha] Univ Tunis El Manar, El Manar, Tunisia. [Mellouli, Fethi; Bejaoui, Mohamed] Bone Marrow Transplantat Ctr, Dept Pediat, Tunis, Tunisia. [Khemiri, Monia] Childrens Hosp, Dept Pediat, Tunis, Tunisia. [Kilic, Sara Sebnem] Uludag Univ, Dept Pediat Immunol, Fac Med, Bursa, Turkey. [Etzioni, Amos] Rambam Hlth Care Campus, Meyers Children Hosp, Haifa, Israel. [Etzioni, Amos] Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel. [Freeman, Alexandra F.] NIAID, Lab Clin Infect Dis, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Al-Herz, Waleed] Kuwait Univ, Fac Med, Dept Pediat, Kuwait, Kuwait. [Al-Herz, Waleed] Al Sabah Hosp, Dept Pediat, Allergy & Clin Immunol Unit, Kuwait, Kuwait. [Metin, Ayse] SB Ankara Diskapi Childrens Hosp, Pediat Immunol Unit, Ankara, Turkey. [Sanal, Oezden; Tezcan, Ilhan] Hacettepe Univ, Childrens Hosp, Div Immunol, Ankara, Turkey. [Niehues, Tim; Dueckers, Gregor] HELIOS Klinikum Krefeld, Zentrum Kinder & Jugendmed, Krefeld, Germany. [Weinspach, Sebastian] Univ Dusseldorf, Dept Pediat Oncol Hematol & Clin Immunol, Ctr Child & Adolescent Med, Dusseldorf, Germany. [Patiroglu, Turkan] Erciyes Univ, Fac Med, Div Pediat Hematol & Immunol, Dept Pediat, Kayseri, Turkey. [Unal, Ekrem] Erciyes Univ, Fac Med, Div Pediat Hematol & Oncol, Dept Pediat, Kayseri, Turkey. [Dasouki, Majed] Univ Kansas, Med Ctr, Dept Pediat, Kansas City, KS USA. [Yilmaz, Mustafa] Cukurova Univ, Adana, Turkey. [Genel, Ferah] Behcet Uz State Hosp, Div Pediat Immunol, Izmir, Turkey. [Aytekin, Caner] Dr Sami Ulus Matern & Childrens Hlth & Dis Traini, Dept Pediat Immunol, Ankara, Turkey. [Kutukculer, Necil] Ege Univ, Fac Med, Dept Pediat, Izmir, Turkey. [Somer, Ayper] Istanbul Univ, Istanbul Fac Med, Div Infect Dis & Immunol, Istanbul, Turkey. [Kilic, Mehmet] Firat Univ, TR-23169 Elazig, Turkey. [Camcioglu, Yildiz] Istanbul Univ, Cerrahpasa Med Fac, Div Pediat Allergy Immunol & Infect Dis, Istanbul, Turkey. [Jones, Alison; Gaspar, Bobby H.] Great Ormond St Hosp Sick Children, Dept Immunol, London, England. [Arkwright, Peter D.] Univ Manchester, Royal Manchester Childrens Hosp, Manchester M13 9PL, Lancs, England. [Pietrogrande, Maria C.] Univ Milan, Dept Pediat, Fdn Policlin IRCCS, Milan, Italy. [Baz, Zeina] St George Hosp Univ, Med Ctr, Dept Pediat, Beirut, Lebanon. [Al-Tamemi, Salem] Sultan Qaboos Univ, Dept Pediat, Muscat, Oman. [Lougaris, Vassilios] Univ Brescia, Spedali Civili Brescia, Pediat Clin, I-25121 Brescia, Italy. [Lougaris, Vassilios] Univ Brescia, Spedali Civili Brescia, Inst Mol Med A Nocivelli, Dept Clin & Expt Sci, I-25121 Brescia, Italy. [Lefranc, Gerard] Univ Montpellier 2, Montpellier, France. [Lefranc, Gerard] CNRS, Inst Human Genet, Montpellier, France. [Megarbane, Andre] St Joseph Univ, Med Genet Unit, Beirut, Lebanon. [Boutros, Jeannette; Galal, Nermeen] Cairo Univ, Specialized Pediat Hosp, Primary Immunodeficiency Clin, Cairo, Egypt. RP Grimbacher, B (reprint author), Univ Freiburg Klinikum, Ctr Chron Immunodeficiency, Engesser Str 4, D-79108 Freiburg, Germany. EM bodo.grimbacher@uniklinik-freiburg.de OI Arkwright, Peter/0000-0002-7411-5375 FU German Federal Ministry of Education and Research [BMBF 01EO1303]; European Community [Health-F5-2008-223292]; Marie Curie Excellence Grant [MEXT-CT-2006-042316-PIAID]; National Institutes of Health [5R01AI065617, 1R21AI087627]; Scientific and Technological Research Council of Turkey (Tubitak) [1059B191300622]; Intramural Research program of the National Institutes of Health; NLM; NIAID FX Supported by the German Federal Ministry of Education and Research (BMBF 01EO1303). The research was funded in part by the European Community's 7th Framework Programmes FP7/2007-2013 under grant agreement Health-F5-2008-223292 (Euro Gene Scan), by a Marie Curie Excellence Grant (to B.G.; MEXT-CT-2006-042316-PIAID), and by National Institutes of Health grants 5R01AI065617 and 1R21AI087627 (to T.A.C.). This research was supported in part by a grant from the Scientific and Technological Research Council of Turkey (Tubitak, grant no. 1059B191300622). This research was supported in part by the Intramural Research program of the National Institutes of Health, NLM, and NIAID. NR 34 TC 25 Z9 25 U1 2 U2 16 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 2015 VL 136 IS 2 BP 402 EP 412 DI 10.1016/j.jaci.2014.12.1945 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA CO2RS UT WOS:000359004900022 PM 25724123 ER PT J AU Moutsopoulos, HM Talal, M Plotz, PH AF Moutsopoulos, Haralampos M. Talal, Marilynn Plotz, Paul H. TI A tribute to Norman Talal OBITUARY SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Biographical-Item C1 [Moutsopoulos, Haralampos M.] Univ Athens, Sch Med, Dept Pathophysiol, GR-11527 Athens, Greece. [Plotz, Paul H.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Moutsopoulos, HM (reprint author), Univ Athens, Sch Med, Dept Pathophysiol, GR-11527 Athens, Greece. EM plotzp@arb.niams.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 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 PY 2015 VL 125 IS 8 BP 2910 EP 2911 DI 10.1172/JCI83241 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CO3CS UT WOS:000359034800003 PM 26168220 ER PT J AU Zhou, Y He, CH Herzog, EL Peng, X Lee, CM Nguyen, TH Gulati, M Gochuico, BR Gah, WA Slade, ML Lee, CG Elias, JA AF Zhou, Yang He, Chuan Hua Herzog, Erica L. Peng, Xueyan Lee, Chang-Min Nguyen, Tung H. Gulati, Mridu Gochuico, Bernadette R. Gah, William A. Slade, Martin L. Lee, Chun Geun Elias, Jack A. TI Chitinase 3-like-1 and its receptors in Hermansky-Pudlak syndrome-associated lung disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID IDIOPATHIC PULMONARY-FIBROSIS; BREAST REGRESSION PROTEIN-39; LYSOSOME-RELATED ORGANELLES; GRANULOMATOUS COLITIS; TISSUE RESPONSES; EPITHELIAL-CELLS; MOUSE MODEL; IL-13; IL-13R-ALPHA-2; INFLAMMATION AB Hermansky-Pudlak syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in patients with subtypes HPS-1 and HPS-4, which both result from defects in biogenesis of lysosome-related organelle complex 3 (BLOC-3). The prototypic chitinase-like protein chitinase 3-like-1 (CHI3L1) plays a protective role in the lung by ameliorating cell death and stimulating fibroproliferative repair. Here, we demonstrated that circulating CHI3L1 levels are higher in HPS patients with pulmonary fibrosis compared with those who remain fibrosis free, and that these levels associate with disease severity. Using murine HPS models, we also determined that these animals have a defect in the ability of CHI3L1 to inhibit epithelial apoptosis but exhibit exaggerated CHI3L1-driven fibroproliferation, which together promote HPS fibrosis. These divergent responses resulted from differences in the trafficking and effector functions of two CHI3L1 receptors. Specifically, the enhanced sensitivity to apoptosis was due to abnormal localization of IL-13R alpha 2 as a consequence of dysfunctional BLOC-3-dependent membrane trafficking. In contrast, the fibrosis was due to interactions between CHI3L1 and the receptor CRTH2, which trafficked normally in BLOC-3 mutant HPS. These data demonstrate that CHI3L1-dependent pathways exacerbate pulmonary fibrosis and suggest CHI3L1 as a potential biomarker for pulmonary fibrosis progression and severity in HPS. C1 [Zhou, Yang; He, Chuan Hua; Lee, Chang-Min; Nguyen, Tung H.; Lee, Chun Geun; Elias, Jack A.] Brown Univ, Dept Mol Microbiol & Immunol, Div Med & Biol Sci, Providence, RI 02912 USA. [Herzog, Erica L.; Peng, Xueyan; Gulati, Mridu] Yale Univ, Sch Med, Dept Internal Med, Sect Pulm Crit Care & Sleep Med, New Haven, CT 06510 USA. [Gochuico, Bernadette R.; Gah, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Slade, Martin L.] Yale Univ, Sch Med, Dept Internal Med, Sect Occupat Med, New Haven, CT 06510 USA. RP Elias, JA (reprint author), Brown Univ, Warren Alpert Med Sch, Biol & Med, Box G-A1,97 Waterman St, Providence, RI 02912 USA. EM jack_elias@brown.edu FU American Thoracic Society/Hermansky-Pudlak Syndrome Network [HL-R01 HL093017, U01HL108638, R01HL-109033, R01 HL115813, P20 GM103652]; Intramural Research Program, NHGRI, NIH FX Funding was provided by the American Thoracic Society/Hermansky-Pudlak Syndrome Network (to Y. Zhou); HL-R01 HL093017 and U01HL108638 (to J.A. Elias); R01HL-109033 (to E.L. Herzog); R01 HL115813 (to C.G. Lee); P20 GM103652 Pilot (to Y. Zhou); and the Intramural Research Program, NHGRI, NIH. NR 68 TC 3 Z9 3 U1 0 U2 2 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 PY 2015 VL 125 IS 8 BP 3178 EP 3192 DI 10.1172/JCI79792 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CO3CS UT WOS:000359034800026 PM 26121745 ER PT J AU Vendruscolo, LF Estey, D Goodell, V Macshane, LG Logrip, ML Schlosburg, JE McGinn, MA Zamora-Martinez, ER Belanoff, JK Hunt, HJ Sanna, PR George, O Koob, GF Edwards, S Mason, BJ AF Vendruscolo, Leandro F. Estey, David Goodell, Vivian Macshane, Lauren G. Logrip, Marian L. Schlosburg, Joel E. McGinn, M. Adrienne Zamora-Martinez, Eva R. Belanoff, Joseph K. Hunt, Hazel J. Sanna, Pietro R. George, Olivier Koob, George F. Edwards, Scott Mason, Barbara J. TI Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CORTICOTROPIN-RELEASING-FACTOR; PITUITARY-ADRENAL AXIS; MEDICATION DEVELOPMENT; ETHANOL WITHDRAWAL; CENTRAL NUCLEUS; KEY ROLE; RATS; MIFEPRISTONE; DRINKING; STRESS AB Alcoholism, or alcohol use disorder, is a major public health concern that is a considerable risk factor for morbidity and disability; therefore, effective treatments are urgently needed. Here, we demonstrated that the glucocorticoid receptor (GR) antagonist mifepristone reduces alcohol intake in alcohol-dependent rats but not in nondependent animals. Both systemic delivery and direct administration into the central nucleus of the amygdala, a critical stress-related brain region, were sufficient to reduce alcohol consumption in dependent animals. We also tested the use of mifepristone in 56 alcohol-dependent human subjects as part of a double-blind clinical and laboratory-based study. Relative to placebo, individuals who received mifepristone (600 mg daily taken orally for 1 week) exhibited a substantial reduction in alcohol-cued craving in the laboratory, and naturalistic measures revealed reduced alcohol consumption during the 1-week treatment phase and 1-week post-treatment phase in mifepristone-treated individuals. Mifepristone was well tolerated and improved liver-function markers. Together, these results support further exploration of GR antagonism via mifepristone as a therapeutic strategy for alcoholism. C1 [Vendruscolo, Leandro F.; Estey, David; Goodell, Vivian; Macshane, Lauren G.; Logrip, Marian L.; Schlosburg, Joel E.; Zamora-Martinez, Eva R.; Sanna, Pietro R.; George, Olivier; Koob, George F.; Mason, Barbara J.] Scripps Res Inst, La Jolla, CA 92037 USA. [McGinn, M. Adrienne; Edwards, Scott] LSU Hlth Sci Ctr, Dept Physiol, New Orleans, LA USA. [McGinn, M. Adrienne; Edwards, Scott] LSU Hlth Sci Ctr, Alcohol & Drug Abuse Ctr Excellence, New Orleans, LA USA. [Belanoff, Joseph K.; Hunt, Hazel J.] Corcept Therapeut, Menlo Pk, CA USA. RP Vendruscolo, LF (reprint author), NIDA, NIH, IRP, INRB, 251 Bayview Blvd,BRC Room 08A727, Baltimore, MD 21224 USA. EM leandro.vendruscolo@nih.gov; mason@scripps.edu RI George, Olivier/G-9921-2011; Mason, Barbara/P-6604-2016; koob, george/P-8791-2016 OI George, Olivier/0000-0002-3700-5003; FU National Institute on Alcohol Abuse and Alcoholism (NIAAA/NIH) [AA012602, AA023152, AA020608, AA022977, AA006420, AA020839]; Pearson Center for Alcoholism and Addiction Research; LSUHSC School of Medicine Start-Up Funds FX Research was financially supported by National Institute on Alcohol Abuse and Alcoholism (NIAAA/NIH) grants AA012602 and AA023152 (to B.J. Mason), AA020608, AA022977, and AA006420 (to O. George), and AA020839 (to S. Edwards), the Pearson Center for Alcoholism and Addiction Research, and LSUHSC School of Medicine Start-Up Funds (to S. Edwards). The authors thank Jordan Malavar and Muhammad Farooq for technical assistance with behavioral and biochemical measures, Michael Arends for editorial assistance, and Farhad Shadan, Mark Kyle, and Adnan Begovic for providing medical coverage for the participants in the clinical study. NR 29 TC 15 Z9 15 U1 0 U2 16 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2015 VL 125 IS 8 BP 3193 EP 3197 DI 10.1172/JCI79828 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CO3CS UT WOS:000359034800027 PM 26121746 ER PT J AU Meyer, M Garron, T Lubaki, NM Mire, CE Fenton, KA Klages, C Olinger, GG Geisbert, TW Collins, PL Bukreyev, A AF Meyer, Michelle Garron, Tania Lubaki, Ndongala M. Mire, Chad E. Fenton, Karla A. Klages, Curtis Olinger, Gene G. Geisbert, Thomas W. Collins, Peter L. Bukreyev, Alexander TI Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NONHUMAN-PRIMATES; VIRUS CHALLENGE; INFLUENZA-VIRUS; GUINEA-PIGS; VECTORED VACCINE; RHESUS-MONKEYS; TH17 CELLS; INFECTION; IMMUNITY; MEMORY AB Direct delivery of aerosolized vaccines to the respiratory mucosa elicits both systemic and mucosal responses. This vaccine strategy has not been tested for Ebola virus (EBOV) or other hemorrhagic fever viruses. Here, we examined the immunogenicity and protective efficacy of an aerosolized human parainfluenza virus type 3 vectored vaccine that expresses the glycoprotein (GP) of EBOV (HPIV3/EboGP) delivered to the respiratory tract. Rhesus macaques were vaccinated with aerosolized HPIV3/EboGP, liquid HPIV3/EboGP, or an unrelated, intramuscular, Venezuelan equine encephalitis replicon vaccine expressing EBOV GP. Serum and mucosal samples from aerosolized HPIV3/EboGP recipients exhibited high EBOV-specific IgG, IgA, and neutralizing antibody titers, which exceeded or equaled titers observed in liquid recipients. The HPIV3/EboGP vaccine induced an EBOV-specific cellular response that was greatest in the lungs and yielded polyfunctional CD8(+) T cells, including a subset that expressed CD103 (alpha E integrin), and CD4(+) T helper cells that were predominately type 1. The magnitude of the CD4+ T cell response was greater in aerosol vaccinees. The HPIV3/EboGP vaccine produced a more robust cell-mediated and humoral immune response than the systemic replicon vaccine. Moreover, 1 aerosol HPIV3/EboGP dose conferred 100% protection to macaques exposed to EBOV. Aerosol vaccination represents a useful and feasible vaccination mode that can be implemented with ease in a filovirus disease outbreak situation. C1 [Meyer, Michelle; Garron, Tania; Lubaki, Ndongala M.; Bukreyev, Alexander] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Meyer, Michelle; Garron, Tania; Lubaki, Ndongala M.; Mire, Chad E.; Fenton, Karla A.; Klages, Curtis; Geisbert, Thomas W.; Bukreyev, Alexander] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Meyer, Michelle; Garron, Tania; Lubaki, Ndongala M.; Mire, Chad E.; Fenton, Karla A.; Klages, Curtis; Geisbert, Thomas W.; Bukreyev, Alexander] Univ Texas Med Branch, Galveston, TX 77555 USA. [Garron, Tania; Mire, Chad E.; Fenton, Karla A.; Geisbert, Thomas W.; Bukreyev, Alexander] Anim Resources Ctr, Dept Microbiol & Immunol, Galveston, TX USA. [Klages, Curtis] Anim Resources Ctr, Galveston, TX USA. [Olinger, Gene G.] US Army Inst Infect Dis, Viral Pathogenesis & Immunol Branch, Div Virol, Frederick, MD USA. [Collins, Peter L.] NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Bukreyev, Alexander] Sealy Ctr Vaccine Dev, Galveston, TX USA. RP Bukreyev, A (reprint author), Univ Texas Med Branch, Dept Pathol, Galveston Natl Lab, Keiller Bldg,Room 3-145,301 Univ Blvd, Galveston, TX 77555 USA. EM alexander.bukreyev@utmb.edu FU National Institute of Allergy and Infectious Diseases; NIH Western Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (WRCE) [5U54AI057156-10, DP007]; National Institute of Allergy and Infectious Diseases, NIH [1R01AI102887-01A1]; National Institute of Allergy and Infectious Diseases, NIH Intramural Program FX We thank Richard Herbert and the staff at the NIH Animal Center for their assistance with the NHP vaccinations. We are indebted to Lijuan Yang and other members of the RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, for helping with extraction of mononuclear cells from organs of NHPs. We also thank Joan Geisbert, Jessica Graber, and the Animal Resources Center of the Galveston National Laboratory for assisting with EBOV infection of NHPs. We thank Luis Holthauzen and the Sealy Center for Structural Biology and Molecular Biophysics of the University of Texas Medical Branch at Galveston for providing valuable support and access to the Biacore T100. This work was supported by the National Institute of Allergy and Infectious Diseases, NIH Western Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (WRCE), grant 5U54AI057156-10, Developmental Project DP007 (to A. Bukreyev); the National Institute of Allergy and Infectious Diseases, NIH, grant 1R01AI102887-01A1 (to A. Bukreyev); and the National Institute of Allergy and Infectious Diseases, NIH Intramural Program (to P.L. Collins). NR 52 TC 10 Z9 10 U1 1 U2 10 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 PY 2015 VL 125 IS 8 BP 3241 EP 3255 DI 10.1172/JCI81532 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CO3CS UT WOS:000359034800031 PM 26168222 ER PT J AU Rigby, MR Harris, KM Pinckney, A DiMeglio, LA Rendell, MS Felner, EI Dostou, JM Gitelman, SE Griffin, KJ Tsalikian, E Gottlieb, PA Greenbaum, CJ Sherry, NA Moore, WV Monzavi, R Willi, SM Raskin, P Keyes-Elstein, L Long, SA Kanaparthi, S Lim, N Phippard, D Soppe, CL Fitzgibbon, ML McNamara, J Nepom, GT Ehlers, MR AF Rigby, Mark R. Harris, Kristina M. Pinckney, Ashley DiMeglio, Linda A. Rendell, Marc S. Felner, Eric I. Dostou, Jean M. Gitelman, Stephen E. Griffin, Kurt J. Tsalikian, Eva Gottlieb, Peter A. Greenbaum, Carla J. Sherry, Nicole A. Moore, Wayne V. Monzavi, Roshanak Willi, Steven M. Raskin, Philip Keyes-Elstein, Lynette Long, S. Alice Kanaparthi, Sai Lim, Noha Phippard, Deborah Soppe, Carol L. Fitzgibbon, Margret L. McNamara, James Nepom, Gerald T. Ehlers, Mario R. CA Immune Tolerance Network ITN TIDAL TI Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID BETA-CELL FUNCTION; ANTI-CD3 MONOCLONAL-ANTIBODY; C-PEPTIDE RESPONSES; MEMORY T-CELLS; DOUBLE-BLIND; NOD MICE; CONTROLLED-TRIAL; PHASE-2 TRIAL; PD-1 PATHWAY; PSORIASIS AB BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic beta cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining 13 cells in patients with newly diagnosed T1D. METHODS. In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS. A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1(+)CD(4+). Tem and Tcm (P < 0.01). CONCLUSIONS. In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. C1 [Rigby, Mark R.; DiMeglio, Linda A.] Indiana Univ Sch Med, Riley Hosp Children, Dept Pediat, Sect Pediat Endocrinol & Diabetol, Indianapolis, IN 46202 USA. [Harris, Kristina M.; Kanaparthi, Sai; Lim, Noha; Phippard, Deborah] ITN, Biomarker Discovery Res, Bethesda, MD USA. [Pinckney, Ashley; Keyes-Elstein, Lynette] Rho Inc, Fed Syst Div, Biostat, Chapel Hill, NC USA. [Rendell, Marc S.] Creighton Diabet Ctr, Omaha, NE USA. [Felner, Eric I.] Emory Univ, Sch Med, Dept Pediat, Div Pediat Endocrinol, Atlanta, GA USA. [Dostou, Jean M.] Univ N Carolina, Sch Med Chapel Hill, Dept Med, Div Endocrinol, Durham, NC USA. [Gitelman, Stephen E.] UCSF, Dept Pediat, Div Endocrinol, San Francisco, CA USA. [Griffin, Kurt J.] Univ Arizona, Dept Pediat Endocrinol, Tucson, AZ USA. [Tsalikian, Eva] Univ Iowa, Dept Pediat, Div Pediat Endocrinol & Diabet, Iowa City, IA 52242 USA. [Gottlieb, Peter A.] Univ Colorado, Sch Med, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Greenbaum, Carla J.; Long, S. Alice; Nepom, Gerald T.] Virginia Mason, Benaroya Res Inst, Seattle, WA USA. [Sherry, Nicole A.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Moore, Wayne V.] Univ Missouri, Childrens Mercy Hosp, Pediat Endocrinol, Kansas City, MO 64108 USA. [Monzavi, Roshanak] USC Keck Sch Med, Dept Pediat, Childrens Hosp Los Angeles, Ctr Endocrinol Diabet & Metab, Los Angeles, CA USA. [Willi, Steven M.] Childrens Hosp Philadelphia, Dept Endocrinol, Philadelphia, PA 19104 USA. [Raskin, Philip] Univ Texas SW Med Ctr Dallas, Div Endocrinol, Dept Internal Med, Dallas, TX 75390 USA. [Soppe, Carol L.; Ehlers, Mario R.] ITN, Clin Trials Grp, San Francisco, CA USA. [Fitzgibbon, Margret L.; McNamara, James] NIAID, Div Allergy Immunol & Transplantat, Rockville, MD USA. RP Rigby, MR (reprint author), Pharmaceut Co Johnson & Johnson, Janssen R&D, Translat Med Immunol Dev, 1460 McKean Rd, Spring House, PA 19477 USA. EM mrigby@its.jnj.com OI Nepom, Gerald/0000-0002-8063-1464 FU National Institute of Allergy and Infectious Diseases (NIAID) [NO1-AI-15416, UM1AI109565]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Indiana Clinical and Translational Sciences Institute - NIH, National Center for Advancing Translational Sciences (NCATS) [TR000006]; National Center for Research Resources (NCRR) [UL1 RR024131, UL1 TR000004]; NCATS, NIH [UL1 RR024131, UL1 TR000004]; NCRR [UL1RR024134, UL1TR000003]; NCATS [UL1RR024134, UL1TR000003]; Bayer HealthCare LLC, Diabetes Care FX Funding/Support: The trial was conducted by the ITN and sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) under Award Numbers NO1-AI-15416 and UM1AI109565. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional funding was provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). This project was in part supported, at Indiana University, by the Indiana Clinical and Translational Sciences Institute, funded in part by Grant Number TR000006 from the NIH, National Center for Advancing Translational Sciences (NCATS), Clinical and Translational Sciences Award; at UCSF, by Grant Numbers UL1 RR024131 and UL1 TR000004 from the National Center for Research Resources (NCRR) and the NCATS, NIH; at CHOP, by Grants UL1RR024134 and UL1TR000003 from the NCRR and the NCATS. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Astellas provided alefacept (Amevive) and gave input regarding dosage and safety, but had no direct involvement with study design, conduct, or management; data collection, analysis, or interpretation; or manuscript preparation. There are no agreements concerning confidentiality of the data between Astellas, the sponsor, and the authors or the institutions named in the credit lines. The authors provided Astellas a copy of the original manuscript prior to submission. Bayer HealthCare LLC, Diabetes Care provided blood glucose monitoring supplies through an investigator-sponsored research grant. The authors provided Bayer a copy of the original manuscript prior to submission. NR 46 TC 29 Z9 29 U1 1 U2 7 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 PY 2015 VL 125 IS 8 BP 3285 EP 3296 DI 10.1172/JCI81722 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CO3CS UT WOS:000359034800035 PM 26193635 ER PT J AU Mondul, A Mancina, RM Merlo, A Dongiovanni, P Rametta, R Montalcini, T Valenti, L Albanes, D Romeo, S AF Mondul, Alison Mancina, Rosellina M. Merlo, Andrea Dongiovanni, Paola Rametta, Raffaela Montalcini, Tiziana Valenti, Luca Albanes, Demetrius Romeo, Stefano TI PNPLA3 1148M Variant Influences Circulating Retinol in Adults with Nonalcoholic Fatty Liver Disease or Obesity SO JOURNAL OF NUTRITION LA English DT Article DE PNPLA3; retinal; NAFLD; obesity; RBP4 ID PROTEIN-CALORIE MALNUTRITION; SERUM VITAMIN-A; BINDING-PROTEIN; HEPATOCELLULAR-CARCINOMA; PREALBUMIN CONCENTRATIONS; I148M POLYMORPHISM; RS738409; ASSOCIATION; METABOLISM; TRANSPORT AB Background: Retinal is a lipid-soluble essential nutrient that is stored as retinyl esters in lipid droplets of hepatic stellate cells. Patatin-like phospholipase domain-containing 3 (PNPLA3), through its retinyl-palmitate lipase activity, releases retinol from lipid droplets in hepatic stellate cells in vitro and ex vivo. We have shown that the genetic variant 1148M (rs738409) reduces the PNPLA3 retinyl-palmitate lipase activity. Objective: The aim of the present genetic association study was to test whether overweight/obese carriers of the PNPLA3 148M mutant allele had lower circulating concentrations of retinal than individuals who are homozygous for the 1481 allele. Methods: PNPLA31148M (rs738409) was genotyped by Taqman assay in 76 overweight/obese individuals [BMI (kg/m(2))>= 25; mean +/- SD age: 59.7 +/- 11.4 y; male gender: 70%] with a histologic diagnosis of nonalcoholic fatty liver disease (NAFLD; namely the Milan NAFLD cohort) and in 413 obese men (BMI >= 30; mean SD age: 57.1 +/- 4.9 y) from the alpha-Tocopherol, (beta-Carotene Cancer Prevention (ATBC) Study. Serum concentrations of retinal and alpha-tocopherol were measured by HPLC in both cohorts. beta-Carotene concentrations in the ATBC study were measured by using HPLC. Results: The PNPLA3 148M mutant allele was associated with lower fasting circulating concentrations of retinal (beta = -0.289, P = 0.03) in adults with NAFLD (Milan NAFLD cohort). The PNPLA3148M mutant allele was also associated with lower fasting circulating concentrations of retinal in adults with a BMI >= 30 (ATBC study; [beta = -0.043, P = 0.041. Conclusion: We showed for the first time, to our knowledge, that carriers of the PNPLA3148M allele with either fatty liver plus obesity or obesity alone have lower fasting circulating retinol concentrations. C1 [Mondul, Alison; Albanes, Demetrius] NCI, NIH, Nutri Epidemiol Branch, Div Canc Epidemiol & Genet,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Mondul, Alison; Romeo, Stefano] Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden. [Merlo, Andrea; Dongiovanni, Paola; Rametta, Raffaela; Valenti, Luca] Univ Milan, Dept Pathophysiol & Transplantat DEPT, Milan, Italy. [Merlo, Andrea; Dongiovanni, Paola; Rametta, Raffaela; Valenti, Luca] Magna Graecia Univ Catanzaro, Dept Med & Surg Sci, Clin Nutr Unit, Catanzaro, Italy. [Montalcini, Tiziana] Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden. RP Romeo, S (reprint author), Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden. EM stefano.romeo@wlab.gu.se RI Mancina, Rosellina/L-6782-2015; Romeo, Stefano/L-6861-2015; Valenti, Luca/B-3695-2009 OI Mancina, Rosellina/0000-0002-1126-3071; Romeo, Stefano/0000-0001-9168-4898; Valenti, Luca/0000-0001-8909-0345 FU Swedish Research Council [254439006]; Swedish Heart Lung Foundation [244439007]; Swedish federal government under Agreement on Medical Training and Medical Research (ALF) [76290]; Novonordisk Foundation Grant for Excellence in Endocrinology [244439012] FX Supported by the Swedish Research Council (Vetenskapsradet (VR) 254439006), the Swedish Heart Lung Foundation (244439007), Swedish federal government funding under the Agreement on Medical Training and Medical Research (ALF) (76290), and the Novonordisk Foundation Grant for Excellence in Endocrinology (244439012). NR 27 TC 14 Z9 14 U1 1 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD AUG PY 2015 VL 145 IS 8 BP 1687 EP 1691 DI 10.3945/jn.115.210633 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CO3DT UT WOS:000359037500002 PM 26136587 ER PT J AU Hernaez, A Remaley, AT Farras, M Fernandez-Castillejo, S Subirana, I Schroer, H Fernandez-Mampel, M Munoz-Aguayo, D Sampson, M Sola, R Farree, M de la Torre, R Lopez-Sabater, MC Nyyssonen, K Zunft, HJF Covas, MI Fito, M AF Hernaez, Alvaro Remaley, Alan T. Farras, Marta Fernandez-Castillejo, Sara Subirana, Isaac Schroeder, Helmut Fernandez-Mampel, Mireia Munoz-Aguayo, Daniel Sampson, Maureen Sola, Rosa Farre, Magi de la Torre, Rafael Lopez-Sabater, Maria-Carmen Nyyssonen, Kristiina Zunft, Hans-Joachim F. Covas, Maria-Isabel Fito, Montserrat TI Olive Oil Polyphenols Decrease LDL Concentrations and LDL Atherogenicity in Men in a Randomized Controlled Trial SO JOURNAL OF NUTRITION LA English DT Article DE olive oil polyphenols; randomized clinical trial; low-density lipoproteins; apolippprotein B-100; LDL particle number; small LDL particles; LDL oxidation; lipoprotein lipase; healthy individuals ID LOW-DENSITY-LIPOPROTEIN; TYPE-2 DIABETES-MELLITUS; PARTICLE NUMBER; HEART-DISEASE; CHOLESTEROL; ATHEROSCLEROSIS; OXIDATION; RISK; SUBFRACTIONS; ASSOCIATION AB Background: Olive oil polyphenols have shown protective effects on cardiovascular risk factors. Their consumption decreased oxidative stress biomarkers and improved some features of the lipid profile. However, their effects on LDL concentrations in plasma and LDL atherogenicity have not yet been elucidated. Objective: Our objective was to assess whether the consumption of olive oil polyphenols could decrease LDL concentrations [measured as apolipoprotein B-100 (apo B-100) concentrations and the total number of LDL particles] and atherogenicity (the number of small LDL particles and LDL oxidizability) in humans. Methods: The study was a randomized, cross-over controlled trial in 25 healthy European men, aged 20-59 y, in the context of the EUROLIVE (Effect of Olive Oil Consumption on Oxidative Damage in European Populations) study. Volunteers ingested 25 mL/d raw low-polyphenol-content olive oil (LPCOO; 366 mg/kg) or high-polyphenol-content olive oil (HPCOO; 2.7 mg/kg) for 3 wk. Interventions were preceded by 2-wk washout periods. Effects of olive oil polyphenols on plasma LDL concentrations and atherogenicity were determined in the sample of 25 men. Effects on lipoprotein lipase (LPL) gene expression were assessed in another sample of 18 men from the EUROLIVE study. Results: Plasma apo B-100 concentrations and the number of total and small LDL particles decreased (mean +/- SD: by 5.94% +/- 16.6%, 11.9% +/- 12.0%, and 15.3% +/- 35.1%, respectively) from baseline after the HPCOO intervention. These changes differed significantly from those after the LPCOO intervention, which resulted in significant increases of 6.39% +/- 16.6%, 4.73% +/- 22.0%, and 13.6% +/- 36.4% from baseline (P < 0.03). LDL oxidation lag time increased by 5.0% +/- 10.3% from baseline after the HPCOO intervention, which was significantly different only relative to preintervention values (P = 0.038). LPL gene expression tended to increase by 26% from baseline after the HPCOO intervention (P = 0.08) and did not change after the LPCOO intervention. Conclusion: The consumption of olive oil polyphenols decreased plasma LDL concentrations and LDL atherogenicity in healthy young men. This trial was registered at ww.controlled-trials.com as ISRCTN09220811. C1 [Hernaez, Alvaro; Farras, Marta; Schroeder, Helmut; Fernandez-Mampel, Mireia; Munoz-Aguayo, Daniel; Covas, Maria-Isabel] Hosp Mar, REGICOR Study Grp, Cardiovasc Risk & Nutr Res Grp, Med Res Inst IMIM, Barcelona, Spain. [Subirana, Isaac] Hosp Mar, REGICOR Study Grp, Cardiovasc Epidemiol & Genet Res Grp, Med Res Inst IMIM, Barcelona, Spain. [de la Torre, Rafael] Hosp Mar, Human Pharmacol & Clin Neurosci Res Grp, Med Res Inst IMIM, Barcelona, Spain. [Subirana, Isaac; Schroeder, Helmut] CIBER Epidemiol & Salud Publ, Donostia San Sebastian, Spain. [Hernaez, Alvaro; Farras, Marta; Munoz-Aguayo, Daniel; Sola, Rosa; Covas, Maria-Isabel; Fito, Montserrat] CIBER Fisiopatol Nutr & Obesidad CIBEROBN, Cordoba, Spain. [Hernaez, Alvaro] Univ Barcelona, PhD Program Food Sci & Nutr, Barcelona, Spain. [Lopez-Sabater, Maria-Carmen] Univ Barcelona, Fac Pharm, Nutr & Bromatol Dept, Barcelona, Spain. [Remaley, Alan T.; Sampson, Maureen] NHLBI, Lipoprot Metab Sect, NIH, Bethesda, MD 20892 USA. [Farras, Marta] Autonomous Univ Barcelona, Dept Biochem & Mol Biol, PhD Program Biochem Mol Biol & Biomed, Barcelona, Spain. [Fernandez-Castillejo, Sara] Univ Rovira & Virgili, IISPV, Hosp Univ St Joan, Res Unit Lipids & Atherosclerosis, Reus, Spain. [Fernandez-Castillejo, Sara] CIBER Diabet & Enfermedades Metabol Asociadas CIB, Barcelona, Spain. [Farre, Magi] Autonomous Univ Barcelona UAB, Barcelona, Spain. [de la Torre, Rafael] Pompeu Fabra Univ UPF CEXS UPF, Dept Expt & Hlth Sci, Barcelona, Spain. [Nyyssonen, Kristiina] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Nyyssonen, Kristiina] Univ Eastern Finland, Dept Clin Chem, Kuopio, Finland. [Nyyssonen, Kristiina] Eastern Finland Lab Ctr, Kuopio, Finland. [Zunft, Hans-Joachim F.] German Inst Human Nutr Potsdam Rehbrucke, Potsdam, Germany. RP Fito, M (reprint author), Hosp Mar, REGICOR Study Grp, Cardiovasc Risk & Nutr Res Grp, Med Res Inst IMIM, Barcelona, Spain. EM mfito@imim.es RI Fito, Montserrat/C-1822-2012; OI Fito, Montserrat/0000-0002-1817-483X; SOLA, Rosa/0000-0002-8359-235X; Hernaez, Alvaro/0000-0001-8593-1477; Schroder, Helmut/0000-0003-2231-5081; Farras Mane, Marta/0000-0001-9776-3773 FU Agenda de Gestio d'Ajuts Universitaris i de Recerca [2014-SGR-240]; Comision Interministerial de Ciencia y Tecnologia-European Regional Development Fund (ERDF) [AGL2009-13517-C03-01]; European Commission [QLRT-2001-00287]; Proyectos de Investigacion en Salud-FIS programs [PI070759, PI11/01647]; Formacion de Personal Investigador fellowship program [BES-2010-040766]; Formacion del Profesorado Universitario fellowship program [FPU12/01318]; [CP06/00100] FX Supported by the Agenda de Gestio d'Ajuts Universitaris i de Recerca (2014-SGR-240), the Comision Interministerial de Ciencia y Tecnologia-European Regional Development Fund (ERDF) (AGL2009-13517-C03-01), the European Commission (QLRT-2001-00287). Proyectos de Investigacion en Salud-FIS programs (PI070759 and PI11/01647), the Formacion de Personal Investigador fellowship program (BES-2010-040766), the Formacion del Profesorado Universitario fellowship program (FPU12/01318), and Miguel Servet contract (CP06/00100). The CIBER de Fisiopatologia de la basic lad y Nutricion (CIBEROBN) is an initiative of the lnstituto de Salud Carlos III, Madrid, Spain. NR 32 TC 12 Z9 12 U1 5 U2 23 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD AUG PY 2015 VL 145 IS 8 BP 1692 EP 1697 DI 10.3945/jn.115.211557 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CO3DT UT WOS:000359037500003 PM 26136585 ER PT J AU Pinal-Fernandez, I Casciola-Rosen, LA Christopher-Stine, L Corse, AM Mammen, AL AF Pinal-Fernandez, Iago Casciola-Rosen, Livia A. Christopher-Stine, Lisa Corse, Andrea M. Mammen, Andrew L. TI The Prevalence of Individual Histopathologic Features Varies according to Autoantibody Status in Muscle Biopsies from Patients with Dermatomyositis SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE MYOSITIS; POLYMYOSITIS; DERMATOMYOSITIS; AUTOIMMUNITY; MUSCLE ID JUVENILE DERMATOMYOSITIS; ANTIBODIES; POLYMYOSITIS; MYOPATHIES; PHENOTYPE; PROTEIN AB Objective. Individual dermatomyositis (DM)-associated autoantibodies are associated with distinct clinical phenotypes. This study was undertaken to explore the association of these autoantibodies with specific muscle biopsy features. Methods. DM subjects with a muscle biopsy reviewed at Johns Hopkins had sera screened for autoantibodies recognizing Mi-2, transcriptional intermediary factor 1-gamma (TIF1-gamma), NXP2, MDA5, Ro52, PM-Scl, and Jo1. We also included anti-Jo1-positive patients with polymyositis (PM) who had a biopsy read at Johns Hopkins. Analyzed histological features included perifascicular atrophy, perivascular inflammation, mitochondrial dysfunction, primary inflammation, and myofiber necrosis. Duration of disease, biopsy location, and treatment at biopsy were also analyzed. Results. We studied 91 DM and 7 anti-Jo1-positive patients with PM. In univariate analyses, TIF1-gamma+ patients had more mitochondrial dysfunction (47% vs 18%; p = 0.05), NXP2+ patients had less primary inflammation (0% vs 28%; p = 0.01), Mi-2+ patients had more primary inflammation (50% vs 19%; p = 0.03), and PM-Scl+ patients had more primary inflammation (67% vs 18%; p = 0.004) than those who were negative for each autoantibody. Although reliability was limited because of small sample numbers, multivariate analysis confirmed that TIF1-gamma+ patients had more mitochondrial dysfunction [prevalence ratio (PR) 2.6, 95% CI 1.0-6.5, p = 0.05] and PM-Scl+ patients had more primary inflammation (PR 5.2, 95% CI 2.0-13.4; p = 0.001) independent of disease duration at biopsy, biopsy site, and treatment at biopsy. No differences in muscle biopsy features were noted between anti-Jo1-positive patients diagnosed with DM and PM. Conclusion. The prevalence of different histological features varies according to autoantibody status in DM. Muscle biopsy features are similar in anti-Jo1 patients with and without a rash. C1 [Pinal-Fernandez, Iago] Vall dHebron Univ Hosp, Autoimmune Syst Dis Unit, Barcelona, Spain. [Casciola-Rosen, Livia A.; Christopher-Stine, Lisa; Corse, Andrea M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, US Natl Inst Hlth NIH, Bethesda, MD USA. RP Mammen, AL (reprint author), NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Express, NIH, 50 South Dr,Room 1146,Bldg 50,MSC 8024, Bethesda, MD 20892 USA. EM andrew.mammen@nih.gov FU Intramural NIH HHS; NIAMS NIH HHS [R56 AR062615, P30 AR053503, P30-AR-053503, R56 AR062615-01A1] NR 18 TC 12 Z9 12 U1 1 U2 3 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD AUG PY 2015 VL 42 IS 8 BP 1448 EP 1454 DI 10.3899/jrheum.141443 PG 7 WC Rheumatology SC Rheumatology GA CO0UD UT WOS:000358868000017 PM 26443871 ER PT J AU Batu, ED Karadag, O Taskiran, EZ Kalyoncu, U Aksentijevich, I Alikasifoglu, M Ozen, S AF Batu, Ezgi Deniz Karadag, Omer Taskiran, Ekim Zihni Kalyoncu, Umut Aksentijevich, Ivona Alikasifoglu, Mehmet Ozen, Seza TI A Case Series of Adenosine Deaminase 2-deficient Patients Emphasizing Treatment and Genotype-phenotype Correlations SO JOURNAL OF RHEUMATOLOGY LA English DT Letter ID POLYARTERITIS-NODOSA; MUTANT ADA2; VASCULOPATHY; CLASSIFICATION; MUTATIONS; CRITERIA C1 [Batu, Ezgi Deniz; Ozen, Seza] Hacettepe Univ, Fac Med, Div Rheumatol, Dept Pediat, TR-06100 Ankara, Turkey. [Karadag, Omer; Kalyoncu, Umut] Hacettepe Univ, Fac Med, Dept Internal Med, Div Rheumatol, TR-06100 Ankara, Turkey. [Taskiran, Ekim Zihni] Hacettepe Univ, Fac Med, Div Rheumatol, Dept Med Biol, TR-06100 Ankara, Turkey. [Aksentijevich, Ivona] NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA. [Alikasifoglu, Mehmet] Hacettepe Univ, Fac Med, Dept Med Genet, TR-06100 Ankara, Turkey. RP Ozen, S (reprint author), Hacettepe Univ, Fac Med, Div Rheumatol, Dept Pediat, TR-06100 Ankara, Turkey. EM sezaozen@hacettepe.edu.tr RI Bayram, Cem/D-7403-2013 OI Bayram, Cem/0000-0001-8717-4668 NR 12 TC 7 Z9 7 U1 1 U2 6 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD AUG PY 2015 VL 42 IS 8 BP 1532 EP U215 DI 10.3899/jrheum.150024 PG 3 WC Rheumatology SC Rheumatology GA CO0UD UT WOS:000358868000030 PM 26233953 ER PT J AU Brown, TA Luby, M Shah, J Giannakidis, D Latour, LL AF Brown, Tyler A. Luby, Marie Shah, Jignesh Giannakidis, Dimitrios Latour, Lawrence L. TI Magnetic Resonance Imaging in Acute Ischemic Stroke Patients with Mild Symptoms: An Opportunity to Standardize Intravenous Thrombolysis SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Article DE Mild stroke; minor stroke; PWI; infarction; volumetric MRI-DWI ID TISSUE-PLASMINOGEN ACTIVATOR; PROSPECTIVE COHORT; DEFUSE 2; DIFFUSION; MRI; OUTCOMES; TRIAL; REPERFUSION; RELIABILITY; VALIDATION AB Background: Patients presenting with mild stroke symptoms are excluded inconsistently from intravenous (IV) thrombolysis. We aimed to compare acute magnetic resonance imaging findings in patients with mild symptoms to those with more severe deficits to identify clinically mild patients who might benefit from IV thrombolysis. Methods: We retrospectively studied consecutive stroke patients presenting with perfusion deficit who underwent time-of-flight magnetic resonance angiography within 24 hours of time last seen normal. Two raters measured the lesion volumes on diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) with mismatch (MM) calculated as PWI minus DWI. Occlusion site was categorized as "proximal,'' "distal,'' or "magnetic resonance angiography-negative'' by consensus review. Stroke with mild symptoms was defined as admit National Institutes of Health Stroke Scale score of 4 or less. Values were reported as n (%). Results: Ninety-one patients were included; 56 (61.5%) with nonmild and 35 (38.5%) with mild symptoms. After stratifying for occlusion site, there were no differences in PWI and MM lesion volumes for the nonmild versus mild patients (P = .34-.98 and P = .54-1, respectively). Furthermore, there was a trend for thrombolyzed mild stroke patients (88%, n= 7 of 8) to more likely have a favorable clinical outcome (discharge modified Rankin score <= 2) versus untreated patients (70%, n = 16 of 23). Conclusions: When present, conspicuous vessel occlusions in clinically mild stroke patients are concomitant with similar perfusion deficit and MM volumes in more clinically severe stroke patients. Coupled with a trend toward better outcomes in mild stroke patients who were treated with IV tissue plasminogen activator (t-PA), this could indicate that advanced imaging may be used in standardizing the way these patients are selected for IV t-PA therapy. Published by Elsevier Inc. on behalf of National Stroke Association C1 [Brown, Tyler A.; Luby, Marie; Shah, Jignesh; Giannakidis, Dimitrios; Latour, Lawrence L.] NINDS, Stroke Diagnost & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Latour, LL (reprint author), Sect Stroke Diagnost & Therapeut, 10 Ctr Dr,MSC 1063,Bldg 10,Room B1D733, Bethesda, MD 20892 USA. EM LatourL@ninds.nih.gov FU Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, NIH (NIH) [1ZIANS003044-08] FX This research was supported by the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, NIH (NIH project number 1ZIANS003044-08). The authors have no disclosures. NR 29 TC 2 Z9 2 U1 5 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 EI 1532-8511 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD AUG PY 2015 VL 24 IS 8 BP 1832 EP 1840 DI 10.1016/j.jstrokecerebrovasdis.2015.04.012 PG 9 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CO6XB UT WOS:000359300000031 PM 25997980 ER PT J AU Shaw, P AF Shaw, Philip TI Defining Cortical Structure in Adolescent Attention-Deficit/Hyperactivity Disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material ID ADULTS; CHILDHOOD; ADHD C1 [Shaw, Philip] NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Shaw, Philip] NIMH, Bethesda, MD 20892 USA. RP Shaw, P (reprint author), NHGRI, B1B37,Bldg 31, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov FU Intramural Program of the National Human Genome Research Institute FX Dr. Shaw is funded by the Intramural Program of the National Human Genome Research Institute. NR 12 TC 0 Z9 0 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2015 VL 54 IS 8 BP 615 EP 616 DI 10.1016/j.jaac.2015.06.002 PG 2 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA CO2GR UT WOS:000358974700003 PM 26210329 ER PT J AU Wakschlag, LS Estabrook, R Petitclerc, A Henry, D Burns, JL Perlman, SB Voss, JL Pine, DS Leibenluft, E Briggs-Gowan, ML AF Wakschlag, Lauren S. Estabrook, Ryne Petitclerc, Amelie Henry, David Burns, James L. Perlman, Susan B. Voss, Joel L. Pine, Daniel S. Leibenluft, Ellen Briggs-Gowan, Margaret L. TI Clinical Implications of a Dimensional Approach: The Normal:Abnormal Spectrum of Early Irritability SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE irritability; dimensional; developmental psychopathology; normal:abnormal spectrum; longitudinal modeling ID PRESCHOOL DISRUPTIVE BEHAVIOR; DEVELOPMENTAL PSYCHOPATHOLOGY; ASSOCIATIONS; DISORDER; CHILDHOOD; SYMPTOMS; OUTCOMES; MOOD AB Objective:. The importance of dimensional approaches is widely recognized, but an empirical base for clinical application is lacking. This is particularly true for irritability, a dimensional phenotype that cuts across many areas of psychopathology and manifests early in life. We examine longitudinal, dimensional patterns of irritability and their clinical import in early childhood. Method: Irritability was assessed longitudinally over an average of 16 months in a clinically enriched, diverse community sample of preschoolers (N = 497; mean = 4.2 years; SD = 0.8). Using the Temper Loss scale of the Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB) as a developmentally sensitive indicator of early childhood irritability, we examined its convergent/divergent, clinical, and incremental predictive validity, and modeled its linear and nonlinear associations with clinical risk. Results: The Temper Loss scale demonstrated convergent and divergent validity to child and maternal factors. In multivariate analyses, Temper Loss predicted mood (separation anxiety disorder [SAD], generalized anxiety disorder [GAD], and depression/dysthymia), disruptive (oppositional defiant disorder [ODD], attention-deficit/hyperactivity disorder [ADHD], and conduct disorder [CD]) symptoms. Preschoolers with even mildly elevated Temper Loss scale scores showed substantially increased risk of symptoms and disorders. For ODD, GAD, SAD, and depression, increases in Temper Loss scale scores at the higher end of the dimension had a greater impact on symptoms relative to increases at the lower end. Temper Loss scale scores also showed incremental validity over DSM-IV disorders in predicting subsequent impairment. Finally, accounting for the substantial heterogeneity in longitudinal patterns of Temper Loss significantly improved prediction of mood and disruptive symptoms. Conclusion: Dimensional, longitudinal characterization of irritability informs clinical prediction. A vital next step will be empirically generating parameters for the incorporation of dimensional information into clinical decision-making with reasonable certainty. C1 [Wakschlag, Lauren S.] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Wakschlag, Lauren S.] Northwestern Univ, Inst Policy Res, Chicago, IL 60611 USA. [Estabrook, Ryne; Petitclerc, Amelie; Burns, James L.; Voss, Joel L.] Northwestern Univ, Chicago, IL 60611 USA. [Henry, David] Univ Illinois, Inst Hlth Res & Policy, Chicago, IL USA. [Perlman, Susan B.] Univ Pittsburgh, Pittsburgh, PA USA. [Pine, Daniel S.; Leibenluft, Ellen] NIMH, Bethesda, MD 20892 USA. [Briggs-Gowan, Margaret L.] Univ Connecticut, Farmington, CT USA. RP Wakschlag, LS (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, 633 St N Clair St,19th Floor, Chicago, IL 60611 USA. EM lauriew@northwestern.edu FU National Institute of Mental Health [R01MH082830, UO1MH090301, 2U01MH082830]; Walden and Jean Young Shaw Foundation; [K01MH094467] FX Drs. Wokschlog, Estabrook, Henry, Voss, and Briggs-Gowan were supported by National Institute of Mental Health grants R01MH082830, UO1MH090301, and 2U01MH082830, and Dr. Perlman was supported by K01MH094467. Dr. Wakschlag was also supported by the Walden and Jean Young Shaw Foundation. NR 38 TC 6 Z9 6 U1 2 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2015 VL 54 IS 8 BP 626 EP 634 DI 10.1016/j.jaac.2015.05.016 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA CO2GR UT WOS:000358974700005 PM 26210331 ER PT J AU Copeland, WE Brotman, MA Costello, EJ AF Copeland, William E. Brotman, Melissa A. Costello, E. Jane TI Normative Irritability in Youth: Developmental Findings From the Great Smoky Mountains Study SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE childhood; irritability; epidemiology; development; longitudinal ID MOOD DYSREGULATION DISORDER; PSYCHIATRIC-ASSESSMENT CAPA; OPPOSITIONAL DEFIANT; ADULT OUTCOMES; FOLLOW-UP; CHILD; PREVALENCE; PSYCHOPATHOLOGY; ASSOCIATIONS; DEPRESSION AB Objective: The goal of this study is to examine the developmental epidemiology of normative irritability and its tonic and phasic components in a longitudinal community sample of youth. Method: Eight waves of data from the prospective, community Great Smoky Mountains Study (6,674 assessments of 1,420 participants) were used, covering children in the community 9 to 16 years of age. Youth and 1 parent were interviewed using the Child and Adolescent Psychiatric Assessment to assess tonic (touchy/easily annoyed, irritable mood, angry or resentful). and phasic (temper tantrums or anger outbursts) components of irritability, including frequency, duration, onset, and cross-context variability. Results: At any given point in childhood/adolescence, 51.4% (standard error [SE] = 1.4) of participants reported phasic irritability, 28.3% (SE = 1.2) reported tonic irritability, and 22.8% (SE = 1.1) reported both. These prevalence levels decreased with age but did not vary by sex. The overlap between tonic and phasic irritability was high (odds ratio = 5.8, 95% CI = 3.3-10.5, p < .0001), with little evidence of tonic occurring without phasic irritability. Both tonic and phasic irritability predicted one another oiler time, supporting both heterotypic and homotypic continuity. Low levels of either tonic or phasic irritability increased risk for disrupted functioning including service use, school suspensions, parental burden, and emotional symptoms both concurrently and at 1-year follow-up. Conclusion: Irritability is relatively common, decreases with age but does not vary by sex, and at almost any level is associated with increased risk of disrupted functioning. Its relative components frequently overlap, although irritable outbursts are more common than irritable mood. Irritability appears to be a high-priority transdiagnostic marker for screening children in need of clinical attention. C1 [Copeland, William E.; Costello, E. Jane] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Brotman, Melissa A.] NIMH, Emot & Dev Branch, Bethesda, MD 20892 USA. RP Copeland, WE (reprint author), Duke Univ, Med Ctr, Ctr Dev Epidemiol, Dept Psychiat & Behav Sci, Box 3454, Durham, NC 27710 USA. EM william.copeland@duke.edu RI copeland, william/N-5413-2014; Brotman, Melissa/H-7409-2013 FU National Institute of Mental Health [MH63970, MH63671, MH48085, MH094605]; National Institute on Drug Abuse [DA/MH11301]; NARSAD; William T. Grant Foundation FX The work presented here was supported by the National Institute of Mental Health (MH63970, MH63671, MH48085, MH094605), the National Institute on Drug Abuse (DA/MH11301), NARSAD (Early Career Award to W.E.C.), and the William T. Grant Foundation. NR 45 TC 5 Z9 5 U1 3 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2015 VL 54 IS 8 BP 635 EP 642 DI 10.1016/j.jacc.2015.05.008 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA CO2GR UT WOS:000358974700006 PM 26210332 ER PT J AU Saliba, Y Karam, R Smayra, V Aftimos, G Abramowitz, J Birnbaumer, L Fares, N AF Saliba, Youakim Karam, Ralph Smayra, Viviane Aftimos, Georges Abramowitz, Joel Birnbaumer, Lutz Fares, Nassim TI Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID UNILATERAL URETERAL OBSTRUCTION; VASCULAR SMOOTH-MUSCLE; CHRONIC KIDNEY-DISEASE; EPITHELIAL-MESENCHYMAL TRANSITION; SPONTANEOUSLY HYPERTENSIVE-RATS; PROTEIN-KINASE-C; TRPC3 CHANNELS; ANGIOTENSIN-II; CARDIAC FIBROBLASTS; GROWTH-FACTOR AB Transient receptor potential canonical (TRPC) Ca2+-permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II- and 1-oleoyl-2-acetyl-sn-glycerol-induced Ca2+ entry in these cells, which was detected by fura-2 Ca2+ imaging. TRPC3 blockade or Ca2+ removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signal-regulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca2+ entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca2+-mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease. C1 [Saliba, Youakim; Karam, Ralph; Fares, Nassim] St Joseph Univ, Physiol & Pathophysiol Res Lab, Fac Med, Pole Technol & Hlth, Beirut, Lebanon. [Smayra, Viviane] St Joseph Univ, Fac Med, Beirut, Lebanon. [Aftimos, Georges] Natl Inst Pathol, Dept Anatomopathol, Baabda, Lebanon. [Abramowitz, Joel; Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. RP Fares, N (reprint author), St Joseph Univ, Physiol Lab, Fac Med, Beirut, Lebanon. EM nassim.fares@usj.edu.lb RI Abramowitz, Joel/A-2620-2015 FU Research Council of the Saint Joseph University Faculty of Medicine; US National Institutes of Health [Z01-ES-101684] FX This work was supported by the Research Council of the Saint Joseph University Faculty of Medicine and in part by Intramural Research Program of the US National Institutes of Health Project Z01-ES-101684 (to L.B.). NR 114 TC 6 Z9 7 U1 2 U2 10 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2015 VL 26 IS 8 BP 1855 EP 1876 DI 10.1681/ASN.2014010065 PG 22 WC Urology & Nephrology SC Urology & Nephrology GA CO1DY UT WOS:000358895100014 PM 25479966 ER PT J AU Xie, BW Avila, JI Ng, BK Fan, B Loo, V Gilsanz, V Hangartner, T Kalkwarf, HJ Lappe, J Oberfield, S Winer, K Zemel, B Shepherd, JA AF Xie, Bowen Avila, Jesus I. Ng, Bennett K. Fan, Bo Loo, Victoria Gilsanz, Vicente Hangartner, Thomas Kalkwarf, Heidi J. Lappe, Joan Oberfield, Sharon Winer, Karen Zemel, Babette Shepherd, John A. TI Accurate body composition measures from whole-body silhouettes SO MEDICAL PHYSICS LA English DT Article DE silhouettes; body composition; dual-energy x-ray; absorptiometry; active shape modeling ID BIOELECTRICAL-IMPEDANCE ANALYSIS; SAGITTAL ABDOMINAL DIAMETER; BONE-MINERAL DENSITY; MASS INDEX; WAIST CIRCUMFERENCE; DIABETES-MELLITUS; REFERENCE CURVES; CHART ANALYSIS; RISK-FACTORS; FAT AB Purpose: Obesity and its consequences, such as diabetes, are global health issues that burden about 171x10(6) adult individuals worldwide. Fat mass index (FMI, kg/m(2)), fat-free mass index (FFMI, kg/m(2)), and percent fat mass may be useful to evaluate under-and overnutrition and muscle development in a clinical or research environment. This proof-of-concept study tested whether frontal whole-body silhouettes could be used to accurately measure body composition parameters using active shape modeling (ASM) techniques. Methods: Binary shape images (silhouettes) were generated from the skin outline of dual-energy x-ray absorptiometry (DXA) whole-body scans of 200 healthy children of ages from 6 to 16 yr. The silhouette shape variation from the average was described using an ASM, which computed principal components for unique modes of shape. Predictive models were derived from the modes for FMI, FFMI, and percent fat using stepwise linear regression. The models were compared to simple models using demographics alone [age, sex, height, weight, and body mass index z-scores (BMIZ)]. Results: The authors found that 95% of the shape variation of the sampled population could be explained using 26 modes. In most cases, the body composition variables could be predicted similarly between demographics-only and shape-only models. However, the combination of shape with demographics improved all estimates of boys and girls compared to the demographics-only model. The best prediction models for FMI, FFMI, and percent fat agreed with the actual measures with R-2 adj. (the coefficient of determination adjusted for the number of parameters used in the model equation) values of 0.86, 0.95, and 0.75 for boys and 0.90, 0.89, and 0.69 for girls, respectively. Conclusions: Whole-body silhouettes in children may be useful to derive estimates of body composition including FMI, FFMI, and percent fat. These results support the feasibility of measuring body composition variables from simple cameras such as those found in cell phones. (C) 2015 American Association of Physicists in Medicine. C1 [Xie, Bowen; Avila, Jesus I.; Ng, Bennett K.; Fan, Bo; Shepherd, John A.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94115 USA. [Loo, Victoria] Yale Univ, Dept Polit Sci, New Haven, CT 06520 USA. [Gilsanz, Vicente] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Hangartner, Thomas] Wright State Univ, Dept Biomed Ind & Human Factors Engn, Dayton, OH 45435 USA. [Kalkwarf, Heidi J.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Lappe, Joan] Creighton Univ, Dept Endocrinol, Omaha, NE 68131 USA. [Oberfield, Sharon] Columbia Univ, Dept Pediat, New York, NY 10032 USA. [Winer, Karen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Zemel, Babette] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Xie, BW (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94115 USA. OI Avila, Jesus/0000-0002-1410-1975 FU USPHS from the National Center for Research Resources (NIH) [UL1-RR-026314]; CTSA [UL1-RR-024134]; National Institute of Child Health and Human Development Bone Mineral Density in Childhood Study [NICHD N01-HD-13328] FX B.X., J.I.A., and J.A.S. designed research; B.X., J.I.A., B.F., H.K., B.Z., J.W., V.L., and J.A.S. conducted research; B.X., J.I.A., B.K.N., B.F., V.L., and J.A.S. analyzed data; B.X., J. I. A., B.K.N., B.F., and J.A.S. wrote the paper; B.X. and J.I.A. had primary responsibility for final content. All authors read and approved the final paper. National Institute of Child Health and Human Development Bone Mineral Density in Childhood Study, NICHD N01-HD-13328, USPHS Grant No. UL1-RR-026314 from the National Center for Research Resources (NIH), and CTSA Grant No. UL1-RR-024134. No author has a potential conflict of interest. NR 35 TC 3 Z9 3 U1 0 U2 7 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD AUG PY 2015 VL 42 IS 8 BP 4668 EP 4677 DI 10.1118/1.4926557 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CO1RN UT WOS:000358933000024 PM 26233194 ER PT J AU Van Itallie, CM Tietgens, AJ Krystofiak, E Kachar, B Anderson, JM AF Van Itallie, Christina M. Tietgens, Amber Jean Krystofiak, Evan Kachar, Bechara Anderson, James M. TI A complex of ZO-1 and the BAR-domain protein TOCA-1 regulates actin assembly at the tight junction SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID PLASMA-MEMBRANE INVAGINATION; EPITHELIAL ZONULA ADHERENS; WASP-WIP COMPLEX; N-WASP; PARACELLULAR PERMEABILITY; OCCLUDENS-1 AND-2; E-CADHERIN; IN-VIVO; CYTOSKELETON; CELLS AB Assembly and sealing of the tight junction barrier are critically dependent on the perijunctional actin cytoskeleton, yet little is known about physical and functional links between barrier-forming proteins and actin. Here we identify a novel functional complex of the junction scaffolding protein ZO-1 and the F-BAR-domain protein TOCA-1. Using MDCK epithelial cells, we show that an alternative splice of TOCA-1 adds a PDZ-binding motif, which binds ZO-1, targeting TOCA-1 to barrier contacts. This isoform of TOCA-1 recruits the actin nucleation-promoting factor N-WASP to tight junctions. CRISPR-Cas9-mediated knockout of TOCA-1 results in increased paracellular flux and delayed recovery in a calcium switch assay. Knockout of TOCA-1 does not alter FRAP kinetics of GFP ZO-1 or occludin, but longer term (12 h) time-lapse microscopy reveals strikingly decreased tight junction membrane contact dynamics in knockout cells compared with controls. Reexpression of TOCA-1 with, but not without, the PDZ-binding motif rescues both altered flux and membrane contact dynamics. Ultrastructural analysis shows actin accumulation at the adherens junction in TOCA-1-knockout cells but unaltered freeze-fracture fibril morphology. Identification of the ZO-1/TOCA-1 complex provides novel insights into the underappreciated dependence of the barrier on the dynamic nature of cell-to-cell contacts and perijunctional actin. C1 [Van Itallie, Christina M.; Tietgens, Amber Jean; Anderson, James M.] NHLBI, Lab Tight Junct Struct & Funct, NIH, Bethesda, MD 20892 USA. [Krystofiak, Evan; Kachar, Bechara] NIDCD, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. RP Van Itallie, CM (reprint author), NHLBI, Lab Tight Junct Struct & Funct, NIH, Bethesda, MD 20892 USA. EM Christina.vanitallie@nih.gov FU Division of Intramural Research, National Institutes of Health FX We acknowledge Joan Lunney and Sam Abrams (U.S. Department of Agriculture, Beltsville, MD) for help with qRT-PCR and use of their ABI 7500, and Haiming Cao (National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD) for use of his QuantStudio 7 Flex Real-Time PCR. We thank Xufeng Wu, Daniela Malide, and Christian Combs (Light Microscopy Core Facility, National Heart, Lung, and Blood Institute) and Patricia Connelly, Erin Stempinski, and Chris Brantner (Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute) for their invaluable help and Mary Anne Conti and the National Heart, Lung, and Blood Institute Pathology Core Facility for mouse kidney frozen tissue sections. We appreciate TOCA-1 cDNAs supplied by Andrew Craig (Queen's University, Kingston, Canada) and Sohail Ahmed (Institute of Medical Biology, Singapore). We also thank Alan Fanning (University of North Carolina, Chapel Hill, NC), Karin Fredriksson, and members of the Clare Waterman laboratory, especially Robert Fischer, Ana Pasapera, and Michelle Baird (National Heart, Lung, and Blood Institute), for thoughtful discussions. This research was supported by the Division of Intramural Research, National Institutes of Health. NR 83 TC 6 Z9 6 U1 2 U2 8 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 2015 VL 26 IS 15 BP 2769 EP 2787 DI 10.1091/mbc.E15-04-0232 PG 19 WC Cell Biology SC Cell Biology GA CO2UQ UT WOS:000359012500005 PM 26063734 ER PT J AU Di Donato, M Bilancio, A D'Amato, L Claudiani, P Oliviero, MA Barone, MV Auricchio, A Appella, E Migliaccio, A Auricchio, F Castoria, G AF Di Donato, Marzia Bilancio, Antonio D'Amato, Loredana Claudiani, Pamela Oliviero, Maria Antonietta Barone, Maria Vittoria Auricchio, Alberto Appella, Ettore Migliaccio, Antimo Auricchio, Ferdinando Castoria, Gabriella TI Cross-talk between androgen receptor/filamin A and TrkA regulates neurite outgrowth in PC12 cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID NERVE GROWTH-FACTOR; BULBAR MUSCULAR-ATROPHY; ESTRADIOL-RECEPTOR; TYROSINE KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; PROGESTERONE-RECEPTOR; ESTROGEN-RECEPTOR; PROSTATE-CANCER; DNA-SYNTHESIS; FILAMIN AB Steroids and growth factors control neuronal development through their receptors under physiological and pathological conditions. We show that PC12 cells harbor endogenous androgen receptor (AR), whose inhibition or silencing strongly interferes with neuritogenesis stimulated by the nonaromatizable synthetic androgen R1881 or NGF. This implies a role for AR not only in androgen signaling, but also in NGF signaling. In turn, a pharmacological TrkA inhibitor interferes with NGF- or androgen-induced neuritogenesis. In addition, androgen or NGF triggers AR association with TrkA, TrkA interaction with PI3-K delta, and downstream activation of PI3-K delta and Rac in PC12 cells. Once associated with AR, filamin A (FlnA) contributes to androgen or NGF neuritogenesis, likely through its interaction with signaling effectors, such as Rac. This study thus identifies a previously unrecognized reciprocal crosstalk between AR and TrkA, which is controlled by beta 1 integrin. The contribution of FlnA/AR complex and PI3-K d to neuronal differentiation by androgens and NGF is also novel. This is the first description of AR function in PC12 cells. C1 [Di Donato, Marzia; Bilancio, Antonio; D'Amato, Loredana; Oliviero, Maria Antonietta; Migliaccio, Antimo; Auricchio, Ferdinando; Castoria, Gabriella] Univ Naples 2, Dept Biochem Biophys & Gen Pathol, I-80138 Naples, Italy. [Claudiani, Pamela; Auricchio, Alberto] Univ Naples Federico II, Telethon Inst Genet & Med, I-80131 Naples, Italy. [Claudiani, Pamela; Barone, Maria Vittoria; Auricchio, Alberto] Univ Naples Federico II, Med Genet & Translat Med Dept, I-80131 Naples, Italy. [Barone, Maria Vittoria] Univ Naples Federico II, European Lab Invest Food Induced Dis, I-80131 Naples, Italy. [Appella, Ettore] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Migliaccio, A (reprint author), Univ Naples 2, Dept Biochem Biophys & Gen Pathol, I-80138 Naples, Italy. EM antimo.migliaccio@unina2.it OI BARONE, Maria Vittoria/0000-0001-6190-4917; BILANCIO, Antonio/0000-0002-5118-3359; Di Donato, Marzia/0000-0001-7207-826X; AURICCHIO, Alberto/0000-0002-0832-2472; Migliaccio, Antimo/0000-0002-4197-2055; Castoria, Gabriella/0000-0002-0576-4494 FU Italian Association for Cancer Research [IG11520]; Italian Ministry of University and Scientific Research [2010NFEB9L_002]; PRIN Grant FX We thank C. S. Chang, F. Claessens, B. J. Eickholt, and C. J. Loy for plasmids, cells, and reagents. This work was supported by grants from the Italian Association for Cancer Research (IG11520 to A.M.) and the Italian Ministry of University and Scientific Research (2010NFEB9L_002 to G.C.). M.D.D. is the recipient of PRIN Grant 2010-2011. NR 67 TC 0 Z9 0 U1 0 U2 1 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 2015 VL 26 IS 15 BP 2858 EP 2872 DI 10.1091/mbc.E14-09-1352 PG 15 WC Cell Biology SC Cell Biology GA CO2UQ UT WOS:000359012500012 PM 26063730 ER PT J AU LoRusso, PM Boerner, SA Pilat, MJ Forman, KM Zuccaro, CY Kiefer, JA Liang, WS Hunsberger, S Redman, BG Markovic, SN Sekulic, A Bryce, AH Joseph, RW Cowey, CL Fecher, LA Sosman, JA Chapman, PB Schwartz, GK Craig, DW Carpten, JD Trent, JM AF LoRusso, Patricia M. Boerner, Scott A. Pilat, Mary Jo Forman, Karen M. Zuccaro, Clarice Y. Kiefer, Jeffrey A. Liang, Winnie S. Hunsberger, Sally Redman, Bruce G. Markovic, Svetomir N. Sekulic, Aleksandar Bryce, Alan H. Joseph, Richard W. Cowey, C. Lance Fecher, Leslie Anne Sosman, Jeffrey Alan Chapman, Paul B. Schwartz, Gary K. Craig, David W. Carpten, John D. Trent, Jeffrey M. TI Pilot Trial of Selecting Molecularly Guided Therapy for Patients with Non-V600 BRAF-Mutant Metastatic Melanoma: Experience of the SU2C/MRA Melanoma Dream Team SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID PERSONALIZED MEDICINE; UNTREATED MELANOMA; DRUG TARGETS; MUTATIONS; CANCER; GENES; GLIOBLASTOMA; INHIBITION; NIVOLUMAB; PARADIGM AB Targeted therapies and immunotherapies have led to significant improvements in the treatment of advanced cancers, including metastatic melanoma. However, new strategies are desperately needed to overcome therapeutic resistance to these agents, as well as to identify effective treatment approaches for cancer patients that fall outside major targetable mutational subtypes (e.g., non-V600 BRAF melanoma). One such strategy is to extend the paradigm of individually tailored, molecularly targeted therapy into a broader spectrum of melanoma patients, particularly those bearing tumors without commonly recognized therapeutic targets, as well as having failed or were ineligible for immunotherapy. In this nontreatment pilot study, next-generation sequencing (NGS) technologies were utilized, including whole genome and whole transcriptome sequencing, to identify molecular aberrations in patients with non-V600 BRAF metastatic melanoma. This information was then rationally matched to an appropriate clinical treatment from a defined pharmacopeia. Five patients with advanced non-V600 BRAF metastatic melanoma were enrolled. We demonstrated successful performance of the following during a clinically relevant time period: patient tumor biopsy, quality DNA/RNA extraction, DNA/RNA-based sequencing for gene expression analysis, analysis utilizing a series of data integration methodologies, report generation, and tumor board review with formulated treatment plan. Streamlining measures were conducted based on the experiences of enrolling, collecting specimens, and analyzing the molecular signatures of patients. We demonstrated the feasibility of using NGS to identify molecular aberrations and generate an individualized treatment plan in this patient population. A randomized treatment study utilizing lessons learned from the conduct of this pilot study is currently underway. C1 [LoRusso, Patricia M.; Boerner, Scott A.; Forman, Karen M.] Yale Canc Ctr, New Haven, CT USA. [LoRusso, Patricia M.; Boerner, Scott A.; Pilat, Mary Jo; Forman, Karen M.; Zuccaro, Clarice Y.] Wayne State Univ, Barbara Ann Karmanos Canc Inst, Detroit, MI USA. [Kiefer, Jeffrey A.; Liang, Winnie S.; Craig, David W.; Carpten, John D.; Trent, Jeffrey M.] Translat Genom Res Inst, Phoenix, AZ USA. [Hunsberger, Sally] NCI, Biometr Res Branch, NIH, Rockville, MD USA. [Redman, Bruce G.; Fecher, Leslie Anne] UMCCC, Ann Arbor, MI USA. [Markovic, Svetomir N.] Mayo Clin, Rochester, MN USA. [Sekulic, Aleksandar; Bryce, Alan H.] Mayo Clin, Scottsdale, AZ USA. [Joseph, Richard W.] Mayo Clin, Jacksonville, FL 32224 USA. [Cowey, C. Lance] Baylor Univ, Med Ctr, Charles A Sammons Canc Ctr, Dallas, TX USA. [Sosman, Jeffrey Alan] Vanderbilt Univ, Nashville, TN 37235 USA. [Chapman, Paul B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Schwartz, Gary K.] Columbia Univ, New York, NY USA. RP LoRusso, PM (reprint author), Yale Univ, 333 Cedar St,WWW217, New Haven, CT 06520 USA. EM patricia.lorusso@yale.edu OI Bryce, Alan H./0000-0002-0206-3895; Joseph, Richard/0000-0001-6102-4661 FU Stand Up To Cancer - Melanoma Research Alliance/Melanoma Dream Team Translational Cancer Research Grant [SU2C-AACR-DT0612] FX All authors received research support from a Stand Up To Cancer - Melanoma Research Alliance/Melanoma Dream Team Translational Cancer Research Grant (SU2C-AACR-DT0612). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (AACR). NR 35 TC 2 Z9 2 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD AUG PY 2015 VL 14 IS 8 BP 1962 EP 1971 DI 10.1158/1535-7163.MCT-15-0153 PG 10 WC Oncology SC Oncology GA CO7FI UT WOS:000359324600019 PM 26063764 ER PT J AU Beane, JD Lee, G Zheng, ZL Mendel, M Abate-Daga, D Bharathan, M Black, M Gandhi, N Yu, ZY Chandran, S Giedlin, M Ando, D Miller, J Paschon, D Guschin, D Rebar, EJ Reik, A Holmes, MC Gregory, PD Restifo, NP Rosenberg, SA Morgan, RA Feldman, SA AF Beane, Joal D. Lee, Gary Zheng, Zhili Mendel, Matthew Abate-Daga, Daniel Bharathan, Mini Black, Mary Gandhi, Nimisha Yu, Zhiya Chandran, Smita Giedlin, Martin Ando, Dale Miller, Jeff Paschon, David Guschin, Dmitry Rebar, Edward J. Reik, Andreas Holmes, Michael C. Gregory, Philip D. Restifo, Nicholas P. Rosenberg, Steven A. Morgan, Richard A. Feldman, Steven A. TI Clinical Scale Zinc Finger Nuclease-mediated Gene Editing of PD-1 in Tumor Infiltrating Lymphocytes for the Treatment of Metastatic Melanoma SO MOLECULAR THERAPY LA English DT Article ID CD8 T-CELLS; CANCER REGRESSION; PROGRAMMED DEATH-1; ANTI-PD-1 ANTIBODY; B7 FAMILY; IMMUNOTHERAPY; RECEPTOR; EXPRESSION; INFECTION; BLOCKADE AB Programmed cell death-1 (PD-1) is expressed on activated T cells and represents an attractive target for gene-editing of tumor targeted T cells prior to adoptive cell transfer (ACT). We used zinc finger nucleases (ZFNs) directed against the gene encoding human PD-1 (PDCD-1) to gene-edit melanoma tumor infiltrating lymphocytes (TIL). We show that our clinical scale TIL production process yielded efficient modification of the PD-1 gene locus, with an average modification frequency of 74.8% (n = 3, range 69.9-84.1%) of the alleles in a bulk TIL population, which resulted in a 76% reduction in PD-1 surface-expression. Forty to 48% of PD-1 gene-edited cells had biallelic PD-1 modification. Importantly, the PD-1 gene-edited TIL product showed improved in vitro effector function and a significantly increased polyfunctional cytokine profile (TNF alpha, GM-CSF, and IFN gamma) compared to unmodified TIL in two of the three donors tested. In addition, all donor cells displayed an effector memory phenotype and expanded approximately 500-2,000-fold in vitro. Thus, further study to determine the efficiency and safety of adoptive cell transfer using PD-1 gene-edited TIL for the treatment of metastatic melanoma is warranted. C1 [Beane, Joal D.; Zheng, Zhili; Abate-Daga, Daniel; Bharathan, Mini; Black, Mary; Yu, Zhiya; Chandran, Smita; Restifo, Nicholas P.; Rosenberg, Steven A.; Morgan, Richard A.; Feldman, Steven A.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Beane, Joal D.] Indiana Univ Sch Med, Dept Surg, Indianapolis, IN 46202 USA. [Lee, Gary; Mendel, Matthew; Gandhi, Nimisha; Giedlin, Martin; Ando, Dale; Miller, Jeff; Paschon, David; Guschin, Dmitry; Rebar, Edward J.; Reik, Andreas; Holmes, Michael C.; Gregory, Philip D.] Sangamo BioSci, Richmond, CA USA. RP Feldman, SA (reprint author), NCI, Ctr Canc Res, Bldg 10 Magnuson ACRF,Room 1B37A, Bethesda, MD 20892 USA. EM feldmanst@mail.nih.gov OI Restifo, Nicholas P./0000-0003-4229-4580 NR 48 TC 12 Z9 13 U1 8 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD AUG PY 2015 VL 23 IS 8 BP 1380 EP 1390 DI 10.1038/mt.2015.71 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CO0LV UT WOS:000358843900012 PM 25939491 ER PT J AU Sun, CQ Chu, MJ Chen, WH Jin, GF Gong, JH Zhu, M Yuan, J Dai, JC Wang, ML Pan, Y Song, YC Ding, XJ Du, ML Dong, J Zhang, ZD Hu, ZB Wu, TC Shen, HB AF Sun, Chongqi Chu, Minjie Chen, Weihong Jin, Guangfu Gong, Jianhang Zhu, Meng Yuan, Jing Dai, Juncheng Wang, Meilin Pan, Yun Song, Yuanchao Ding, Xiaojie Du, Mulong Dong, Jing Zhang, Zhengdong Hu, Zhibin Wu, Tangchun Shen, Hongbing TI Genetic variants of H2AX gene were associated with PM2.5-modulated DNA damage levels in Chinese Han populations SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Phosphorylation; DNA damage; Particulate matter 2.5 exposure; Genotype; Comet assay ID AIR-POLLUTION; HISTONE H2AX; COMET ASSAY; IN-VITRO; EXPOSURE; REPAIR; PATHWAY; HEALTH; CANCER; CELLS AB Exposure to particulate matter 2.5 (PM2.5) may result in DNA damage. Histone variant H2AX phosphorylation plays a central role in the response to damaged chromatin. In the current study, we investigated whether H2AX gene polymorphisms account for PM2.5-modulated DNA damage levels. A total of 307 healthy urban residents were collected from three cities in southern, central, and northern China, Zhuhai, Wuhan, and Tianjin, respectively. The dust mass concentrations of PM2.5 were detected by Gilian 5000 pumps, and the DNA damage levels were measured using comet assay. Seven potentially functional single nucleotide polymorphisms (SNPs) of H2AX gene were selected and genotyped by Illumina Infinium (R) BeadChip. We found that three SNPs (rs10790283 G >A, rs604714 C > A and rs7759 A > G) were significantly associated with DNA damage levels (adjusted P = 0.002, 0.018 and 0.027, respectively). Significant interactions (P< 0.05) were observed between certain genetic polymorphisms and PM2.5-modulated DNA damage levels. These results suggested that genetic variations of H2AX might be associated with the DNA damage levels in urban residents with different exposure to PM2.5. Further studies with large sample size in independent populations merit validating these findings. (C) 2015 Elsevier B.V. All rights reserved. C1 [Sun, Chongqi; Chu, Minjie; Jin, Guangfu; Gong, Jianhang; Zhu, Meng; Dai, Juncheng; Pan, Yun; Hu, Zhibin; Shen, Hongbing] Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Dept Epidemiol & Biostat,Sch Publ Hlth, Nanjing 211166, Jiangsu, Peoples R China. [Chen, Weihong; Yuan, Jing; Song, Yuanchao; Wu, Tangchun] Huazhong Univ Sci & Technol, Tone Med Coll, Sch Publ Hlth, Minist Educ,Key Lab Environm & Hlth, Wuhan 430074, Peoples R China. [Wang, Meilin; Ding, Xiaojie; Du, Mulong; Zhang, Zhengdong] Nanjing Med Univ, Sch Publ Hlth, Dept Genet Toxicol, Key Lab Modern Toxicol,Minist Educ, Nanjing 211166, Jiangsu, Peoples R China. [Dong, Jing] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Shen, HB (reprint author), Nanjing Med Univ, Sch Publ Hlth, Dept Biostat & Epidemiol, Nanjing 211166, Jiangsu, Peoples R China. EM hbshen@njmu.edu.cn FU National Key Basic Research Program Grant [2011CB503805]; National Science and Technology Support Program [2011BAI09B02]; Major Program of the National Natural Science Foundation of China [81390543]; State Key Program of National Natural Science of China [81230067]; Jiangsu Province Clinical Science and Technology Projects [BL2012008]; Priority Academic Program for the Development of Jiangsu Higher Education Institutions [Public Health and Preventive Medicine] FX This work was funded by the National Key Basic Research Program Grant (2011CB503805), the National Science and Technology Support Program (2011BAI09B02), the Major Program of the National Natural Science Foundation of China (81390543), the State Key Program of National Natural Science of China (81230067), Jiangsu Province Clinical Science and Technology Projects (BL2012008), the Priority Academic Program for the Development of Jiangsu Higher Education Institutions [Public Health and Preventive Medicine]. The authors wish to thank all the study participants, research staff and students who participated in this work. NR 30 TC 0 Z9 1 U1 4 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 EI 1873-135X J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD AUG PY 2015 VL 778 BP 41 EP 45 DI 10.1016/j.mrfmmm.2015.05.007 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA CO5AR UT WOS:000359172500005 PM 26073471 ER PT J AU Alizadeh, AA Aranda, V Bardelli, A Blanpain, C Bock, C Borowski, C Caldas, C Califano, A Doherty, M Elsner, M Esteller, M Fitzgerald, R Korbel, JO Lichter, P Mason, CE Navin, N Pe'er, D Polyak, K Roberts, CWM Siu, L Snyder, A Stower, H Swanton, C Verhaak, RGW Zenklusen, JC Zuber, J Zucman-Rossi, J AF Alizadeh, Ash A. Aranda, Victoria Bardelli, Alberto Blanpain, Cedric Bock, Christoph Borowski, Christine Caldas, Carlos Califano, Andrea Doherty, Michael Elsner, Markus Esteller, Manel Fitzgerald, Rebecca Korbel, Jan O. Lichter, Peter Mason, Christopher E. Navin, Nicholas Pe'er, Dana Polyak, Kornelia Roberts, Charles W. M. Siu, Lillian Snyder, Alexandra Stower, Hannah Swanton, Charles Verhaak, Roel G. W. Zenklusen, Jean C. Zuber, Johannes Zucman-Rossi, Jessica TI Toward understanding and exploiting tumor heterogeneity SO NATURE MEDICINE LA English DT Article ID INTRATUMOR HETEROGENEITY; BREAST-CANCER; SINGLE CELLS; IN-SITU; RNA; RESISTANCE; EVOLUTION; CHALLENGE; PATIENT; TISSUES AB The extent of tumor heterogeneity is an emerging theme that researchers are only beginning to understand. How genetic and epigenetic heterogeneity affects tumor evolution and clinical progression is unknown. The precise nature of the environmental factors that influence this heterogeneity is also yet to be characterized. Nature Medicine, Nature Biotechnology and the Volkswagen Foundation organized a meeting focused on identifying the obstacles that need to be overcome to advance translational research in and tumor heterogeneity. Once these key questions were established, the attendees devised potential solutions. Their ideas are presented here. C1 [Alizadeh, Ash A.] Stanford Univ, Div Oncol, Dept Med, Sch Med, Stanford, CA 94305 USA. [Alizadeh, Ash A.] Stanford Univ, Div Hematol, Dept Med, Sch Med, Stanford, CA 94305 USA. [Alizadeh, Ash A.] Stanford Univ, Inst Canc, Dept Med, Sch Med, Stanford, CA 94305 USA. [Aranda, Victoria; Borowski, Christine] Nat Med, New York, NY 10021 USA. [Bardelli, Alberto] Univ Turin, Dept Oncol, Turin, Italy. [Bardelli, Alberto] IRCCS, Candiolo Canc Inst, FPO, Turin, Italy. [Blanpain, Cedric] ULB, Brussels, Belgium. [Bock, Christoph] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1010 Vienna, Austria. [Bock, Christoph] Med Univ Vienna, Dept Lab Med, Vienna, Austria. [Caldas, Carlos] Univ Cambridge, Dept Oncol, Cambridge, England. [Califano, Andrea; Pe'er, Dana] Columbia Univ, Dept Syst Biol, New York, NY USA. [Califano, Andrea] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA. [Califano, Andrea] Columbia Univ, Dept Biomed Informat, New York, NY USA. [Doherty, Michael] Genentech Inc, San Francisco, CA USA. [Elsner, Markus] Nat Biotechnol, New York, NY USA. [Esteller, Manel] Bellvitge Biomed Res Inst, Canc Epigenet & Biol Program, Barcelona, Catalonia, Spain. [Fitzgerald, Rebecca] Univ Cambridge, Hutchison MRC Res Ctr, MRC Canc Unit, Cambridge, England. [Korbel, Jan O.] European Mol Biol Lab, Genome Biol Unit, D-69012 Heidelberg, Germany. [Lichter, Peter] DKFZ, German Canc Res Ctr, Heidelberg, Germany. [Mason, Christopher E.] Weill Cornell Med Coll, New York, NY USA. [Navin, Nicholas] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Navin, Nicholas; Verhaak, Roel G. W.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Pe'er, Dana] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Polyak, Kornelia] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Roberts, Charles W. M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Siu, Lillian] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Snyder, Alexandra] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Swanton, Charles] UCL, Inst Canc, London, England. [Swanton, Charles] Univ Coll London Hosp NHS Fdn Trust, London, England. [Swanton, Charles] Francis Crick Inst, London, England. [Verhaak, Roel G. W.] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Zenklusen, Jean C.] NCI, Canc Genome Atlas Ctr Canc Gen, Bethesda, MD 20892 USA. [Zuber, Johannes] Vienna Bioctr VBC, Res Inst Mol Pathol IMP, Vienna, Austria. [Zucman-Rossi, Jessica] IUH, Inserm, UMR Genom Fonct Tumeurs Solides 1162, Paris, France. RP Stower, H (reprint author), Nat Med, New York, NY 10021 USA. EM h.stower@us.nature.com RI Bock, Christoph/B-6723-2008; OI Bock, Christoph/0000-0001-6091-3088; Snyder Charen, Alexandra/0000-0002-2606-3523; zucman-rossi, Jessica/0000-0002-5687-0334; Caldas, Carlos/0000-0003-3547-1489; Esteller, Manel/0000-0003-4490-6093; Alizadeh, Arash Ash/0000-0002-5153-5625 FU NCI NIH HHS [R01 CA169244] NR 36 TC 61 Z9 63 U1 7 U2 49 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 2015 VL 21 IS 8 BP 846 EP 853 DI 10.1038/nm.3915 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CO5DY UT WOS:000359181000009 PM 26248267 ER PT J AU Wilson, WH Young, RM Schmitz, R Yang, YD Pittaluga, S Wright, G Lih, CJ Williams, PM Shaffer, AL Gerecitano, J de Vos, S Goy, A Kenkre, VP Barr, PM Blum, KA Shustov, A Advani, R Fowler, NH Vose, JM Elstrom, RL Habermann, TM Barrientos, JC McGreivy, J Fardis, M Chang, BY Clow, F Munneke, B Moussa, D Beaupre, DM Staudt, LM AF Wilson, Wyndham H. Young, Ryan M. Schmitz, Roland Yang, Yandan Pittaluga, Stefania Wright, George Lih, Chih-Jian Williams, P. Mickey Shaffer, Arthur L. Gerecitano, John de Vos, Sven Goy, Andre Kenkre, Vaishalee P. Barr, Paul M. Blum, Kristie A. Shustov, Andrei Advani, Ranjana Fowler, Nathan H. Vose, Julie M. Elstrom, Rebecca L. Habermann, Thomas M. Barrientos, Jacqueline C. McGreivy, Jesse Fardis, Maria Chang, Betty Y. Clow, Fong Munneke, Brian Moussa, Davina Beaupre, Darrin M. Staudt, Louis M. TI Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma SO NATURE MEDICINE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NF-KAPPA-B; MUTATIONS; PATHOGENESIS; GENES; BTK AB The two major subtypes of diffuse large B cell lymphoma (DLBCL)-activated B cell-like (ABC) and germinal center B cell-like (GCB)-arise by distinct mechanisms, with ABC selectively acquiring mutations that target the B cell receptor (BCR), fostering chronic active BCR signaling(1). The ABC subtype has a similar to 40% cure rate with currently available therapies, which is worse than the rate for GCB DLBCL, and highlights the need for ABC subtype-specific treatment strategies(2). We hypothesized that ABC, but not GCB, DLBCL tumors would respond to ibrutinib, an inhibitor of BCR signaling. In a phase 1/2 clinical trial that involved 80 subjects with relapsed or refractory DLBCL, ibrutinib produced complete or partial responses in 37% (14/38) of those with ABC DLBCL, but in only 5% (1/20) of subjects with GCB DLBCL (P = 0.0106). ABC tumors with BCR mutations responded to ibrutinib frequently (5/9; 55.5%), especially those with concomitant myeloid differentiation primary response 88 (MYD88) mutations (4/5; 80%), a result that is consistent with in vitro cooperation between the BCR and MYD88 pathways. However, the highest number of responses occurred in ABC tumors that lacked BCR mutations (9/29; 31%), suggesting that oncogenic BCR signaling in ABC does not require BCR mutations and might be initiated by non-genetic mechanisms. These results support the selective development of ibrutinib for the treatment of ABC DLBCL. C1 [Wilson, Wyndham H.; Young, Ryan M.; Schmitz, Roland; Yang, Yandan; Shaffer, Arthur L.; Staudt, Louis M.] NCI, NIH, Lymphoid Malignancies Branch, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NCI, NIH, Lab Pathol, Bethesda, MD 20892 USA. [Wright, George] NCI, NIH, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Lih, Chih-Jian; Williams, P. Mickey] Frederick Natl Lab Canc Res, Frederick, MD USA. [Gerecitano, John] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Gerecitano, John] Weill Cornell Med Coll, Dept Med, New York, NY USA. [de Vos, Sven] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Goy, Andre] Hackensack Univ, John Theurer Canc Ctr, Med Ctr, Hackensack, NJ USA. [Kenkre, Vaishalee P.] Univ Wisconsin, Div Hematol & Med Oncol, Madison, WI USA. [Barr, Paul M.] Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY USA. [Blum, Kristie A.] Ohio State Univ, Ctr Comprehens Canc, Div Hematol, Columbus, OH 43210 USA. [Shustov, Andrei] Univ Washington, Sch Med, Dept Med, Hematol, Seattle, WA 98195 USA. [Advani, Ranjana] Stanford Univ, Med Ctr, Med Oncol, Stanford, CA 94305 USA. [Fowler, Nathan H.] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USA. [Vose, Julie M.] Univ Nebraska, Div Hematol & Oncol, Dept Internal Med, Omaha, NE 68182 USA. [Elstrom, Rebecca L.] Genentech Inc, Clin Dev, San Francisco, CA 94080 USA. [Habermann, Thomas M.] Mayo Clin, Div Hematol, Rochester, MN USA. [Barrientos, Jacqueline C.] Hofstra North Shore Long Isl Jewish Sch Med, Dept Med, Div Hematol & Med Oncol, Hempstead, NY USA. [McGreivy, Jesse; Fardis, Maria; Chang, Betty Y.; Clow, Fong; Munneke, Brian; Moussa, Davina; Beaupre, Darrin M.] Pharmacyclics Inc, Sunnyvale, CA USA. RP Staudt, LM (reprint author), NCI, NIH, Lymphoid Malignancies Branch, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov OI Barr, Paul/0000-0002-9733-401X FU United States National Institutes of Health, National Cancer Institute, Center for Cancer Research; Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe); Pharmacyclics, Inc., Sunnyvale, California FX This research was supported in part by the Intramural Research Program of the United States National Institutes of Health, National Cancer Institute, Center for Cancer Research. Research grant was provided by the Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe; R.S.). Medical writing and editorial support were provided by M. Gersh and funded by Janssen Pharmaceuticals, Titusville, New Jersey. These studies, NCT00849654 and NCT01325701, were sponsored by Pharmacyclics, Inc., Sunnyvale, California. NR 17 TC 115 Z9 117 U1 5 U2 28 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 2015 VL 21 IS 8 BP 922 EP 926 DI 10.1038/nm.3884 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CO5DY UT WOS:000359181000019 PM 26193343 ER PT J AU Gharwan, H Tomita, Y Lee, MJ Thomas, A Berman, A Giaccone, G Trepel, J Rajan, A AF Gharwan, Helen Tomita, Yusuke Lee, Min-Jung Thomas, Anish Berman, Arlene Giaccone, Giuseppe Trepel, Jane Rajan, Arun TI Alterations of immune cell subsets in relapsed, thymoma-associated minimal change disease: A case report SO ONCOLOGY LETTERS LA English DT Article DE thymoma; proteinuria; nephrotic syndrome; minimal change disease; T-cells ID NEPHROTIC SYNDROME AB The most frequently described glomerulopathy in patients with thymoma is minimal change disease (MCD). The present study reports the case of a 63-year-old female with recurrent thymoma and poorly-controlled paraneoplastic MCD, who was enrolled on a phase I/II clinical trial (no. NCT01100944) and treated with the histone deacetylase inhibitor, belinostat, in combination with cisplatin, doxorubicin and cyclophosphamide. Treatment resulted in a complete radiological response, a dramatic reduction in proteinuria and changes in immune cell subset composition, consisting of a reduction in the number of T helper (Th) 1, Th2, Th17 and regulatory T cells. Changes in T-cell polarization were also observed with an increase in the Th1/Th2 ratio. To the best of our knowledge, the current study is the first to provide a detailed description of changes in immune cell subset composition in thymoma-associated MCD. Early administration of effective antitumor therapy should be considered in these cases, particularly when proteinuria is poorly controlled despite the use of steroids and other immunosuppressive therapies. C1 [Gharwan, Helen; Thomas, Anish; Berman, Arlene; Rajan, Arun] NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. [Tomita, Yusuke; Lee, Min-Jung; Trepel, Jane] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Giaccone, Giuseppe] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20007 USA. RP Rajan, A (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM rajana@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX The authors would like to acknowledge the Intramural Research Program of the NIH, the National Cancer Institute and the Center for Cancer Research for their support of this study. NR 12 TC 0 Z9 0 U1 0 U2 0 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 2015 VL 10 IS 2 BP 1155 EP 1158 DI 10.3892/ol.2015.3325 PG 4 WC Oncology SC Oncology GA CN8FX UT WOS:000358676200109 PM 26622643 ER PT J AU Bornstein, MH Putnick, DL Cote, LR Haynes, OM Suwalsky, JTD AF Bornstein, Marc H. Putnick, Diane L. Cote, Linda R. Haynes, O. Maurice Suwalsky, Joan T. D. TI Mother-Infant Contingent Vocalizations in 11 Countries SO PSYCHOLOGICAL SCIENCE LA English DT Article DE language development; cross-cultural differences and similarities ID DIRECTED SPEECH; TURN-TAKING; MATERNAL RESPONSIVENESS; UNITED-STATES; CONVERSATION; JAPAN; ORGANIZATION; 3-MONTH-OLD; UNIVERSALS; BEHAVIOR AB Mother-infant vocal interactions serve multiple functions in child development, but it remains unclear whether key features of these interactions are community-common or community-specific. We examined rates, interrelations, and contingencies of vocal interactions in 684 mothers and their 51/2-month-old infants in diverse communities in 11 countries (Argentina, Belgium, Brazil, Cameroon, France, Israel, Italy, Japan, Kenya, South Korea, and the United States). Rates of mothers' and infants' vocalizations varied widely across communities and were uncorrelated. However, collapsing the data across communities, we found that mothers' vocalizations to infants were contingent on the offset of the infants' nondistress vocalizing, infants' vocalizations were contingent on the offset of their mothers' vocalizing, and maternal and infant contingencies were significantly correlated. These findings point to the beginnings of dyadic conversational turn taking. Despite broad differences in the overall talkativeness of mothers and infants, maternal and infant contingent vocal responsiveness is found across communities, supporting essential functions of turn taking in early-childhood socialization. C1 [Bornstein, Marc H.; Putnick, Diane L.; Haynes, O. Maurice; Suwalsky, Joan T. D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Bethesda, MD 20892 USA. [Cote, Linda R.] Marymount Univ, Dept Psychol, Arlington, VA 22207 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Rockledge 1,Suite 8030,6705 Rockledge Dr,MSC 797, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov OI Putnick, Diane/0000-0002-6323-749X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 67 TC 4 Z9 4 U1 5 U2 17 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0956-7976 EI 1467-9280 J9 PSYCHOL SCI JI Psychol. Sci. PD AUG PY 2015 VL 26 IS 8 BP 1272 EP 1284 DI 10.1177/0956797615586796 PG 13 WC Psychology, Multidisciplinary SC Psychology GA CO6JJ UT WOS:000359262700011 PM 26133571 ER PT J AU Waford, RN MacDonald, A Goines, K Novacek, DM Trotman, HD Walker, EF Addington, J Bearden, CE Cadenhead, KS Cannon, TD Cornblatt, BA Heinssen, R Mathalon, DH Tsuang, MT Perkins, DO Seidman, LJ Woods, SW McGlashan, TH AF Waford, Rachel N. MacDonald, Allison Goines, Katrina Novacek, Derek M. Trotman, Hanan D. Walker, Elaine F. Addington, Jean Bearden, Carrie E. Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. Heinssen, Robert Mathalon, Daniel H. Tsuang, Ming T. Perkins, Diana O. Seidman, Larry J. Woods, Scott W. McGlashan, Thomas H. TI Demographic correlates of attenuated positive psychotic symptoms SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Prodrome; Psychosis; Sex; Education; Early identification ID 1ST EPISODE PSYCHOSIS; HIGH-RISK; GENDER-DIFFERENCES; BASE-LINE; FOLLOW-UP; 1ST-EPISODE SCHIZOPHRENIA; PRODROMAL SYMPTOMS; SEX-DIFFERENCES; YOUNG-PEOPLE; AGE AB It is now well established that the utilization of standardized clinical criteria can enhance prediction of psychosis. These criteria are primarily concerned with the presence and severity of attenuated positive symptoms. Because these symptom criteria are used to derive algorithms for designating clinical high risk (CHR) status and for maximizing prediction of psychosis risk, it is important to know whether the symptom ratings vary as a function of demographic factors that have previously been linked with symptoms in diagnosed psychotic patients. Using a sample of 356 CHR individuals from the NAPLS-II multi-site study, we examined the relation of three sex, age, and educational level, with the severity of attenuated positive symptom scores from the Scale of Prodromal Symptoms (SOPS). Demographic factors accounted for little of the variance in symptom ratings (5-6%). Older CHR individuals manifested more severe suspiciousness, and female CHR participants reported more unusual perceptual experiences than male participants. Contrary to prediction, higher educational level was associated-with more severe ratings of unusual thought content, but less severe perceptual abnormalities. Overall, sex, age and education were modestly related to unusual thought content and perceptual abnormalities, only, suggesting minimal implication for designating CHR status and predicting psychosis-risk. (C) 2015 Elsevier B.V. All rights reserved. C1 [Waford, Rachel N.; MacDonald, Allison; Goines, Katrina; Novacek, Derek M.; Trotman, Hanan D.; Walker, Elaine F.] Emory Univ, Atlanta, GA 30322 USA. [Addington, Jean] Univ Calgary, Calgary, AB, Canada. [Bearden, Carrie E.] Univ Calif Los Angeles, Los Angeles, CA USA. [Cadenhead, Kristin S.; Tsuang, Ming T.] Univ Calif San Diego, San Diego, CA 92103 USA. [Cannon, Tyrone D.; Woods, Scott W.; McGlashan, Thomas H.] Yale Univ, New Haven, CT USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Great Neck, NY USA. [Heinssen, Robert] NIMH, Bethesda, MD 20892 USA. [Mathalon, Daniel H.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Perkins, Diana O.] Univ N Carolina, Chapel Hill, NC USA. [Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Boston, MA USA. RP Waford, RN (reprint author), Emory Univ, Sch Publ Hlth, 1518 Clifton Rd, Atlanta, GA 30322 USA. EM rwaford@emory.edu FU National Institute of Mental Health [U01MH081988, U01MH081984, P50 MH066286, U01MH081928, P50 MH080272, R01 MH60720, U01 MH082022, K24 MH76191, MH081902, U01MH082004-01A1, U01MH082022, UO1 MH081857-05]; National Institute of Mental Health (Commonwealth of Massachusetts) [SCDMH82101008006]; National Institute of Mental Health (Staglin Music Festival for Mental Health) FX This study was supported by the National Institute of Mental Health (grant U01MH081988 to Dr. Walker; grant U01MH081984 to Dr. Addington; grant P50 MH066286 and Staglin Music Festival for Mental Health to Dr. Bearden; grants U01MH081928; P50 MH080272; Commonwealth of Massachusetts SCDMH82101008006 to Dr. Seidman; grants R01 MH60720, U01 MH082022 and K24 MH76191 to Dr. Cadenhead; grant MH081902 to Dr. Cannon; grant U01MH082004-01A1 to Dr. Perkins; grant U01MH082022 to Dr. Woods; and grant UO1 MH081857-05 to Dr. Comblatt). The NIMH had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 41 TC 0 Z9 0 U1 3 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2015 VL 166 IS 1-3 BP 31 EP 36 DI 10.1016/j.schres.2015.04.035 PG 6 WC Psychiatry SC Psychiatry GA CO5AO UT WOS:000359172200005 PM 25999040 ER PT J AU Adkins, DE Clark, SL Copeland, WE Kennedy, M Conway, K Angold, A Maes, H Liu, YF Kumar, G Erkanli, A Patkar, AA Silberg, J Brown, TH Fergusson, DM Horwood, LJ Eaves, L van den Oord, EJCG Sullivan, PF Costello, EJ AF Adkins, Daniel E. Clark, Shaunna L. Copeland, William E. Kennedy, Martin Conway, Kevin Angold, Adrian Maes, Hermine Liu, Youfang Kumar, Gaurav Erkanli, Alaattin Patkar, Ashwin A. Silberg, Judy Brown, Tyson H. Fergusson, David M. Horwood, L. John Eaves, Lindon van den Oord, Edwin J. C. G. Sullivan, Patrick F. Costello, E. J. TI Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood SO TWIN RESEARCH AND HUMAN GENETICS LA English DT Article DE alcohol; genome-wide; longitudinal; developmental trajectory; SLC6A1; GABA ID DEFICIT HYPERACTIVITY DISORDER; ENVIRONMENTAL-INFLUENCES; YOUNG ADULTHOOD; GENE-EXPRESSION; CANDIDATE GENE; MESSENGER-RNA; ASSOCIATION; DEPENDENCE; ADOLESCENCE; ADRA2A AB The public health burden of alcohol is unevenly distributed across the life course, with levels of use, abuse, and dependence increasing across adolescence and peaking in early adulthood. Here, we leverage this temporal patterning to search for common genetic variants predicting developmental trajectories of alcohol consumption. Comparable psychiatric evaluations measuring alcohol consumption were collected in three longitudinal community samples (N = 2,126, obs = 12,166). Consumption-repeated measurements spanning adolescence and early adulthood were analyzed using linear mixed models, estimating individual consumption trajectories, which were then tested for association with Illumina 660W-Quad genotype data (866,099 SNPs after imputation and QC). Association results were combined across samples using standard meta-analysis methods. Four meta-analysis associations satisfied our pre-determined genome-wide significance criterion (FDR < 0.1) and six others met our 'suggestive' criterion (FDR < 0.2). Genome-wide significant associations were highly biological plausible, including associations within GABA transporter 1, SLC6A1 (solute carrier family 6, member 1), and exonic hits in LOC100129340 (mitofusin-1-like). Pathway analyses elaborated single marker results, indicating significant enriched associations to intuitive biological mechanisms, including neurotransmission, xenobiotic pharmacodynamics, and nuclear hormone receptors (NHR). These findings underscore the value of combining longitudinal behavioral data and genome-wide genotype information in order to study developmental patterns and improve statistical power in genomic studies. C1 [Adkins, Daniel E.; Clark, Shaunna L.; Kumar, Gaurav; van den Oord, Edwin J. C. G.] Virginia Commonwealth Univ, Ctr Biomarker Res & Personalized Med, Sch Pharm, Richmond, VA 23298 USA. [Copeland, William E.; Angold, Adrian; Erkanli, Alaattin; Patkar, Ashwin A.; Costello, E. J.] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. [Kennedy, Martin] Univ Otago, Dept Pathol, Christchurch, New Zealand. [Conway, Kevin] NIDA, Div Epidemiol, Serv & Prevent Res, Bethesda, MD 20892 USA. [Maes, Hermine; Silberg, Judy; Eaves, Lindon] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23298 USA. [Liu, Youfang] Univ N Carolina, Thurston Arthrit Res Ctr, Chapel Hill, NC USA. [Brown, Tyson H.] Vanderbilt Univ, Ctr Med Hlth & Soc, Nashville, TN 37235 USA. [Fergusson, David M.; Horwood, L. John] Univ Otago, Dept Psychol Med, Christchurch, New Zealand. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet & Psychiat, Chapel Hill, NC USA. RP Adkins, DE (reprint author), Virginia Commonwealth Univ, Ctr Biomarker Res & Precis Med, Sch Pharm, McGuire Hall,Room 216B,POB 980533, Richmond, VA 23298 USA. EM deadkins@vcu.edu RI Kennedy, Martin/A-4942-2008; OI Kennedy, Martin/0000-0002-6445-8526; Conway, Kevin/0000-0002-7638-339X FU National Institute on Drug Abuse [U01DA024413, R01DA11301]; National Institute of Mental Health [R01MH063970, R01MH063671, R01MH048085, K01MH093731, K23MH080230]; NARSAD; William T. Grant Foundation; Health Research Council of New Zealand; National Child Health Research Foundation; Canterbury Medical Research Foundation; NewZealand Lottery Grants Board; University of Otago; Carney Centre for Pharmacogenomics; James Hume Bequest Fund; NIH [MH077874] FX We would like to thank to the study participants from the Great Smoky Mountain Study, Virginia Twin Study on Adolescent Behavioral Development, and Christchurch Health and Development Study. Also, thanks to Karolina Aberg and colleagues at the VCU Center for Biomarker Research and Precision Medicine for helpful discussion and sharing analytical resources. Dr Conway's role on this paper is as a Science Officer on U01DA014413, with no involvement in other cited grants. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of NIDA or any of the sponsoring organizations, agencies, or the US government. This research was supported by the National Institute on Drug Abuse (U01DA024413, R01DA11301), National Institute of Mental Health (R01MH063970, R01MH063671, R01MH048085, K01MH093731, and K23MH080230), NARSAD, and the William T. Grant Foundation. The CHDS was supported by the Health Research Council of New Zealand, National Child Health Research Foundation, Canterbury Medical Research Foundation, New Zealand Lottery Grants Board, University of Otago, Carney Centre for Pharmacogenomics, James Hume Bequest Fund, and NIH grant MH077874. NR 75 TC 1 Z9 1 U1 0 U2 6 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1832-4274 EI 1839-2628 J9 TWIN RES HUM GENET JI Twin Res. Hum. Genet. PD AUG PY 2015 VL 18 IS 4 BP 335 EP 347 DI 10.1017/thg.2015.36 PG 13 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA CO0WM UT WOS:000358874400001 PM 26081443 ER PT J AU Giri, N Alter, BP Penrose, K Falk, RT Pan, YJ Savage, SA Williams, M Kemp, TJ Pinto, LA AF Giri, Neelam Alter, Blanche P. Penrose, Keri Falk, Roni T. Pan, Yuanji Savage, Sharon A. Williams, Marcus Kemp, Troy J. Pinto, Ligia A. TI Immune status of patients with inherited bone marrow failure syndromes SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID FANCONI-ANEMIA PATIENTS; COLONY-STIMULATING FACTOR; NECROSIS-FACTOR-ALPHA; VIRUS-LIKE PARTICLES; DYSKERATOSIS-CONGENITA; MONONUCLEAR-CELLS; APLASTIC-ANEMIA; IN-VITRO; IMMUNODEFICIENCY; RESPONSES AB Immune function abnormalities have been reported in patients with Fanconi anemia (FA), dyskeratosis congenita (DC) and, rarely, in Shwachman-Diamond syndrome (SDS), and Diamond-Blackfan anemia (DBA), but large systematic studies are lacking. We assessed immunological parameters in 118 patients with these syndromes and 202 unaffected relatives. We compared the results in patients with reference values, and with values in relatives after adjusting for age, sex, corticosteroid treatment, and severe bone marrow failure (BMF). Adult patients (18 years) with FA had significantly lower immunoglobulins (IgG, IgA and IgM), total lymphocytes, and CD4 T cells than reference values or adult relatives (P<0.001); children with FA had normal values. Both children and adults with FA had lower B- and NK cells (P<0.01) than relatives or reference values. Patients with DC had essentially normal immunoglobulins but lower total lymphocytes than reference values or relatives, and lower T-, B-, and NK-cells; these changes were more marked in children than adults (P<0.01). Most patients with DBA and SDS had normal immunoglobulins and lymphocytes. Lymphoproliferative responses, serum cytokine levels, including tumor necrosis factor- and interferon-, and cytokine levels in supernatants from phytohemagglutinin-stimulated cultures were similar across patient groups and relatives. Only patients with severe BMF, particularly those with FA and DC, had higher serum G-CSF and Flt3-ligand and lower RANTES levels compared with all other groups or relatives (P<0.05). Overall, immune function abnormalities were seen mainly in adult patients with FA, which likely reflects their disease-related progression, and in children with DC, which may be a feature of early-onset severe disease phenotype. Am. J. Hematol. 90:702-708, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Giri, Neelam; Alter, Blanche P.; Savage, Sharon A.] NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, NIH, Rockville, MD USA. [Penrose, Keri; Pan, Yuanji; Williams, Marcus; Kemp, Troy J.; Pinto, Ligia A.] Frederick Natl Lab Canc Res, Div Infect Dis, Dept Med, Human Papillomavirus Immunol Lab,Leidos Biomed Re, Frederick, MD USA. [Falk, Roni T.] NCI, Div Canc Epidemiol & Genet, Hormonal Reprod Branch, NIH, Rockville, MD USA. RP Giri, N (reprint author), NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, NIH, 9609 Med Ctr Dr,Room 6E-538,MSC 9772, Bethesda, MD 20892 USA. EM girin@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Fanconi Anemia Research Fund; National Institutes of Health, The National Cancer Institute [HHSN261201100018C, HHSN261200800001E] FX Contract grant sponsors: Fanconi Anemia Research Fund (Fanconi.org), The Intramural Research Program of the National Institutes of Health, The National Cancer Institute; Contract grant number: HHSN261201100018C with Westat.; Contract grant sponsor: The National Cancer Institute, National Institutes of Health; Contract grant number: HHSN261200800001E. NR 38 TC 4 Z9 4 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2015 VL 90 IS 8 BP 702 EP 708 DI 10.1002/ajh.24046 PG 7 WC Hematology SC Hematology GA CN5QI UT WOS:000358483700066 PM 25963299 ER PT J AU Cokic, BB Noguchi, CT Cokic, V Damjanovic, S AF Cokic, Bojana Beleslin Noguchi, Constance Tom Cokic, Vladan Damjanovic, Svetozar TI The effect of inactivated VHL gene on proliferative pathways in renal cell carcinoma SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [Cokic, Bojana Beleslin; Damjanovic, Svetozar] Clin Ctr Serbia, Clin Endocrinol Diabet & Metab Dis, Genet Lab, Belgrade, Serbia. [Noguchi, Constance Tom] NIDDKD, NIH, Bethesda, MD USA. [Cokic, Vladan] Univ Belgrade, Inst Med Res, Lab Expt Hematol, Belgrade, Serbia. 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 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2015 VL 90 IS 8 BP E177 EP E177 PG 1 WC Hematology SC Hematology GA CN5QI UT WOS:000358483700056 ER PT J AU Noguchi, CT Zhang, YY Rogers, H Wang, L Alnaeeli, M AF Noguchi, Constance Tom Zhang, Yuanyuan Rogers, Heather Wang, Li Alnaeeli, Mawadda TI Erythropoietin and Metabolic Response SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [Noguchi, Constance Tom; Zhang, Yuanyuan; Rogers, Heather] NIDDK, Mol Med Branch, NIH, Bethesda, MD USA. [Wang, Li] Univ Macau, Macau, Peoples R China. [Alnaeeli, Mawadda] Ohio Univ, Zanesville, OH 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 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2015 VL 90 IS 8 BP E158 EP E158 PG 1 WC Hematology SC Hematology GA CN5QI UT WOS:000358483700018 ER PT J AU Wolf Basel-Vanagaite, L Cassidy, S Cole, T Newbury-Ecob, R Smith, A Biesecker, L Gripp, K Curry, C Innes, M Allanson, J AF Wolf Basel-Vanagaite, L. Cassidy, S. Cole, T. Newbury-Ecob, R. Smith, A. Biesecker, L. Gripp, K. Curry, C. Innes, M. Allanson, J. TI EVALUATION OF FACIAL MORPHOLOGY: COMPARISON OF ABSOLUTE AND RELATIVE MEASUREMENTS, OBJECTIVE AND SUBJECTIVE APPROACHES SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 35th Annual David W Smith Workshop on Malformations and Morphogenesis CY JUL 25-30, 2014 CL Univ Wisconsin, Madison, WI HO Univ Wisconsin C1 [Wolf; Basel-Vanagaite, L.] FDNA Ltd, Herzlyia, Israel. [Wolf; Basel-Vanagaite, L.] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. [Basel-Vanagaite, L.] Schneider Childrens Med Ctr Israel, Rabin Med Ctr, Petah Tiqwa, Israel. [Cassidy, S.] UC Irvine, Irvine, CA USA. [Cole, T.] West Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Newbury-Ecob, R.] Clin Genet, Bristol, Avon, England. [Smith, A.; Biesecker, L.] Natl Inst Hlth, NHGRI, Irvine, CA USA. [Gripp, K.] AIDHC, Med Genet, Wilmington, DE USA. [Curry, C.] UCSF, Fresno, CA USA. [Innes, M.] Univ Calgary, Dept Med Genet, Calgary, AB T2N 1N4, Canada. [Innes, M.] Univ Calgary, ACHRI, Calgary, AB T2N 1N4, Canada. [Allanson, J.] Univ Ottawa, Ottawa, ON K1N 6N5, Canada. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2015 VL 167 IS 8 BP 1692 EP 1692 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA CN7ER UT WOS:000358597400020 ER PT J AU Tan, WH Marinakis, N Yi, L Kurek, KC Lawlor, MW Towne, MC Joshi, M Li, H Beggs, AH Kinsman, SL Agrawal, PB Kaler, SG AF Tan, W. H. Marinakis, N. Yi, L. Kurek, K. C. Lawlor, M. W. Towne, M. C. Joshi, M. Li, H. Beggs, A. H. Kinsman, S. L. Agrawal, P. B. Kaler, S. G. TI BRAIN MALFORMATION, OCULAR MALFORMATION, AND CONNECTIVE TISSUE DISORDER- EXPANDING THE PHENOTYPE OF A NOVEL COPPER DEFICIENCY SYNDROME SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 35th Annual David W Smith Workshop on Malformations and Morphogenesis CY JUL 25-30, 2014 CL Univ Wisconsin, Madison, WI HO Univ Wisconsin C1 [Tan, W. H.; Marinakis, N.; Towne, M. C.; Joshi, M.; Beggs, A. H.; Agrawal, P. B.] Boston Childrens Hosp, Div Genet & Genom Manton, Ctr Orphan Dis Res, Boston, MA USA. [Kurek, K. C.] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Agrawal, P. B.] Boston Childrens Hosp, Div Neonatol, Boston, MA USA. [Yi, L.; Kaler, S. G.] NICHD, Sect Translat Neurosci, NIH, Boston, MA USA. [Lawlor, M. W.] Med Coll Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. [Li, H.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. [Kinsman, S. L.] Med Univ S Carolina, Dept Neurosci, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 1 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 2015 VL 167 IS 8 BP 1712 EP 1712 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA CN7ER UT WOS:000358597400068 ER PT J AU Keppler-Noreuil, KM Patronas, N Sapp, JC Lindhurst, MJ Biesecker, LG AF Keppler-Noreuil, Kim M. Patronas, Nicholas Sapp, Julie C. Lindhurst, Marjorie J. Biesecker, Leslie G. TI PATTERN OF CRANIOFACIAL HYPEROSTOSIS IN PROTEUS SYNDROME - ASSOCIATION WITH UNDERLYING BRAIN MALFORMATIONS & MENINGIOMAS SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 35th Annual David W Smith Workshop on Malformations and Morphogenesis CY JUL 25-30, 2014 CL Univ Wisconsin, Madison, WI HO Univ Wisconsin C1 [Keppler-Noreuil, Kim M.; Sapp, Julie C.; Lindhurst, Marjorie J.; Biesecker, Leslie G.] NHGRI, GDRB, Bethesda, MD 20892 USA. [Patronas, Nicholas] NIH, DRD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2015 VL 167 IS 8 BP 1721 EP 1721 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA CN7ER UT WOS:000358597400090 ER PT J AU Kruszka, PS Solomon, BD Iyer, RK Ahmad, M Thach, DC Bodian, D Wong, WS Hart, RA Martinez, AF Robin, NH Opitz, JM Vockley, JG Niederhuber, J Muenke, M AF Kruszka, Paul S. Solomon, Benjamin D. Iyer, Ramaswamy K. Ahmad, Moin Thach, Dzung C. Bodian, Dale Wong, Wendy Shukwan Hart, Rachel A. Martinez, Ariel F. Robin, Nathaniel H. Opitz, John M. Vockley, Joseph G. Niederhuber, John Muenke, Maximilian TI AUTOSOMAL DOMINANT OPITZ GBBB SYNDROME SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 35th Annual David W Smith Workshop on Malformations and Morphogenesis CY JUL 25-30, 2014 CL Univ Wisconsin, Madison, WI HO Univ Wisconsin C1 [Kruszka, Paul S.; Solomon, Benjamin D.; Hart, Rachel A.; Martinez, Ariel F.; Muenke, Maximilian] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Solomon, Benjamin D.; Iyer, Ramaswamy K.; Ahmad, Moin; Thach, Dzung C.; Bodian, Dale; Wong, Wendy Shukwan; Vockley, Joseph G.; Niederhuber, John] Inova Translat Med Inst ITIMI, Falls Church, VA USA. [Robin, Nathaniel H.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Opitz, John M.] Univ Utah, Dept Pediat, Salt Lake City, UT 84112 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2015 VL 167 IS 8 BP 1723 EP 1723 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA CN7ER UT WOS:000358597400094 ER PT J AU Niceta, M Gripp, KW Zampino, G Ciolfi, A Keppler-Noreuil, K Niyazov, DM Leoni, C Nakane, T Philip, N Stabley, D Sol-Church, K Tartaglia, M AF Niceta, Marcello Gripp, Karen W. Zampino, Giuseppe Ciolfi, Andrea Keppler-Noreuil, Kim Niyazov, Dmitriy M. Leoni, Chiara Nakane, Takaya Philip, Nicole Stabley, Deborah Sol-Church, Katia Tartaglia, Marco TI MISSENSE MUTATIONS IN MAF CAUSE FINE-LUBINSKY SYNDROME SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 35th Annual David W Smith Workshop on Malformations and Morphogenesis CY JUL 25-30, 2014 CL Univ Wisconsin, Madison, WI HO Univ Wisconsin C1 [Niceta, Marcello; Ciolfi, Andrea; Tartaglia, Marco] Ist Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, Italy. [Gripp, Karen W.] Alfred I DuPont Hosp Children, Med Genet, Wilmington, DE USA. [Stabley, Deborah; Sol-Church, Katia] Alfred I DuPont Hosp Children, Biomed Res, Wilmington, DE USA. [Zampino, Giuseppe; Leoni, Chiara] Univ Cattolica Sacro Cuore, Dept Pediat, Rome, Italy. [Keppler-Noreuil, Kim] NHGRI, NIH, Bethesda, MD 20892 USA. [Niyazov, Dmitriy M.] Ochsner Clin & Alton Ochsner Med Fdn, Dept Med Genet, New Orleans, LA USA. [Nakane, Takaya] Univ Yamanashi, Dept Pediat, Chuo Ku, Yamanashi, Japan. [Philip, Nicole] Aix Marseille Univ, APHM, Marseille, France. [Philip, Nicole] Aix Marseille Univ, UMR S910, Marseille, France. 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 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2015 VL 167 IS 8 BP 1726 EP 1727 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA CN7ER UT WOS:000358597400103 ER PT J AU Muenke, M Kruszka, PS Solomon, BD Carney, T Hart, RA Addissie, Y Martinez, AF Hu, P Roessler, E AF Muenke, Maximilian Kruszka, Paul S. Solomon, Benjamin D. Carney, Tyler Hart, Rachel A. Addissie, Yonit Martinez, Ariel F. Hu, Ping Roessler, Erich CA Clinicians Around World TI HOLOPROSENCEPHALY: NEW DIRECTIONS SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 35th Annual David W Smith Workshop on Malformations and Morphogenesis CY JUL 25-30, 2014 CL Univ Wisconsin, Madison, WI HO Univ Wisconsin C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Solomon, Benjamin D.] Inova Translat Med Inst ITIMI, Falls Church, VA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2015 VL 167 IS 8 BP 1727 EP 1727 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA CN7ER UT WOS:000358597400104 ER PT J AU Sacoto, MJG Kruszka, PS Yarnell, CMP Agochukwu, NB de Jong, T Boyadjiev, SA Platte, P Paelecke, Y Schweitzer, T Collmann, H Muenke, M AF Sacoto, M. J. Guillen Kruszka, P. S. Yarnell, C. M. P. Agochukwu, N. B. de Jong, T. Boyadjiev, S. A. Platte, P. Paelecke, Y. Schweitzer, T. Collmann, H. Muenke, M. TI COGNITIVE AND BEHAVIORAL PHENOTYPE IN MUENKE SYNDROME SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 35th Annual David W Smith Workshop on Malformations and Morphogenesis CY JUL 25-30, 2014 CL Univ Wisconsin, Madison, WI HO Univ Wisconsin C1 [Sacoto, M. J. Guillen; Kruszka, P. S.; Yarnell, C. M. P.; Agochukwu, N. B.; Muenke, M.] NHGRI, Bethesda, MD 20892 USA. [Platte, P.; Paelecke, Y.; Schweitzer, T.; Collmann, H.] Univ Wurzburg, D-97070 Wurzburg, Germany. [de Jong, T.] Dutch Craniofacial Ctr, Rotterdam, Netherlands. [Boyadjiev, S. A.] Univ Calif Davis, Sacramento, CA 95817 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 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2015 VL 167 IS 8 BP 1733 EP 1734 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA CN7ER UT WOS:000358597400119 ER PT J AU Korf, B Ahmadian, R Allanson, J Aoki, Y Bakker, A Wright, EB Denger, B Elgersma, Y Gelb, BD Gripp, KW Kerr, B Kontaridis, M Lazaro, C Linardic, C Lozano, R MacRae, CA Messiaen, L Mulero-Navarro, S Neel, B Plotkin, S Rauen, KA Roberts, A Silva, AJ Sittampalam, SG Zhang, C Schoyer, L AF Korf, Bruce Ahmadian, Reza Allanson, Judith Aoki, Yoko Bakker, Annette Wright, Emma Burkitt Denger, Brian Elgersma, Ype Gelb, Bruce D. Gripp, Karen W. Kerr, Bronwyn Kontaridis, Maria Lazaro, Conxi Linardic, Corinne Lozano, Reymundo MacRae, Calum A. Messiaen, Ludwine Mulero-Navarro, Sonia Neel, Benjamin Plotkin, Scott Rauen, Katherine A. Roberts, Amy Silva, Alcino J. Sittampalam, Sitta G. Zhang, Chao Schoyer, Lisa TI The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Toward a Therapeutic Approach SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Ras; neurofibromatosis; noonan syndrome; costello syndrome; cardio-facio-cutaneous syndrome ID FACIO-CUTANEOUS SYNDROME; NEUROFIBROMATOSIS TYPE-1; GERMLINE MUTATIONS; COSTELLO-SYNDROME; NOONAN SYNDROME; PHENOTYPE; CANCER; SPECTRUM; GAIN AB "The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach" was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion. (C) 2015 Wiley Periodicals, Inc. C1 [Korf, Bruce; Messiaen, Ludwine] Univ Alabama Birmingham, Birmingham, AL USA. [Ahmadian, Reza] Univ Dusseldorf, Dusseldorf, Germany. [Allanson, Judith] Childrens Hosp Eastern Ontario, Ottawa, ON K1H 8L1, Canada. [Aoki, Yoko] Tohoku Univ, Sch Med, Sendai, Miyagi 980, Japan. [Bakker, Annette] Childrens Tumor Fdn, New York, NY USA. [Wright, Emma Burkitt] Manchester Ctr Genom Med, Manchester, Lancs, England. [Wright, Emma Burkitt] Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Denger, Brian] Parent Project Muscular Dystrophy, Hackensack, NJ USA. [Elgersma, Ype] Erasmus Univ, NL-3000 DR Rotterdam, Netherlands. [Gelb, Bruce D.; Mulero-Navarro, Sonia] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Gripp, Karen W.] Alfred I DuPont Hosp Children, Wilmington, NC USA. [Kerr, Bronwyn] Manchester Ctr Genom Med, Manchester, Lancs, England. [Kontaridis, Maria; MacRae, Calum A.; Roberts, Amy] Harvard Univ, Sch Med, Boston, MA USA. [Kontaridis, Maria] Beth Israel Deaconess Med Canc Ctr, Boston, MA USA. [Lazaro, Conxi] Catalan Inst Oncol ICO IDIBELL, Barcelona, Spain. [Linardic, Corinne] Duke Univ, Sch Med, Durham, NC USA. [Lozano, Reymundo] UC Calif, Davis, CA USA. [MacRae, Calum A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Neel, Benjamin] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Plotkin, Scott] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rauen, Katherine A.] Univ Calif Davis, Davis MIND Inst, Sacramento, CA 95817 USA. [Roberts, Amy] Boston Childrens Hosp, Boston, MA USA. [Silva, Alcino J.] Univ Calif Los Angeles, Los Angeles, CA USA. [Sittampalam, Sitta G.] NIH, NCATS, Baltimore, MD USA. [Zhang, Chao] Plexxikon Inc, Berkeley, CA USA. [Schoyer, Lisa] RASopathies Network USA, Altadena, CA USA. RP Korf, B (reprint author), 230 Kaul Human Genet Bldg,720 20th St South, Birmingham, AL 35294 USA. EM bkorf@uab.edu FU NCI NIH HHS [1R13CA177217-01, R13 CA177217]; NHLBI NIH HHS [R01 HL114775]; NIAMS NIH HHS [R01 AR062165]; NIGMS NIH HHS [T32 GM082773]; NIMH NIH HHS [R01 MH084315] NR 19 TC 1 Z9 1 U1 2 U2 8 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 2015 VL 167 IS 8 BP 1741 EP 1746 DI 10.1002/ajmg.a.37089 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA CN7ER UT WOS:000358597400134 PM 25900621 ER PT J AU Regier, DS Leon, E Counts, DR Tifft, CJ Zand, DJ AF Regier, Debra S. Leon, Eyby Counts, Debra R. Tifft, Cynthia J. Zand, Dina J. TI Concurrent Diagnoses of Prader-Willi Syndrome and GM2 Gangliosidosis Caused by Uniparental Disomy of Chromosome 15 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter ID TAY-SACHS-DISEASE C1 [Regier, Debra S.; Tifft, Cynthia J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Leon, Eyby; Zand, Dina J.] Childrens Natl Med Ctr, Div Genet & Metab, Washington, DC 20010 USA. [Counts, Debra R.] Univ Maryland, Med Ctr, Dept Pediat, Baltimore, MD 21201 USA. RP Zand, DJ (reprint author), Childrens Natl Med Ctr, Div Genet & Metab, 111 Michigan Ave NW, Washington, DC 20010 USA. EM dzand@childrensnational.org NR 12 TC 0 Z9 0 U1 1 U2 4 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 2015 VL 167 IS 8 BP 1944 EP 1948 DI 10.1002/ajmg.a.37090 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA CN7ER UT WOS:000358597400165 PM 25900722 ER PT J AU Lin, M Mahmooth, Z Dedhia, N Frutchey, R Mercado, CE Epstein, DH Preston, KL Gibbons, MC Bowie, JV Labrique, AB Cheskin, LJ AF Lin, Michael Mahmooth, Zayan Dedhia, Nicket Frutchey, Robin Mercado, Catherine E. Epstein, David H. Preston, Kenzie L. Gibbons, Michael C. Bowie, Janice V. Labrique, Alain B. Cheskin, Lawrence J. TI Tailored, Interactive Text Messages for Enhancing Weight Loss Among African American Adults: The TRIMM Randomized Controlled Trial SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE African-American; Obesity; Text messaging; Weight loss ID BODY-MASS INDEX; UNITED-STATES; PHYSICAL-ACTIVITY; MOBILE PHONE; LOSS PROGRAM; OBESITY; PREVALENCE; OVERWEIGHT; WOMEN; INTERVENTION AB BACKGROUND: Helping patients control obesity remains a clinical challenge for internists, and African Americans experience obesity rates higher than other racial/ethnic groups. PURPOSE: To investigate whether a behavioral theory-based mobile health intervention would enhance weight loss when added to standard care among overweight/obese African American adults. METHODS: A randomized controlled trial of 124 adults recruited from Baltimore-area African American churches. Participant follow-up ended March 2013. Participants were randomized to standard care (included one-on-one counseling sessions with a dietitian and a physician) or standard care plus daily tailored text messages for 6 months. Text messages were delivered in phases: preparation, reinforcement of participant-selected diet and exercise goals, reflection, goal integration, weight loss methods, and maintenance. There were follow-up visits at 3, 6, and 12 months. Primary outcome was weight change from baseline to end-intervention at 6 months. Secondary outcomes included weight change at 3 months, engagement, and satisfaction with the intervention. RESULTS: Sixty-three participants were randomized to the mobile health intervention and 61 to standard-care control. Weights were collected in-window for 45 (36.3%) at 3 months and 51 (41.1%) at 6 months. Mean weight loss at 3 months was 2.5 kg greater in the intervention group compared with standard care (95% confidence interval [CI], -4.3 to -0.6; P < .001), and 3.4 kg greater (95% CI, -5.2 to -1.7; P = .001) at 6 months. Degree of engagement with messages was correlated with weight loss. CONCLUSIONS: While attrition was high, this study supports a tailored, interactive text-message intervention to enhance weight loss among obese African-American adults. (C) 2015 Elsevier Inc. All rights reserved. C1 [Lin, Michael] Johns Hopkins Sch Med, Baltimore, MD USA. [Mahmooth, Zayan; Frutchey, Robin; Gibbons, Michael C.; Bowie, Janice V.; Labrique, Alain B.; Cheskin, Lawrence J.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Dedhia, Nicket] Johns Hopkins Univ, Baltimore, MD USA. [Mercado, Catherine E.] Georgetown Univ, Sch Med, Washington, DC USA. [Epstein, David H.; Preston, Kenzie L.] Natl Inst Drug Abuse Intramural Res Program, Clin Pharmacol & Therapeut Res Branch, Baltimore, MD USA. RP Cheskin, LJ (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, 550 North Broadway,Suite 1001, Baltimore, MD 21205 USA. EM cheskin@jhu.edu RI Emchi, Karma/Q-1952-2016 FU Mobilizing for Health grant from the McKesson Foundation; Doris Duke Charitable Foundation; Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health; National Center for Advancing Translational Sciences (NCATS) of the National Institute of Health [UL1T000424] FX This trial was conducted by the Johns Hopkins Weight Management Center, supported by a Mobilizing for Health grant from the McKesson Foundation, by a grant from the Doris Duke Charitable Foundation to Johns Hopkins University to fund Clinical Research Fellow ML, and by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. The trial received support for statistical analysis from the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS) of the National Institute of Health through Grant Number UL1T000424. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; or decision to submit the manuscript for publication. NR 24 TC 4 Z9 4 U1 3 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD AUG PY 2015 VL 128 IS 8 BP 896 EP 904 DI 10.1016/j.amjmed.2015.03.013 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CN4GL UT WOS:000358388500035 PM 25840035 ER PT J AU Romero, R Nygaard, I AF Romero, Roberto Nygaard, Ingrid TI CDC updates guidelines for treating sexually transmitted diseases SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material C1 [Romero, Roberto] Wayne State Univ, Sch Med,Dept Hlth & Human Serv, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH,Perinatol Res Branch,Program Perinatal Res &, Detroit, MI 48202 USA. [Romero, Roberto] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Nygaard, Ingrid] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. RP Romero, R (reprint author), Wayne State Univ, Sch Med,Dept Hlth & Human Serv, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH,Perinatol Res Branch,Program Perinatal Res &, Detroit, MI 48202 USA. NR 1 TC 1 Z9 1 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD AUG PY 2015 VL 213 IS 2 BP 117 EP 118 DI 10.1016/j.ajog.2015.06.053 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CN6NG UT WOS:000358550900001 PM 26216176 ER PT J AU Grantz, KL Gonzalez-Quintero, V Troendle, J Reddy, UM Hinkle, SN Kominiarek, MA Lu, ZH Zhang, J AF Grantz, Katherine L. Gonzalez-Quintero, Victor Troendle, James Reddy, Uma M. Hinkle, Stefanie N. Kominiarek, Michelle A. Lu, Zhaohui Zhang, Jun TI Labor patterns in women attempting vaginal birth after cesarean with normal neonatal outcomes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE first stage of labor; trial of labor after cesarean; vaginal birth after cesarean ID DELIVERY; TRIAL AB OBJECTIVE: We sought to describe labor patterns in women with a trial of labor after cesarean (TOLAC) with normal neonatal outcomes. STUDY DESIGN: In a retrospective observational study at 12 US centers (2002 through 2008), we examined time interval for each centimeter of cervical dilation and compared labor progression stratified by spontaneous or induced labor in 2892 multiparous women with TOLAC (second delivery) and 56,301 nulliparous women at 37 0/7 to 41 6/7 weeks of gestation. Analyses were performed including women with intrapartum cesarean delivery, and also limiting only to women who delivered vaginally. RESULTS: Labor was induced in 23.4% of TOLAC and 44.1% of nulliparous women (P <.001). Cesarean delivery rates were 57.7% in TOLAC vs 19.0% in nulliparous women (P <.001). Oxytocin was used in 52.4% of TOLAC vs 64.3% of nulliparous women with spontaneous labor (P <.001) and 89.8% of TOLAC vs 91.6% of nulliparous women with induced labor (P =.099); however, TOLAC had lower maximum doses of oxytocin compared to nulliparous women: median (90th percentile): 6 (18) mU/min vs 12 (28) mU/min, respectively (P <.001). Median (95th percentile) labor duration for TOLAC vs nulliparous women with spontaneous labor from 4-10 cm was 0.9 (2.2) hours longer (P =.007). For women who entered labor spontaneously and achieved vaginal delivery, labor patterns for TOLAC were similar to nulliparous women. For induced labor, labor duration for TOLAC vs nulliparous women from 4-10 cm was 1.5 (4.6) hours longer (P <.001). For women who achieved vaginal delivery, labor patterns were slower for induced TOLAC compared to nulliparous women. CONCLUSION: Labor duration for TOLAC was slower compared to nulliparous labor, particularly for induced labor. By improved understanding of the rates of progress at different points in labor, this new information on labor curves in women undergoing TOLAC, particularly for induction, should help physicians when managing labor. C1 [Grantz, Katherine L.; Hinkle, Stefanie N.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. [Lu, Zhaohui] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Glotech Inc, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Troendle, James] NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Gonzalez-Quintero, Victor] Univ Miami, Sch Med, Dept Obstet & Gynecol, Miami, FL 33101 USA. [Kominiarek, Michelle A.] Univ Illinois, Coll Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Chicago, IL 60612 USA. [Zhang, Jun] Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Shanghai Key Lab Childrens Environm Hlth,Minist E, Shanghai 200030, Peoples R China. RP Grantz, KL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. EM katherine.grantz@nih.gov RI Hinkle, Stefanie/F-8253-2013; OI Hinkle, Stefanie/0000-0003-4312-708X; 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); Intramural Research Program of the NICHD [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). The Consortium on Safe Labor was funded by the Intramural Research Program of the NICHD through contract number HHSN267200603425C. NR 15 TC 0 Z9 1 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD AUG PY 2015 VL 213 IS 2 AR 226.e1 DI 10.1016/j.ajog.2015.04.033 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CN6NG UT WOS:000358550900029 PM 25935774 ER PT J AU Boutin, RD Chang, J Bateni, C Giza, E Wisner, ER Yaos, L AF Boutin, Robert D. Chang, Jennifer Bateni, Cyrus Giza, Eric Wisner, Erik R. Yaos, Lawrence TI The Notch of Harty (Pseudodefect of the Tibial Plafond): Frequency and Characteristic Findings at MRI of the Ankle SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE ankle; MRI; normal variation; osteochondral lesion ID OSTEOCHONDRAL LESIONS; ARTHROSCOPIC TREATMENT; PITFALL AB OBJECTIVE. The purpose of this study is to report the frequency and characteristic findings of the notch of Harty as seen on MRI. MATERIALS AND METHODS. One hundred six consecutive ankle MRI studies performed at 1.5 or 3 T were reviewed retrospectively by two radiologists. Findings relating to the notch of Harty and ankle joint were recorded and analyzed, including qualitative assessment of the presence of the notch, focal chondral thinning or focal subcortical osteosclerosis at the notch, notch width and depth, osteochondral lesions elsewhere in the ankle, subchondral edema signal or cystic change at the tibial plafond, and the presence of an ankle joint effusion. RESULTS. The study group of 106 patients consisted of 48 male and 58 female patients, with a mean age of 44.5 years (SD, 17.5 years). The notch was identified in 48 of 106 patients (45%) (24 male and 24 female patients; mean age, 43.1 years; range, 7-79 years). When present, the notch averaged 6.2 mm (SD, 1.6 mm) in width and 1.2 mm (SD, 0.5 mm) in depth. The notch was graded as prominent in six of the 106 ankle MRI examinations (6%). Subchondral edemalike signal or cystic change was not localized to the notch in any case. Between patients with versus those without a notch, there was no statistically significant difference in age, sex, subjacent subcortical osteosclerosis, ankle joint effusion, osteochondral lesions elsewhere in the ankle, or subchondral bone marrow edema at the tibial plafond. CONCLUSION. The notch of Harty can be observed as an anatomic variant on MRI and should be differentiated from a traumatic osteochondral lesion. C1 [Boutin, Robert D.; Bateni, Cyrus] Univ Calif Davis, Dept Radiol, Sacramento, CA 95817 USA. [Chang, Jennifer] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Chang, Jennifer] Harvard Univ, Sch Med, Boston, MA USA. [Giza, Eric] Univ Calif Davis, Dept Orthopaed Surg, Sacramento, CA 95817 USA. [Wisner, Erik R.] Univ Calif Davis, Sch Vet Med, Davis, CA 95616 USA. [Yaos, Lawrence] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Boutin, RD (reprint author), Univ Calif Davis, Dept Radiol, 4860 Y St,Ste 3100, Sacramento, CA 95817 USA. EM robert.boutin@ucdmc.ucdavis.edu NR 23 TC 1 Z9 1 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2015 VL 205 IS 2 BP 358 EP 362 DI 10.2214/AJR.14.14012 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN4YH UT WOS:000358436000037 PM 26204288 ER PT J AU Tektonidou, MG Wang, Z Dasgupta, A Ward, MM AF Tektonidou, Maria G. Wang, Zhong Dasgupta, Abhijit Ward, Michael M. TI Burden of Serious Infections in Adults With Systemic Lupus Erythematosus: A National Population-Based Study, 1996-2011 SO ARTHRITIS CARE & RESEARCH LA English DT Article ID UNITED-STATES; RISK-FACTORS; OPPORTUNISTIC INFECTIONS; RHEUMATOID-ARTHRITIS; BACTERIAL-INFECTIONS; BRITISH PATIENTS; SINGLE COHORT; SEVERE SEPSIS; MORTALITY; HOSPITALIZATIONS AB ObjectiveTo compare rates of hospitalization for serious infections, trends in rates from 1996 to 2011, and in-hospital mortality between patients with systemic lupus erythematosus (SLE) and those without SLE in a national sample. MethodsWe analyzed hospitalizations for pneumonia, bacteremia/sepsis, urinary tract infections, skin infections, and opportunistic infections among adults in the Nationwide Inpatient Sample. We compared rates of hospitalization yearly among patients with SLE and the general population. We also computed odds ratios (ORs) for in-hospital mortality. ResultsIn 1996, the estimated number of hospitalizations for pneumonia in patients with SLE was 4,382, followed by sepsis (2,305), skin infections (1,422), urinary tract infections (643), and opportunistic infections (370). Rates were much higher in patients with SLE than in those without SLE, with age-adjusted relative risks ranging from 5.7 (95% confidence interval [95% CI] 5.5-6.0) for pneumonia to 9.8 (95% CI 9.1-10.7) for urinary tract infection in 1996. Risks increased over time, so that by 2011, all relative risks exceeded 12.0. Overall risk of in-hospital mortality was higher in SLE only for opportunistic infections (adjusted OR 1.52 [95% CI 1.12-2.07]). However, in pneumonia and sepsis, mortality risks were higher in SLE among those who required mechanical ventilation. ConclusionHospitalization rates for serious infections in SLE increased substantially between 1996 and 2011, reaching over 12 times higher than in patients without SLE in 2011. Reasons for this acceleration are unclear. In-hospital mortality was higher among patients with SLE and opportunistic infections and those with pneumonia or sepsis who required mechanical ventilation. C1 [Tektonidou, Maria G.] Univ Athens, Athens, Greece. [Wang, Zhong; Dasgupta, Abhijit; Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU NIH/Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases [ZIA-AR-041153] FX Supported by the NIH/Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant ZIA-AR-041153). NR 45 TC 8 Z9 8 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD AUG PY 2015 VL 67 IS 8 BP 1078 EP 1085 DI 10.1002/acr.22575 PG 8 WC Rheumatology SC Rheumatology GA CN7LW UT WOS:000358617000006 PM 25732901 ER PT J AU Grayson, PC Steiling, K Platt, M Berman, JS Zhang, XH Xiao, J Alekseyev, YO Liu, G Monach, PA Kaplan, MJ Spira, A Merkel, PA AF Grayson, Peter C. Steiling, Katrina Platt, Michael Berman, Jeffrey S. Zhang, Xiaohui Xiao, Ji Alekseyev, Yuriy O. Liu, Gang Monach, Paul A. Kaplan, Mariana J. Spira, Avrum Merkel, Peter A. TI BRIEF REPORT Defining the Nasal Transcriptome in Granulomatosis With Polyangiitis (Wegener's) SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID RHEUMATOLOGY 1990 CRITERIA; MYELOID CELLS-1; VASCULITIS; GENE; CLASSIFICATION; TISSUE AB Objective. To determine whether disease processes related to granulomatosis with polyangiitis (Wegener's) (GPA) are reflected in gene expression profiles of the nasal mucosa. Methods. Nasal brushings of the inferior turbinate were obtained from 32 patients with GPA (10 with active nasal disease, 13 with prior nasal disease, and 9 with no history of nasal disease) and a composite comparator group with and without inflammatory nasal disease (12 healthy people, 15 with sarcoidosis, and 8 with allergic rhinitis). Differential gene expression was assessed between subgroups of GPA and comparators. Results. A total of 339 genes were differentially expressed between the GPA and comparator groups (absolute fold change >1.5; false discovery rate <0.05). Top canonical pathways up-regulated in nasal brushings from patients with GPA included granulocyte adhesion and diapedesis (P=8.6(-22)), agranulocyte adhesion and diapedesis (P=1.3(-14)), IL10 signaling (P=3.0(-11)), LXR/RXR activation (P=4.3(-11)), and TREM1 signaling (P=9.0(-11)). A set of genes differentially expressed in GPA independently of nasal disease activity status included genes related to epithelial barrier integrity (fibronectin 1, desmosomal proteins) and several matricellular proteins (e.g., osteonectin, osteopontin). Significant overlap of differentially expressed genes was observed between active and prior nasal disease GPA subgroups. Peripheral blood neutrophil and mononuclear gene expression levels associated with GPA were similarly altered in the nasal gene expression profiles of patients with active or prior nasal disease. Conclusion. Profiling the nasal transcriptome in GPA reveals gene expression signatures related to innate immunity, inflammatory cell chemotaxis, extracellular matrix composition, and epithelial barrier integrity. Thus, airway-based expression profiling is feasible and informative in GPA. C1 [Grayson, Peter C.; Kaplan, Mariana J.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Grayson, Peter C.; Steiling, Katrina; Platt, Michael; Berman, Jeffrey S.; Zhang, Xiaohui; Xiao, Ji; Alekseyev, Yuriy O.; Liu, Gang; Monach, Paul A.; Spira, Avrum; Merkel, Peter A.] Boston Univ, Boston, MA 02215 USA. [Merkel, Peter A.] Univ Penn, Philadelphia, PA 19104 USA. RP Grayson, PC (reprint author), NIAMSD, NIH, 10 Ctr Dr,Bldg 10,Room 216G, Bethesda, MD 20892 USA. EM peter.grayson@nih.gov FU NIH through the National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program; Vasculitis Research Fund at Boston University; Rheumatology Research Foundation (Rheumatology Scientist Development Award); NIH (National Center for Advancing Translational Science, Boston University, Clinical and Translational Science Institute microarray initiative grant) [UL1-RR-025771] FX Supported by the NIH through the National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program and by the Vasculitis Research Fund at Boston University. Dr. Grayson's work was supported by the Rheumatology Research Foundation (Rheumatology Scientist Development Award) and the NIH (National Center for Advancing Translational Science, Boston University, Clinical and Translational Science Institute microarray initiative grant UL1-RR-025771). NR 18 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD AUG PY 2015 VL 67 IS 8 BP 2233 EP 2239 DI 10.1002/art.39185 PG 7 WC Rheumatology SC Rheumatology GA CN7JA UT WOS:000358609300029 PM 25939343 ER PT J AU Mohan, S Barsalou, J Bradley, TJ Slorach, C Reynolds, JA Hasni, S Thompson, B Ng, L Levy, D Silverman, E Kaplan, MJ AF Mohan, Smriti Barsalou, Julie Bradley, Timothy J. Slorach, Cameron Reynolds, John A. Hasni, Sarfaraz Thompson, Becky Ng, Lawrence Levy, Deborah Silverman, Earl Kaplan, Mariana J. TI Brief Report: Endothelial Progenitor Cell Phenotype and Function Are Impaired in Childhood-Onset Systemic Lupus Erythematosus SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID ATHEROSCLEROSIS; VASCULOGENESIS; PATHWAY; ALPHA; RISK AB Objective Systemic lupus erythematosus (SLE) is characterized by increased cardiovascular risk in adult-onset and childhood-onset SLE. Type I interferons (IFNs) appear to play a prominent role in premature vascular damage in adult-onset SLE, at least in part, by inducing impairments in the phenotype and function of endothelial progenitor cells (EPCs), thereby hampering vascular repair. It is not clear whether EPC dysfunction is present in childhood-onset SLE in association with a type I IFN signature. Methods The phenotype and numbers of EPCs were quantified in patients with childhood-onset SLE, patients with juvenile idiopathic arthritis (JIA), and matched healthy control subjects. In a separate cohort of patients with childhood-onset SLE, markers of subclinical atherosclerosis and endothelial dysfunction were quantified using standardized protocols and analyzed for associations with serum type I IFN activity. Results EPC numbers and function were significantly decreased in patients with childhood-onset SLE compared with patients with JIA and healthy control subjects. Serum from patients with childhood-onset SLE impaired differentiation of EPCs into mature endothelial cells in healthy controls, and this effect was blocked by inhibition of the type I IFN pathway. Type I IFN activity in serum was not significantly associated with subclinical atherosclerosis and endothelial function in patients with childhood-onset SLE. Conclusion As in adult-onset SLE, childhood-onset SLE is characterized by phenotypic and functional EPC abnormalities, which are likely triggered by type I IFNs. Although cross-sectional analysis revealed no global association between type I IFN signatures and vascular measures of subclinical atherosclerosis, longitudinal assessments are needed to evaluate whether progression of vascular damage in patients with childhood-onset SLE is associated with type I IFNs, as observed in patients with adult-onset SLE. C1 [Mohan, Smriti; Thompson, Becky] Univ Michigan, Ann Arbor, MI 48109 USA. [Barsalou, Julie; Bradley, Timothy J.; Slorach, Cameron; Ng, Lawrence; Levy, Deborah; Silverman, Earl] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Reynolds, John A.; Hasni, Sarfaraz; Kaplan, Mariana J.] NIAMS, NIH, Bethesda, MD 20892 USA. RP Kaplan, MJ (reprint author), NIAMS, Syst Autoimmun Branch, NIH, 10 Ctr Dr,6D47C, Bethesda, MD 20892 USA. EM mariana.kaplan@nih.gov OI Reynolds, John/0000-0002-8962-4404 FU NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program); Heart and Stroke Foundation of Canada; NIH (US Public Health Service) [T32-HD-7513-15]; Charles Woodson Biostatistics Award; North West England Medical Research Council Clinical Pharmacology and Therapeutics Training Scheme [G1000417/94909] FX Supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program) and the Heart and Stroke Foundation of Canada. Dr. Mohan's work was supported by the NIH (grant T32-HD-7513-15 from the US Public Health Service) and a Charles Woodson Biostatistics Award. Dr. Reynolds' work was supported by the North West England Medical Research Council Clinical Pharmacology and Therapeutics Training Scheme (grant G1000417/94909). NR 18 TC 11 Z9 11 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD AUG PY 2015 VL 67 IS 8 BP 2257 EP 2262 DI 10.1002/art.39149 PG 6 WC Rheumatology SC Rheumatology GA CN7JA UT WOS:000358609300033 PM 25891295 ER PT J AU Martin, PJ Lee, SJ Przepiorka, D Horowitz, MM Koreth, J Vogelsang, GB Walker, I Carpenter, PA Griffith, LM Akpek, G Mohty, M Wolff, D Pavletic, SZ Cutler, CS AF Martin, Paul J. Lee, Stephanie J. Przepiorka, Donna Horowitz, Mary M. Koreth, John Vogelsang, Georgia B. Walker, Irwin Carpenter, Paul A. Griffith, Linda M. Akpek, Gorgun Mohty, Mohamad Wolff, Daniel Pavletic, Steven Z. Cutler, Corey S. TI National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. The 2014 Clinical Trial Design Working Group Report SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; Allogeneic hematopoietic cell transplantation; Clinical trials; Design; Consensus; Guidelines ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; MEASURING THERAPEUTIC RESPONSE; REFRACTORY CHRONIC GVHD; FAILURE-FREE SURVIVAL; ACTIVITY INDEX; EXTRACORPOREAL PHOTOPHERESIS; MARROW-TRANSPLANTATION; PRELIMINARY DEFINITION; RHEUMATOID-ARTHRITIS; AMERICAN-COLLEGE AB Treatment of chronic graft-versus-host disease is intended to produce a sustainable benefit by reducing symptom burden, controlling objective manifestations of disease activity, preventing damage and impairment, and improving overall survival without causing disproportionate harms related to the treatment itself. Successful management can control the disease until systemic treatment is no longer needed. The complexity of the disease, the extended duration of follow-up needed to observe disease resolution and withdrawal of immunosuppressive treatment, and the lack of fully developed shorter term endpoints impede progress in the field. Identification and characterization of primary endpoints demonstrating clinical benefit without requiring years of follow-up is urgently needed, with the understanding that clinical benefit encompasses not only the self-evident benefit of the primary endpoint but also any other associated benefits. This report discusses regulatory considerations, eligibility criteria, the value of controlled trial designs, the merits of proposed primary endpoints, and key considerations elaborated from experience and progress during the past decade. The report concludes by mapping an overall approach that could support and lead to maximally informative clinical trials, especially those that seek to demonstrate clinical benefit along a pathway to regulatory review and approval. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Martin, Paul J.; Lee, Stephanie J.; Carpenter, Paul A.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Przepiorka, Donna] US FDA, Ctr Drug Evaluat Res, Silver Spring, MD USA. [Horowitz, Mary M.] Med Coll Wisconsin, Div Hematol & Oncol, Milwaukee, WI 53226 USA. [Koreth, John; Cutler, Corey S.] Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. [Vogelsang, Georgia B.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Walker, Irwin] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Griffith, Linda M.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Akpek, Gorgun] Banner MD Anderson Canc Ctr, Stem Cell Transplant Program, Gilbert, AZ USA. [Mohty, Mohamad] Univ Paris 06, Hop St Antoine, INSERM, Clin Hematol & Cellular Therapy Dept,U938, Paris, France. [Wolff, Daniel] Univ Regensburg, Dept Internal Med 3, D-93053 Regensburg, Germany. [Pavletic, Steven Z.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Martin, PJ (reprint author), Fred Hutchinson Canc Res Ctr, D2-100,POB 19024, Seattle, WA 98109 USA. EM pmartin@fredhutch.org OI Martin, Paul/0000-0001-9051-1215 FU NIH: National Cancer Institute (NCI), Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research (ORD), National Center for Advancing Translational Sciences; Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases; National Heart, Lung and Blood Institute, Division of Blood Diseases and Resources; NCI, NIH [CA118953, CA18029]; U.S. Department of Health and Human Services FX This project was supported by the NIH: National Cancer Institute (NCI), Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research (ORD), National Center for Advancing Translational Sciences; Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases; National Heart, Lung and Blood Institute, Division of Blood Diseases and Resources. Supported by grants CA118953 and CA18029 from the NCI, NIH, and U.S. Department of Health and Human Services (to P.J.M. and S.J.L.). The opinions expressed are those of the authors and do not represent the position of the NCI, the National Heart, Lung and Blood Institute, the National Institute of Allergy and Infectious Diseases, the NIH, the FDA, or the US Government. NR 71 TC 11 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2015 VL 21 IS 8 BP 1343 EP 1359 DI 10.1016/j.bbmt.2015.05.004 PG 17 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CN6PW UT WOS:000358557700003 PM 25985921 ER PT J AU Grace, PM Shimizu, K Strand, KA Rice, KC Deng, GY Watkins, LR Herson, PS AF Grace, Peter M. Shimizu, Kaori Strand, Keith A. Rice, Kenner C. Deng, Guiying Watkins, Linda R. Herson, Paco S. TI (+)-Naltrexone is neuroprotective and promotes alternative activation in the mouse hippocampus after cardiac arrest/cardiopulmonary resuscitation SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE TLR4; Ischemia; Neurotoxicity; M2 microglia; M2 macrophages; HIF1 alpha; HIF2 alpha ID TRANSIENT GLOBAL-ISCHEMIA; CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; CARDIOPULMONARY-RESUSCITATION; CEREBRAL-ISCHEMIA; NEUROPATHIC PAIN; INNATE IMMUNITY; STRESS-RESPONSE; ARREST; INJURY AB Despite dramatic improvement in cardiopulmonary resuscitation (CPR) and other techniques for cardiac arrest (CA), the majority of survivors continue to show signs of decreased memory or executive cognitive function. Such memory impairment may be due to hippocampal CA1 neuronal death, which is delayed by several days after CA/CPR. Classical microgliosis in the CA1 region may contribute to neuronal death, yet the role of a key activation receptor Toll Like Receptor 4 (TLR4) has not been previously investigated for such neuronal death after CA/CPR. We show that (+)-naltrexone was neuroprotective after CA/CPR. TLR4 blockade was associated with decreased expression of markers for microglial/macrophage activation and T cell and B cell infiltration, as well as decreased pro-inflammatory cytokine levels. Notably, IL-10 expression was elevated in response to CA/CPR, but was not attenuated by (+)-naltrexone, suggesting that the local monocyte/microglial phenotype had shifted towards alternative activation. This was confirmed by elevated expression of Arginase-1, and decreased expression of NF kappa B p65 subunit. Thus, (+)-naltrexone and other TLR4 antagonists may represent a novel therapeutic strategy to alleviate the substantial burden of memory or executive cognitive function impairment after CA/CPR. (C) 2015 Elsevier Inc. All rights reserved. C1 [Grace, Peter M.; Strand, Keith A.; Watkins, Linda R.] Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. [Grace, Peter M.; Strand, Keith A.; Watkins, Linda R.] Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA. [Shimizu, Kaori; Herson, Paco S.] Univ Colorado Denver, Dept Anesthesiol, Aurora, CO 80045 USA. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Rockville, MD USA. [Rice, Kenner C.] NIAAA, Rockville, MD 20852 USA. [Deng, Guiying; Herson, Paco S.] Univ Colorado Denver, Dept Pharmacol, Aurora, CO 80045 USA. RP Herson, PS (reprint author), Univ Colorado Denver, 12800 E 19th Ave,Anschutz Med Campus, Aurora, CO 80045 USA. EM paco.herson@ucdenver.edu OI Strand, Keith/0000-0001-8885-0162; Grace, Peter/0000-0002-8999-1220 FU University of Colorado Boulder Innovative Seed Grant Program; NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA); National Institute of Alcohol Abuse and Alcoholism (NIAAA) FX Supported by the University of Colorado Boulder Innovative Seed Grant Program. P.M.G. is an NHMRC CJ Martin Fellow (ID: 1054091) and an American Australian Association Sir Keith Murdoch Fellow. The work of the Drug Design and Synthesis Section, CBRB, NIDA, and NIAAA was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism (NIAAA). The authors have no conflict of interest to declare. NR 37 TC 4 Z9 4 U1 1 U2 4 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 2015 VL 48 BP 115 EP 122 DI 10.1016/j.bbi.2015.03.005 PG 8 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA CN5HP UT WOS:000358460700014 PM 25774010 ER PT J AU Madar, R Rotter, A Ben-Asher, HW Mughal, MR Arumugam, TV Wood, WH Becker, KG Mattson, MP Okun, E AF Madar, Ravit Rotter, Aviva Ben-Asher, Hiba Waldman Mughal, Mohamed R. Arumugam, Thiruma V. Wood, W. H., III Becker, K. G. Mattson, Mark P. Okun, Eitan TI Postnatal TLR2 activation impairs learning and memory in adulthood SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Toll-like receptors; TLR2; Hippocampus; Spatial learning; Morris water maze; Fear conditioning; Cognition ID NF-KAPPA-B; HIPPOCAMPUS; EXPOSURE; AMYGDALA; DISEASE AB Neuroinflammation in the central nervous system is detrimental for learning and memory, as evident form epidemiological studies linking developmental defects and maternal exposure to harmful pathogens. Postnatal infections can also induce neuroinflammatory responses with long-term consequences. These inflammatory responses can lead to motor deficits and/or behavioral disabilities. Toll like receptors (TLRs) are a family of innate immune receptors best known as sensors of microbial-associated molecular patterns, and are the first responders to infection. TLR2 forms heterodimers with either TLR1 or TLR6, is activated in response to gram-positive bacterial infections, and is expressed in the brain during embryonic development. We hypothesized that early postnatal TLR2-mediated neuroinflammation would adversely affect cognitive behavior in the adult. Our data indicate that postnatal TLR2 activation affects learning and memory in adult mice in a heterodimer-dependent manner. TLR2/6 activation improved motor function and fear learning, while TLR2/1 activation impaired spatial learning and enhanced fear learning. Moreover, developmental TLR2 deficiency significantly impairs spatial learning and enhances fear learning, stressing the involvement of the TLR2 pathway in learning and memory. Analysis of the transcriptional effects of TLR2 activation reveals both common and unique transcriptional programs following heterodimer-specific TLR2 activation. These results imply that adult cognitive behavior could be influenced in part, by activation or alterations in the TLR2 pathway at birth. (C) 2015 Elsevier Inc. All rights reserved. C1 [Madar, Ravit; Rotter, Aviva; Ben-Asher, Hiba Waldman; Okun, Eitan] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-5290000 Ramat Gan, Israel. [Madar, Ravit; Rotter, Aviva; Okun, Eitan] Bar Ilan Univ, Leslie & Susan Gonda Multidisciplinary Brain Res, IL-5290002 Ramat Gan, Israel. [Mughal, Mohamed R.; Wood, W. H., III; Becker, K. G.; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Arumugam, Thiruma V.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117595, Singapore. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Okun, E (reprint author), Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Bldg 901,Room 315, IL-5290002 Ramat Gan, Israel. EM eitan.okun@biu.ac.il RI okun, eitan/K-1314-2016; OI okun, eitan/0000-0001-8474-1487; Madar, Ravit/0000-0002-2025-8178 FU Intramural Research Program of the National Institute on Aging FX This work was supported, in part, by the Intramural Research Program of the National Institute on Aging. NR 26 TC 2 Z9 2 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD AUG PY 2015 VL 48 BP 301 EP 312 DI 10.1016/j.bbi.2015.04.020 PG 12 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA CN5HP UT WOS:000358460700031 PM 26021559 ER PT J AU Rogers, T Ratnayaka, K Schenke, WH Faranesh, AZ Mazal, JR O'Neill, WW Greenbaum, AB Lederman, RJ AF Rogers, Toby Ratnayaka, Kanishka Schenke, William H. Faranesh, Anthony Z. Mazal, Jonathan R. O'Neill, William W. Greenbaum, Adam B. Lederman, Robert J. TI Intentional right atrial exit for microcatheter infusion of pericardial carbon dioxide or iodinated contrast to facilitate sub-xiphoid access SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE pericardial access; epicardial intervention; transatrial puncture; structural heart intervention; electrophysiology ID VENTRICULAR-TACHYCARDIA ABLATION; PERCUTANEOUS TRANSATRIAL ACCESS; EPICARDIAL ABLATION; CARDIAC-ARRHYTHMIAS; SAFETY; SPACE; COMPLICATIONS; MULTICENTER; PREVENTION; EFFICACY AB Objectives: We test the safety of transatrial pericardial access using small catheters, infusion of carbon dioxide (CO2) or iodinated contrast to facilitate sub-xiphoid access, and catheter withdrawal under full anticoagulation. Background: Sub-xiphoid pericardial access is required for electrophysiological and structural heart interventions. If present, an effusion protects the heart from needle injury by separating the myocardium from the pericardium. However, if the pericardium is dry' then there is a significant risk of right ventricle or coronary artery laceration caused by the heart beating against the needle tip. Intentional right atrial exit is an alternative pericardial access route, through which contrast media could be infused to separate pericardial layers. Methods: Transatrial pericardial access was obtained in a total of 30 Yorkshire swine using 4Fr or 2.8Fr catheters. In 16 animals, transatrial catheters were withdrawn under anticoagulation and MRI was performed to monitor for pericardial hemorrhage. In 14 animals, iodinated contrast or CO2 was infused before sub-xiphoid access was obtained. Results: Small effusions (mean 18.5 ml) were observed after 4Fr (1.3 mm outer-diameter) but not after 2.8Fr (0.9 mm outer-diameter) transatrial catheter withdrawal despite full anticoagulation (mean activated clotting time 383 sec), with no hemodynamic compromise. Pericardial CO2 resorbed spontaneously within 15 min. Conclusions: Intentional transatrial exit into the pericardium using small catheters is safe and permits infusion of CO2 or iodinated contrast to separate pericardial layers and facilitate sub-xiphoid access. This reduces the risk of right ventricular or coronary artery laceration. 2.8Fr transatrial catheter withdrawal does not cause any pericardial hemorrhage, even under full anticoagulation. (c) 2014 Wiley Periodicals, Inc. C1 [Rogers, Toby; Ratnayaka, Kanishka; Schenke, William H.; Faranesh, Anthony Z.; Mazal, Jonathan R.; Lederman, Robert J.] NHLBI, NIH, Cardiovasc & Pulm Branch, Div Intramural Res, Bethesda, MD 20892 USA. [Ratnayaka, Kanishka] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. [O'Neill, William W.; Greenbaum, Adam B.] Henry Ford Hlth Syst, Inst Struct Heart Dis, Div Cardiol, Detroit, MI USA. RP Lederman, RJ (reprint author), NHLBI, NIH, Bldg 10,Room 2c713, Bethesda, MD 20892 USA. EM lederman@nih.gov OI Rogers, Toby/0000-0002-6043-3137; lederman, robert/0000-0003-1202-6673 FU Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health [Z01-HL006040-01, Z01-HL005062] FX Contract grant sponsor: Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health; Contract grant number: Z01-HL006040-01, Z01-HL005062.. NR 25 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 EI 1522-726X J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD AUG PY 2015 VL 86 IS 2 BP E111 EP E118 DI 10.1002/ccd.25698 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CN5TN UT WOS:000358493700013 PM 25315516 ER PT J AU Steel, C Golden, A Stevens, E Yokobe, L Domingo, GJ de los Santos, T Nutman, TB AF Steel, Cathy Golden, Allison Stevens, Eric Yokobe, Lindsay Domingo, Gonzalo J. de los Santos, Tala Nutman, Thomas B. TI Rapid Point-of-Contact Tool for Mapping and Integrated Surveillance of Wuchereria bancrofti and Onchocerca volvulus Infection SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID LYMPHATIC FILARIASIS; DRUG; ANTIGEN; ANTIBODY; CHILDREN; MARKER; WB123; HAITI; AREA AB Elimination programs for Wuchereria bancrofti and Onchocerca volvulus are in critical need of sensitive, specific, and point-of-contact (POC) tools that can be used for surveillance years beyond cessation of mass drug administration when infection intensities are low. Previously, Wb123 and Ov16 were identified individually as potential filarial antigens for an antibody-based POC test. The present study compares single-antigen Wb123- and Ov16-based POC tests with an integrated configuration to detect antibodies to Wb123 and Ov16 simultaneously. Wb123 and Ov16 isolates were striped onto lateral flow strips containing anti-IgG4. Sera from W. bancrofti-, O. volvulus-, and other helminth-infected or -uninfected individuals were added to the strips with buffer. Strips were read for the appearance of a positive or negative test line for both antigens at 20 min and following drying. Sensitivity, specificity, and predictive values were calculated for the single-antigen and biplex strips. Single and biplex lateral flow strips showed nearly identical results, with >90% sensitivity for Ov16 and >92% sensitivity for Wb123. Overall specificities for the single and biplex tests were 98% and 96% for Ov16 and Wb123, respectively. Biplex tests performed as well as the single-antigen tests regardless of the intensity of patient IgG4 response. The high sensitivity and specificity make these new biplex tests extremely useful for POC long-term surveillance following mass drug administration in Africa that should reduce time and cost in areas where bancroftian filariasis and onchocerciasis are coendemic. C1 [Steel, Cathy; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Golden, Allison; Stevens, Eric; Yokobe, Lindsay; Domingo, Gonzalo J.; de los Santos, Tala] PATH, Diagnost Grp, Seattle, WA USA. RP Nutman, TB (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM tnutman@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bill and Melinda Gates Foundation FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and, in part, by the Bill and Melinda Gates Foundation. NR 13 TC 5 Z9 5 U1 1 U2 11 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 2015 VL 22 IS 8 BP 896 EP 901 DI 10.1128/CVI.00227-15 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CN8DR UT WOS:000358668600007 PM 26018537 ER PT J AU Chen, ZC Schneerson, R Lovchik, JA Dai, ZD Kubler-Kielb, J Agulto, L Leppla, SH Purcell, RH AF Chen, Zhaochun Schneerson, Rachel Lovchik, Julie A. Dai, Zhongdong Kubler-Kielb, Joanna Agulto, Liane Leppla, Stephen H. Purcell, Robert H. TI Bacillus anthracis Capsular Conjugates Elicit Chimpanzee Polyclonal Antibodies That Protect Mice from Pulmonary Anthrax SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID GLUTAMIC ACID CAPSULE; MONOCLONAL-ANTIBODIES; VACCINE DEVELOPMENT; ANTIGEN; TOXIN; IMMUNOGENICITY; INFECTION; EFFICACY; VIRUS; DISSEMINATION AB The immunogenicity of Bacillus anthracis capsule (poly-gamma-D-glutamic acid [PGA]) conjugated to recombinant B. anthracis protective antigen (rPA) or to tetanus toxoid (TT) was evaluated in two anthrax-naive juvenile chimpanzees. In a previous study of these conjugates, highly protective monoclonal antibodies (MAbs) against PGA were generated. This study examines the polyclonal antibody response of the same animals. Preimmune antibodies to PGA with titers of >10(3) were detected in the chimpanzees. The maximal titer of anti-PGA was induced within 1 to 2 weeks following the 1st immunization, with no booster effects following the 2nd and 3rd immunizations. Thus, the anti-PGA response in the chimpanzees resembled a secondary immune response. Screening of sera from nine unimmunized chimpanzees and six humans revealed antibodies to PGA in all samples, with an average titer of 10(3). An anti-PA response was also observed following immunization with PGA-rPA conjugate, similar to that seen following immunization with rPA alone. However, in contrast to anti-PGA, preimmune anti-PA antibody titers and those following the 1st immunization were <= 300, with the antibodies peaking above 10(4) following the 2nd immunization. The polyclonal anti-PGA shared the MAb 11D epitope and, similar to the MAbs, exerted opsonophagocytic killing of B. anthracis. Most important, the PGA-TT-induced antibodies protected mice from a lethal challenge with virulent B. anthracis spores. Our data support the use of PGA conjugates, especially PGA-rPA targeting both toxin and capsule, as expanded-spectrum anthrax vaccines. C1 [Chen, Zhaochun; Agulto, Liane; Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Leppla, Stephen H.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Schneerson, Rachel; Dai, Zhongdong; Kubler-Kielb, Joanna] NICHHD, Program Dev & Mol Immun, NIH, Bethesda, MD 20892 USA. [Lovchik, Julie A.] Univ New Mexico, Dept Internal Med, Hlth Sci Ctr, Albuquerque, NM 87131 USA. RP Chen, ZC (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM zchen@niaid.nih.gov FU NIAID; NICHD; NIH FX This research was supported by the Intramural Research Programs of NIAID and NICHD, NIH. NR 37 TC 0 Z9 0 U1 4 U2 8 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 2015 VL 22 IS 8 BP 902 EP 908 DI 10.1128/CVI.00137-15 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CN8DR UT WOS:000358668600008 PM 26041039 ER PT J AU Jones, GC Dong, T Simone, CB Stinson, S AF Jones, Guy C. Dong, Tuo Simone, Charles B., II Stinson, Susan TI Are the Conclusions of Z11 Relevant to Community Practice? SO CLINICAL BREAST CANCER LA English DT Article DE Axillary; Breast-conservation therapy; Lymph node; Radiation therapy; Sentinel dissection ID NO AXILLARY DISSECTION; BREAST-CANCER; TRIAL; COMPLICATIONS; SURGEONS; Z0011; WOMEN AB We reviewed our own experience with Z11-eligible patients who did not undergo ALND to determine their survival and disease control outcomes. Our institution's 5-year OS for Z11-eligible patients closely resembled those from the Z11 trial and our 10-year data provide evidence of what to expect for Z11-enrolled patients with continued follow-up. Background: Findings of the American College of Surgeons Oncology Group (ACOSOG) Z11 trial have proven controversial, leaving physicians divided over which patients with positive sentinel lymph nodes (+SLNs) benefit from axillary lymph node dissection (ALND). We reviewed our experience at our institution with Z11-eligible patients who did not undergo ALND and explored factors that predicted for positive lymph nodes (+LNs) on ALND after 1 to 2 +SLNs to determine which patients benefit from adjuvant therapy. Materials and Methods: All breast cancer pathology reports from our institution containing the word "sentinel" between July 1998 and December 2001 were reviewed. We obtained follow-up information on patients meeting Z11 eligibility criteria who did not undergo ALND. We also compared pathological characteristics between patients with 1 to 2 +SLNs and +LNs on ALND to those with no further +LNs. Results: Of the 432 pathology reports reviewed, 38 were from patients meeting Z11 criteria who did not undergo ALND. At a median follow-up of 11.9 years, these patients had 5-year overall survival (OS) of 93.3% and 10-year OS of 79.3%. No patient had recurrent disease in the axilla. Of the 80 patients with 1 to 2 +SLNs who underwent ALND, tumors with +LNs on ALND were generally larger, nonductal histology, more likely to be estrogen receptor positive (ER+) and progesterone receptor positive (PR+), and less likely to be HER2(+). Conclusion: Our institution's 5-year OS (93.3%) for Z11-eligible patients closely resembled those from the Z11 trial (92.5%) and our 10-year data provide evidence of what to expect for Z11-enrolled patients with continued follow-up. Larger tumor, nonductal, ER+, PR+, and HER2- were predictive for further +LNs on ALND, which might reflect surgical bias. Published by Elsevier Inc. C1 [Jones, Guy C.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Dong, Tuo] Howard Univ, Coll Med, Washington, DC USA. [Simone, Charles B., II] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Stinson, Susan] Johns Hopkins Med, Suburban Hosp, Dept Radiat Oncol, Bethesda, MD USA. RP Jones, GC (reprint author), NCI, Ctr Canc Res, Radiat Oncol Branch, NIH, 10 Ctr Dr,MSC 1682,Bldg 10 CRC Room B2-3561, Bethesda, MD 20892 USA. EM guy.jones@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 11 TC 0 Z9 0 U1 1 U2 2 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1526-8209 EI 1938-0666 J9 CLIN BREAST CANCER JI Clin. Breast Cancer PD AUG PY 2015 VL 15 IS 4 BP 285 EP 288 DI 10.1016/j.clbc.2014.12.013 PG 4 WC Oncology SC Oncology GA CN9GV UT WOS:000358756200008 PM 25659905 ER PT J AU Roederer, M AF Roederer, Mario TI A proposal for unified flow cytometer parameter naming SO CYTOMETRY PART A LA English DT Editorial Material ID DATA FILE STANDARD C1 [Roederer, Mario] NIAID, Flow Cytometry Core & ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Roederer, M (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr,Room 5509, Bethesda, MD 20892 USA. EM Roederer@nih.gov NR 7 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD AUG PY 2015 VL 87A IS 8 BP 689 EP 691 DI 10.1002/cyto.a.22670 PG 3 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CN7VU UT WOS:000358643200002 PM 25929439 ER PT J AU Rubinow, DR Johnson, SL Schmidt, PJ Girdler, S Gaynes, B AF Rubinow, David R. Johnson, Sarah Lanier Schmidt, Peter J. Girdler, Susan Gaynes, Bradley TI EFFICACY OF ESTRADIOL IN PERIMENOPAUSAL DEPRESSION: SO MUCH PROMISE AND SO FEW ANSWERS SO DEPRESSION AND ANXIETY LA English DT Article DE hormone; depression; menopause; mood disorder; HRT ID QUALITY-OF-LIFE; HORMONE-REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; ESTROGEN-RECEPTOR-ALPHA; HEALTHY POSTMENOPAUSAL WOMEN; PITUITARY-ADRENAL AXIS; CORONARY-HEART-DISEASE; LONG-TERM OVARIECTOMY; FORCED SWIM TEST; MENSTRUAL-CYCLE AB BackgroundControversy regarding the antidepressant efficacy of hormone replacement therapy (HRT) stems almost from its inception and reflects the same methodological inconsistencies that have compromised efforts to determine whether the perimenopause is accompanied by an increase in mood symptoms or depression. Methodologic differences of note (other than study design) include menopausal state (perimenopause vs. postmenopause), determination of state (earlier studies used age as a proxy measure), baseline symptomatology (asymptomatic vs. depressive symptoms vs. syndromic depression), route of hormone administration (transdermal vs. oral), and symptom or syndrome measure. Zweifel and O'Brien's 1997 meta-analysis included 26 studies of the effects of menopausal HRT on depressed mood and revealed an overall effect size of 0.68. This moderate to large effect size, showing lower ratings of depressed mood in treated patients compared with controls, implicated HRT as a potential treatment of or prophylactic for depression in menopausal women. Since this publication, multiple studies have aimed to discern the relationship between HRT and menopausal mood. MethodsThe purpose of this systematic review is to examine the findings and quality of the evidence amassed since Zweifel and O'Brien's meta-analysis. ResultsOf the 24 studies meeting criteria for review, only five RCTs examined depressed subjects, and only two of the study samples were solely perimenopausal. ConclusionsOne can generalize from the studies reviewed here only with great caution, but there is little evidence to support the use of estradiol to improve mood in nondepressed patients (not surprisingly) and some evidence to support the antidepressant efficacy of estradiol in perimenopausal but not postmenopausal women. C1 [Rubinow, David R.; Johnson, Sarah Lanier; Girdler, Susan; Gaynes, Bradley] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Schmidt, Peter J.] NIMH, Behav Endocrinol Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Rubinow, DR (reprint author), Univ N Carolina, Sch Med, Dept Psychiat, Campus Box 7160, Chapel Hill, NC 27599 USA. EM david_rubinow@med.unc.edu NR 89 TC 5 Z9 6 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD AUG PY 2015 VL 32 IS 8 BP 539 EP 549 DI 10.1002/da.22391 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CN7NS UT WOS:000358621900001 PM 26130315 ER PT J AU Dashti, HS Follis, JL Smith, CE Tanaka, T Garaulet, M Gottlieb, DJ Hruby, A Jacques, PF Kiefte-de Jong, JC Lamon-Fava, S Scheer, FAJL Bartz, TM Kovanen, L Wojczynski, MK Frazier-Wood, AC Ahluwalia, TS Perala, MM Jonsson, A Muka, T Kalafati, IP Mikkila, V Ordovas, JM AF Dashti, Hassan S. Follis, Jack L. Smith, Caren E. Tanaka, Toshiko Garaulet, Marta Gottlieb, Daniel J. Hruby, Adela Jacques, Paul F. Kiefte-de Jong, Jessica C. Lamon-Fava, Stefania Scheer, Frank A. J. L. Bartz, Traci M. Kovanen, Leena Wojczynski, Mary K. Frazier-Wood, Alexis C. Ahluwalia, Tarunveer S. Perala, Mia-Maria Jonsson, Anna Muka, Taulant Kalafati, Ioanna P. Mikkila, Vera Ordovas, Jose M. CA CHARGE Nutr Study Grp TI Gene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits SO DIABETES CARE LA English DT Article ID FASTING PLASMA-GLUCOSE; TYPE-2 DIABETES RISK; METABOLIC SYNDROME; INSULIN-RESISTANCE; SLEEP DURATION; NORTH-AMERICAN; CLOCK; VARIANTS; OBESITY; ASSOCIATION AB OBJECTIVE Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations. RESEARCH DESIGN AND METHODS We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. RESULTS We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (>= 9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m(2) higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (>= 7 to < 9 h). CONCLUSIONS Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet-specifically higher carbohydrate and lower fat composition-and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants. C1 [Dashti, Hassan S.; Smith, Caren E.; Ordovas, Jose M.] Tufts Univ, Nutr & Genom Lab, Human Nutr Res Ctr, Jean Mayer US Dept Agr, Boston, MA 02111 USA. [Follis, Jack L.] Univ St Thomas, Dept Math Comp Sci & Cooperat Engn, Houston, TX 77006 USA. [Tanaka, Toshiko] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Garaulet, Marta] Univ Murcia, Dept Physiol, Murcia, Spain. [Gottlieb, Daniel J.; Scheer, Frank A. J. L.] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, Boston, MA 02115 USA. [Gottlieb, Daniel J.; Scheer, Frank A. J. L.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [Gottlieb, Daniel J.] VA Boston Healthcare Syst, Sleep Disorders Ctr, Boston, MA USA. [Hruby, Adela] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Jacques, Paul F.] Tufts Univ, Nutr Epidemiol Lab, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Kiefte-de Jong, Jessica C.; Muka, Taulant] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Kiefte-de Jong, Jessica C.] Leiden Univ Coll, Global Publ Hlth, The Hague, Netherlands. [Lamon-Fava, Stefania] Tufts Univ, Cardiovasc Nutr Lab, Human Nutr Res Ctr, Jean Mayer US Dept Agr, Boston, MA 02111 USA. [Bartz, Traci M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Bartz, Traci M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Kovanen, Leena] Natl Inst Hlth & Welf THL, Dept Mental Hlth & Subst Abuse Serv, Helsinki, Finland. [Wojczynski, Mary K.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Frazier-Wood, Alexis C.] ARS, USDA, Childrens Nutr Res Ctr, Dept Pediat,Baylor Coll Med, Houston, TX USA. [Ahluwalia, Tarunveer S.; Jonsson, Anna] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res,Sect Metab Genet, Copenhagen, Denmark. [Ahluwalia, Tarunveer S.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen Prospect Studies Asthma Childhood, Copenhagen, Denmark. [Ahluwalia, Tarunveer S.] Gentofte Univ Hosp, Danish Pediat Asthma Ctr, Copenhagen, Denmark. [Perala, Mia-Maria] Natl Inst Hlth & Welf THL, Dept Chron Dis Prevent, Helsinki, Finland. [Kalafati, Ioanna P.] Harokopio Univ, Dept Nutr & Dietet, Athens, Greece. [Mikkila, Vera] Univ Helsinki, Dept Food & Environm Sci, Div Nutr, Helsinki, Finland. [Mikkila, Vera] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Ordovas, Jose M.] Ctr Nacl Invest Cardiovasc CNIC, Dept Epidemiol, Madrid, Spain. [Ordovas, Jose M.] Inst Madrileno Estudios Avanzados Alimentac IMDEA, Madrid, Spain. RP Dashti, HS (reprint author), Tufts Univ, Nutr & Genom Lab, Human Nutr Res Ctr, Jean Mayer US Dept Agr, Boston, MA 02111 USA. EM hassan.dashti@tufts.edu RI Deloukas, Panos/B-2922-2013; OI Deloukas, Panos/0000-0001-9251-070X; Dashti, Hassan S/0000-0002-1650-679X; Kovanen, Leena/0000-0002-3552-124X; Mannisto, Satu/0000-0002-8668-3046; Kiefte-de Jong, Jessica/0000-0002-8136-0918; Jorgensen, Torben/0000-0001-9453-2830; Lahti, Jari/0000-0002-4310-5297; Linneberg, Allan/0000-0002-0994-0184 FU National Heart, Lung, and Blood Institute [HHSN268200800007C]; U.S. Department of Agriculture [58-1950-0-014]; American Heart Association [14BGIA18740011]; Academy of Finland [117787]; Italian Ministry of Health [ICS110.1/RF97.71]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; National Center for Advancing Translational Sciences [UL1TR000124]; National Institutes of Health [R21-DK-089378, R01-HL-094806]; [K08-HL-112845-01] FX Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant HHSN268200800007C. Support was provided by the U.S. Department of Agriculture, under agreement no. 58-1950-0-014, American Heart Association (grant 14BGIA18740011), Academy of Finland (grant 117787), Italian Ministry of Health (grant ICS110.1/RF97.71), National Institute of Diabetes and Digestive and Kidney Diseases (grant DK063491), National Center for Advancing Translational Sciences (grant UL1TR000124). C.E.S. is supported by K08-HL-112845-01. F.A.J.L.S. was supported in part by National Institutes of Health grants R21-DK-089378 and R01-HL-094806. Cohort-specific sources of support and acknowledgments are presented in Supplementary Table 1. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture. NR 40 TC 8 Z9 8 U1 1 U2 15 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 2015 VL 38 IS 8 BP 1456 EP 1466 DI 10.2337/dc14-2709 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CN8EY UT WOS:000358673200021 PM 26084345 ER PT J AU Pollett, S Nelson, MI Kasper, M Tinoco, Y Simons, M Romero, C Silva, M Lin, XD Halpin, RA Fedorova, N Stockwell, TB Wentworth, D Holmes, EC Bausch, DG AF Pollett, Simon Nelson, Martha I. Kasper, Matthew Tinoco, Yeny Simons, Mark Romero, Candice Silva, Marita Lin, Xudong Halpin, Rebecca A. Fedorova, Nadia Stockwell, Timothy B. Wentworth, David Holmes, Edward C. Bausch, Daniel G. TI Phylogeography of Influenza A(H3N2) Virus in Peru, 2010-2012 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID A VIRUSES; EPIDEMIOLOGIC DYNAMICS; MAXIMUM-LIKELIHOOD; GLOBAL MIGRATION; H1N1 INFLUENZA; H3N2 VIRUSES; PERSISTENCE; AMAZON; SURVEILLANCE; SEASONALITY AB It remains unclear whether lineages of influenza A(H3N2) virus can persist in the tropics and seed temperate areas. We used viral gene sequence data sampled from Peru to test this source sink model for a Latin American country. Viruses were obtained during 2010-2012 from influenza surveillance cohorts in Cusco, Tumbes, Puerto Maldonado, and Lima. Specimens positive for influenza A(H3N2) virus were randomly selected and underwent hemagglutinin sequencing and phylogeographic analyses. Analysis of 389 hemagglutinin sequences from Peru and 2,192 global se quences demonstrated interseasonal extinction of Peruvian lineages. Extensive mixing occurred with global clades, but some spatial structure was observed at all sites; this structure was weakest in Lima and Puerto Maldonado, indicating that these locations may experience greater viral traffic. The broad diversity and co-circulation of many simultaneous lineages of H3N2 virus in Peru suggests that this country should not be overlooked as a potential source for novel pandemic strains. C1 [Pollett, Simon] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Pollett, Simon; Kasper, Matthew; Tinoco, Yeny; Simons, Mark; Romero, Candice; Silva, Marita; Bausch, Daniel G.] US Naval Med Res Unit 6, Lima, Peru. [Pollett, Simon] Univ Sydney, Marie Bashir Inst, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney, NSW 2006, Australia. [Nelson, Martha I.] NIH, Bethesda, MD 20892 USA. [Nelson, Martha I.] Arizona State Univ, Tempe, AZ USA. [Lin, Xudong; Halpin, Rebecca A.; Fedorova, Nadia; Stockwell, Timothy B.; Wentworth, David] J Craig Venter Inst, Rockville, MD USA. [Bausch, Daniel G.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. RP Pollett, S (reprint author), US Naval Med Res Unit 6, Callao, Peru. EM spollett@med.usyd.edu.au OI Wentworth, David/0000-0002-5190-980X; Holmes, Edward/0000-0001-9596-3552 FU CDC; National Institutes of Health, Fogarty International Center; US Department of Defense Global Emerging Infections Surveillance [I0082_09_LI]; National Health and Medical Research Council fellowship from the Australian government [AF30] FX The study was funded by the CDC; the National Institutes of Health, Fogarty International Center; and the US Department of Defense Global Emerging Infections Surveillance (grant no. I0082_09_LI). Sequencing was performed by the J. Craig Venter Institute as a partner to the National Institute of Allergy and Infectious Disease's Influenza Genome Sequencing Project. E.C.H. is supported by a National Health and Medical Research Council fellowship from the Australian government (AF30). NR 36 TC 3 Z9 3 U1 1 U2 6 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD AUG PY 2015 VL 21 IS 8 BP 1330 EP 1338 DI 10.3201/eid2108.150084 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CN5GR UT WOS:000358458300007 PM 26196599 ER PT J AU Nelson, MI Schaefer, R Gava, D Cantao, ME Ciacci-Zanella, JR AF Nelson, Martha I. Schaefer, Rejane Gava, Danielle Cantao, Mauricio Egidio Ciacci-Zanella, Janice Reis TI Influenza A Viruses of Human Origin in Swine, Brazil SO EMERGING INFECTIOUS DISEASES LA English DT Article ID PANDEMIC H1N1 2009; TIME RT-PCR; PIGS; OUTBREAK; AMPLIFICATION; TRANSMISSION; REASSORTMENT; REVEALS; ARGENTINA; SAMPLES AB The evolutionary origins of the influenza A(H1N1)pdm09 virus that caused the first outbreak of the 2009 pandemic in Mexico remain unclear, highlighting the lack of swine surveillance in Latin American countries. Although Brazil has one of the largest swine populations in the world, influenza was not thought to be endemic in Brazil's swine until the major outbreaks of influenza A(H1N1)pdm09 in 2009. Through phylogenetic analysis of whole-genome sequences of influenza viruses of the H1N1, H1N2, and H3N2 subtypes collected in swine in Brazil during 2009-2012, we identified multiple previously uncharacterized influenza viruses of human seasonal H1N2 and H3N2 virus origin that have circulated undetected in swine for more than a decade. Viral diversity has further increased in Brazil through reassortment between co-circulating viruses, including A(H1N1)pdm09. The circulation of multiple divergent hemagglutinin lineages challenges the design of effective cross-protective vaccines and highlights the need for additional surveillance. C1 [Nelson, Martha I.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Schaefer, Rejane; Gava, Danielle; Cantao, Mauricio Egidio; Ciacci-Zanella, Janice Reis] EMBRAPA Swine & Poultry, Concordia, Brazil. RP Nelson, MI (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, 16 Ctr Dr,Rm 202, Bethesda, MD 20892 USA. EM nelsonma@mail.nih.gov RI Gava, Danielle/D-7230-2013 OI Gava, Danielle/0000-0002-1917-2633 FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [578102/2008-0]; EMBRAPA; Multinational Influenza Seasonal Mortality Study; Office of Pandemics and Emerging Threats at the US Department of Health and Human Services FX This work was financially supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq process no. 578102/2008-0) and EMBRAPA. This work was supported in part by the Multinational Influenza Seasonal Mortality Study, an ongoing international collaborative effort to understand influenza epidemiology and evolution, led by the Fogarty International Center, National Institutes of Health, with funding from Office of Pandemics and Emerging Threats at the US Department of Health and Human Services. NR 40 TC 8 Z9 8 U1 0 U2 7 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD AUG PY 2015 VL 21 IS 8 BP 1339 EP 1347 DI 10.3201/eid2108.141891 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CN5GR UT WOS:000358458300008 PM 26196759 ER PT J AU Parra, GI Green, KY AF Parra, Gabriel I. Green, Kim Y. TI Genome of Emerging Norovirus GII.17, United States, 2014 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID GASTROENTERITIS AB To determine whether the norovirus Strain GII.17 recently detected in Maryland, USA, (Hu/GII.17/Gaithersburg/2014/US) is spreading globally, we characterized the genome. High similarity with the norovirus GII.17 that caused recent outbreaks in Asia indicates that the same strain was present in the United States during the 2014-15 norovirus season (winter). C1 [Parra, Gabriel I.; Green, Kim Y.] NIH, Bethesda, MD 20892 USA. RP Parra, GI (reprint author), NIAID, Caliciviruses Sect, Infect Dis Lab, NIH, Room 6318,Bldg 50,50 South Dr, Bethesda, MD 20892 USA. EM gabriel_parra@hotmail.com OI Parra, Gabriel/0000-0002-1102-4740 FU Division of Intramural Research in the National Institute of Allergy and Infectious Diseases, NIH FX This research was funded by the Division of Intramural Research in the National Institute of Allergy and Infectious Diseases, NIH. NR 12 TC 30 Z9 31 U1 0 U2 3 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD AUG PY 2015 VL 21 IS 8 BP 1477 EP 1479 DI 10.3201/eid2108.150652 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CN5GR UT WOS:000358458300035 PM 26196235 ER PT J AU Protano, MA Xu, H Wang, GQ Polydorides, AD Dawsey, SM Cui, JS Xue, LY Zhang, F Quang, T Pierce, MC Shin, D Schwarz, RA Bhutani, MS Lee, M Parikh, N Hur, C Xu, WR Moshier, E Godbold, J Mitcham, J Hudson, C Richards-Kortum, RR Anandasabapathy, S AF Protano, Marion-Anna Xu, Hong Wang, Guiqi Polydorides, Alexandros D. Dawsey, Sanford M. Cui, Junsheng Xue, Liyan Zhang, Fan Quang, Timothy Pierce, Mark C. Shin, Dongsuk Schwarz, Richard A. Bhutani, Manoop S. Lee, Michelle Parikh, Neil Hur, Chin Xu, Weiran Moshier, Erin Godbold, James Mitcham, Josephine Hudson, Courtney Richards-Kortum, Rebecca R. Anandasabapathy, Sharmila TI Low-Cost High-Resolution Microendoscopy for the Detection of Esophageal Squamous Cell Neoplasia: An International Trial SO GASTROENTEROLOGY LA English DT Article DE Esophageal Neoplasm; Endoscopy; Early Detection of Cancer ID CONFOCAL LASER ENDOMICROSCOPY; RANDOMIZED CONTROLLED-TRIAL; IN-VIVO; BARRETTS-ESOPHAGUS; CARCINOMA; CANCER; CHINA; RISK; EPIDEMIOLOGY; LINXIAN AB BACKGROUND & AIMS: Esophageal squamous cell neoplasia has a high mortality rate as a result of late detection. In high-risk regions such as China, screening is performed by Lugol's chromoendoscopy (LCE). LCE has low specificity, resulting in unnecessary tissue biopsy with a subsequent increase in procedure cost and risk. The purpose of this study was to evaluate the accuracy of a novel, low-cost, high-resolution microendoscope (HRME) as an adjunct to LCE. METHODS: In this prospective trial, 147 consecutive high-risk patients were enrolled from 2 US and 2 Chinese tertiary centers. Three expert and 4 novice endoscopists performed white-light endoscopy followed by LCE and HRME. All optical images were compared with the gold standard of histopathology. RESULTS: By using a per-biopsy analysis, the sensitivity of LCE vs LCE + HRME was 96% vs 91% (P = .0832), specificity was 48% vs 88% (P < .001), positive predictive value was 22% vs 45% (P < .0001), negative predictive value was 98% vs 98% (P = .3551), and overall accuracy was 57% vs 90% (P < .001), respectively. By using a per-patient analysis, the sensitivity of LCE vs LCE + HRME was 100% vs 95% (P = .16), specificity was 29% vs 79% (P < .001), positive predictive value was 32% vs 60%, 100% vs 98%, and accuracy was 47% vs 83% (P < .001). With the use of HRME, 136 biopsies (60%; 95% confidence interval, 53%-66%) could have been spared, and 55 patients (48%; 95% confidence interval, 38%-57%) could have been spared any biopsy. CONCLUSIONS: In this trial, HRME improved the accuracy of LCE for esophageal squamous cell neoplasia screening and surveillance. HRME may be a cost-effective optical biopsy adjunct to LCE, potentially reducing unnecessary biopsies and facilitating real-time decision making in globally underserved regions. ClinicalTrials.gov, NCT 01384708. C1 [Protano, Marion-Anna; Lee, Michelle; Mitcham, Josephine; Hudson, Courtney; Anandasabapathy, Sharmila] Mt Sinai Med Ctr, Div Gastroenterol, New York, NY 10029 USA. [Polydorides, Alexandros D.] Mt Sinai Med Ctr, Dept Pathol, New York, NY 10029 USA. [Moshier, Erin; Godbold, James] Mt Sinai Med Ctr, Dept Preventat Med, New York, NY 10029 USA. [Xu, Hong; Zhang, Fan; Xu, Weiran] Jilin Univ, Dept Endoscopy, Hosp 1, Changchun, Jilin, Peoples R China. [Cui, Junsheng] Jilin Univ, Dept Pathol, Hosp 1, Changchun, Jilin, Peoples R China. [Wang, Guiqi] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Endoscopy, Beijing 100730, Peoples R China. [Xue, Liyan] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Pathol, Beijing 100730, Peoples R China. [Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Quang, Timothy; Shin, Dongsuk; Schwarz, Richard A.; Richards-Kortum, Rebecca R.] Rice Univ, Dept Bioengn, Houston, TX USA. [Pierce, Mark C.] Rutgers State Univ, Biomed Engn, Piscataway, NJ USA. [Bhutani, Manoop S.] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA. [Parikh, Neil] Yale Univ, Div Digest Dis, New Haven, CT USA. [Hur, Chin] Massachusetts Gen Hosp, GI Unit, Boston, MA 02114 USA. [Hur, Chin] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. RP Anandasabapathy, S (reprint author), Baylor Global Initiat, Dept Med & Gastroenterol, One Baylor Plaza, Houston, TX 77030 USA. EM Sharmila.Anandasabapathy@bcm.edu OI Hur, Chin/0000-0002-2819-7576 FU [NCI R21 CA156704] FX Supported by grant NCI R21 CA156704 and ClinicalTrials.gov, NCT 01384708. NR 42 TC 1 Z9 2 U1 1 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2015 VL 149 IS 2 BP 321 EP 329 DI 10.1053/j.gastro.2015.04.055 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CN4VX UT WOS:000358429600025 PM 25980753 ER PT J AU Bharucha, AE Batey-Schaefer, B Cleary, PA Murray, JA Cowie, C Lorenzi, G Driscoll, M Harth, J Larkin, M Christofi, M Bayless, M Wimmergren, N Herman, W Whitehouse, F Jones, K Kruger, D Martin, C Ziegler, G Zinsmeister, AR Nathan, DM AF Bharucha, Adil E. Batey-Schaefer, Barbara Cleary, Patricia A. Murray, Joseph A. Cowie, Catherine Lorenzi, Gayle Driscoll, Marsha Harth, Judy Larkin, Mary Christofi, Marielle Bayless, Margaret Wimmergren, Nyra Herman, William Whitehouse, Fred Jones, Kim Kruger, Davida Martin, Cathy Ziegler, Georgia Zinsmeister, Alan R. Nathan, David M. CA Diabet Control Complications TI Delayed Gastric Emptying Is Associated With Early and Long-term Hyperglycemia in Type 1 Diabetes Mellitus SO GASTROENTEROLOGY LA English DT Article DE Diabetic Gastroparesis; HbA1c; Glycemic Control; Neuropathy ID CARDINAL SYMPTOM INDEX; UPPER GASTROINTESTINAL DISORDERS; COMPLICATIONS TRIAL COHORT; ISOTOPE BREATH TEST; GLYCEMIC CONTROL; MICROVASCULAR COMPLICATIONS; FUNCTIONAL DYSPEPSIA; DAILY DIARY; GASTROPARESIS; INTERVENTIONS AB BACKGROUND & AIMS: After the Diabetes Control and Complications Trial (DCCT), the Epidemiology of Diabetes Interventions and Complications (EDIC) study continued to show persistent benefit of prior intensive therapy on neuropathy, retinopathy, and nephropathy in type 1 diabetes mellitus (DM). The relationship between control of glycemia and gastric emptying (GE) is unclear. METHODS: We assessed GE with a C-13-spirulina breath test and symptoms in 78 participants with type 1 diabetes at year 20 of EDIC. The relationship between delayed GE and glycated hemoglobin (HbA1c), complications of DM, and gastrointestinal symptoms were evaluated. RESULTS: GE was normal (37 participants; 50%), delayed (35 participants; 47%), or rapid (2 participants; 3%). The latest mean HbA1c was 7.7%. In univariate analyses, delayed GE was associated with greater DCCT baseline HbA1c and duration of DM before DCCT (P < .04), greater mean HbA1c over an average of 27 years of follow-up evaluation (during DCCT-EDIC, P = .01), lower R-R variability during deep breathing (P = .03) and severe nephropathy (P = .05), and a greater composite upper gastrointestinal symptom score (P < .05). In multivariate models, retinopathy was the only complication of DM associated with delayed GE. Separately, DCCT baseline HbA1c (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.3) and duration of DM (OR, 1.2; 95% CI, 1.01-1.3) before DCCT entry and mean HbA1c during DCCT-EDIC (OR, 2.2; 95% CI, 1.04-4.5) were associated independently with delayed GE. CONCLUSIONS: In the DCCT/EDIC study, delayed GE was remarkably common and associated with gastrointestinal symptoms and with measures of early and long-term hyperglycemia. ClinicalTrials.gov numbers NCT00360815 and NCT00360893. C1 [Bharucha, Adil E.; Murray, Joseph A.] Mayo Clin, Div Gastroentrol & Hepatol, Rochester, MN 55905 USA. [Ziegler, Georgia] Mayo Clin, Div Endocrinol, Rochester, MN 55905 USA. [Zinsmeister, Alan R.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Batey-Schaefer, Barbara] Northwestern Univ, Div Endocrinol, Chicago, IL 60611 USA. [Cleary, Patricia A.] George Washington Univ, Biostat Ctr, Washington, DC 20052 USA. [Cowie, Catherine] NIDDK, Div Diabet Endocrinol & Metab Dis, Washington, DC USA. [Lorenzi, Gayle] Univ Calif San Diego, Div Endocrinol, San Diego, CA 92103 USA. [Driscoll, Marsha; Harth, Judy] Univ Western Ontario, Div Endocrinol, London, ON, Canada. [Larkin, Mary; Christofi, Marielle; Nathan, David M.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. [Bayless, Margaret] Univ Iowa, Gen Hosp, Div Endocrinol, Iowa City, IA USA. [Wimmergren, Nyra] Univ Minnesota, Div Endocrinol, Minneapolis, MN USA. [Herman, William; Martin, Cathy] Univ Michigan, Div Endocrinol, Ann Arbor, MI 48109 USA. [Whitehouse, Fred; Jones, Kim; Kruger, Davida] Henry Ford Medical New Ctr One, Dept Endocrinol, Detroit, MI USA. RP Bharucha, AE (reprint author), Mayo Clin, Div Gastroentrol & Hepatol, 200 First St SW, Rochester, MN 55905 USA. EM bharucha.adil@mayo.edu FU Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease [U01 DK094176, U01 DK094157]; National Eye Institute; National Institute of Neurologic Disorders and Stroke; General Clinical Research Centers Program; Clinical Translational Science Center Program, Bethesda, Maryland; US Public Health Service National Institutes of Health [P01 DK068055] FX The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications has been supported by cooperative agreement grants (1982-1993 and 2012-2017), and contracts (1982-2012) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease (current grant numbers U01 DK094176 and U01 DK094157), and through support by the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the General Clinical Research Centers Program (1993-2007), and the Clinical Translational Science Center Program (2006 to present), Bethesda, Maryland. This ancillary study was supported in part by US Public Health Service National Institutes of Health grant P01 DK068055 (A.E.B.). NR 47 TC 10 Z9 10 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2015 VL 149 IS 2 BP 330 EP 339 DI 10.1053/j.gastro.2015.05.007 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CN4VX UT WOS:000358429600026 PM 25980755 ER PT J AU Talley, NJ Locke, GR Saito, YA Almazar, AE Bouras, EP Howden, CW Lacy, BE DiBaise, JK Prather, CM Abraham, BP El-Serag, HB Moayyedi, P Herrick, LM Szarka, LA Camilleri, M Hamilton, FA Schleck, CD Tilkes, KE Zinsmeister, AR AF Talley, Nicholas J. Locke, G. Richard Saito, Yuri A. Almazar, Ann E. Bouras, Ernest P. Howden, Colin W. Lacy, Brian E. DiBaise, John K. Prather, Charlene M. Abraham, Bincy P. El-Serag, Hashem B. Moayyedi, Paul Herrick, Linda M. Szarka, Lawrence A. Camilleri, Michael Hamilton, Frank A. Schleck, Cathy D. Tilkes, Katherine E. Zinsmeister, Alan R. TI Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: A Multicenter, Randomized Controlled Study SO GASTROENTEROLOGY LA English DT Article DE Functional Dyspepsia; Abdominal Pain; Functional Gastrointestinal Disorder; Antidepressant ID IRRITABLE-BOWEL-SYNDROME; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; PERFORMANCE-CHARACTERISTICS; NEPEAN DYSPEPSIA; ADEQUATE RELIEF; CLINICAL-TRIAL; END-POINT; SYMPTOMS; ANTIDEPRESSANTS AB BACKGROUND & AIMS: Antidepressants are frequently prescribed to treat functional dyspepsia (FD), a common disorder characterized by upper abdominal symptoms, including discomfort or postprandial fullness. However, there is little evidence of the efficacy of these drugs in patients with FD. We performed a randomized, double-blind, placebo-controlled trial to evaluate the effects of antidepressant therapy on symptoms, gastric emptying (GE), and meal-induced satiety in patients with FD. METHODS: We performed a study at 8 North American sites of patients who met the Rome II criteria for FD and did not have depression or use antidepressants. Patients (n = 292; 44 +/- 15 years old, 75% were female, 70% with dysmotility-like FD, and 30% with ulcer-like FD) were randomly assigned to groups given placebo, 50 mg amitriptyline, or 10 mg escitalopram for 10 weeks. The primary end point was adequate relief of FD symptoms for >= 5 weeks of the last 10 weeks (of 12). Secondary end points included GE time, maximum tolerated volume in Nutrient Drink Test, and FD-related quality of life. RESULTS: An adequate relief response was reported by 39 subjects given placebo (40%), 51 given amitriptyline (53%), and 37 given escitalopram (38%) (P = .05, after treatment, adjusted for baseline balancing factors including all subjects). Subjects with ulcer-like FD given amitriptyline were >3-fold more likely to report adequate relief than those given placebo (odds ratio = 3.1; 95% confidence interval: 1.1-9.0). Neither amitriptyline nor escitalopram appeared to affect GE or meal-induced satiety after the 10-week period in any group. Subjects with delayed GE were less likely to report adequate relief than subjects with normal GE (odds ratio = 0.4; 95% confidence interval: 0.2-0.8). Both antidepressants improved overall quality of life. CONCLUSIONS: Amitriptyline, but not escitalopram, appears to benefit some patients with FD, particularly those with ulcer-like (painful) FD. Patients with delayed GE do not respond to these drugs. ClinicalTrials.gov ID: NCT00248651. C1 [Talley, Nicholas J.; Locke, G. Richard; Saito, Yuri A.; Almazar, Ann E.; Herrick, Linda M.; Szarka, Lawrence A.; Camilleri, Michael; Tilkes, Katherine E.] Mayo Clin, Gastroenterol & Hepatol, Rochester, MN USA. [Talley, Nicholas J.] Univ Newcastle, Fac Hlth & Med, Callaghan, NSW 2308, Australia. [Bouras, Ernest P.] Mayo Clin, Gastroenterol & Hepatol, Jacksonville, FL 32224 USA. [Howden, Colin W.] Northwestern Univ, Gastroenterol, Chicago, IL 60611 USA. [Lacy, Brian E.] Dartmouth Hitchcock Med Ctr, Gastroenterol & Hepatol, Lebanon, NH 03766 USA. [DiBaise, John K.] Mayo Clin, Gastroenterol & Hepatol, Scottsdale, AZ USA. [Prather, Charlene M.] St Louis Univ, Gastroenterol, St Louis, MO 63103 USA. [Abraham, Bincy P.; El-Serag, Hashem B.] Baylor Coll Med, Gastroenterol & Hepatol, Houston, TX 77030 USA. [Moayyedi, Paul] McMaster Univ, Gastroenterol, Hamilton, ON, Canada. [Hamilton, Frank A.] NIDDK, Div Digest Dis & Nutr, Bethesda, MD USA. [Schleck, Cathy D.; Zinsmeister, Alan R.] Mayo Clin, Biomed Stat & Informat, Rochester, MN USA. RP Talley, NJ (reprint author), Univ Newcastle, Fac Hlth & Med, Bowman Bldg, Callaghan, NSW 2308, Australia. EM Nicholas.Talley@newcastle.edu.au FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [DK065713] FX This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (DK065713). Forest Pharmaceuticals provided the escitalopram and identical placebo for the study. NR 40 TC 25 Z9 30 U1 2 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 2015 VL 149 IS 2 BP 340 EP + DI 10.1053/j.gastro.2015.04.020 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CN4VX UT WOS:000358429600027 PM 25921377 ER PT J AU Angulo, P Kleiner, DE Dam-Larsen, S Adams, LA Bjornsson, ES Charatcharoenwitthaya, P Mills, PR Keach, JC Lafferty, HD Stahler, A Haflidadottir, S Bendtsen, F AF Angulo, Paul Kleiner, David E. Dam-Larsen, Sanne Adams, Leon A. Bjornsson, Einar S. Charatcharoenwitthaya, Phunchai Mills, Peter R. Keach, Jill C. Lafferty, Heather D. Stahler, Alisha Haflidadottir, Svanhildur Bendtsen, Flemming TI Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease SO GASTROENTEROLOGY LA English DT Article DE NASH; Prognosis; PRELHIN Study; Prediction ID CLINICAL-RESEARCH NETWORK; NATURAL-HISTORY; PORTAL-HYPERTENSION; FOLLOW-UP; STEATOHEPATITIS; NAFLD; PROGRESSION; INFLAMMATION; MORTALITY; CIRRHOSIS AB BACKGROUND & AIMS: Histologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD. METHODS: We performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were examined every 3-12 months after their diagnosis. Outcomes analyzed were overall mortality, liver transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HRs). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination. RESULTS: Over a median follow-up period of 12.6 years (range, 0.3-35.1 y), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% confidence interval [CI], 1.28-2.77), stage 2 (HR, 2.89; 95% CI, 1.93-4.33), stage 3 (HR, 3.76; 95% CI, 2.40-5.89), and stage 4 (HR, 10.9; 95% CI, 6.06-19.62) compared with stage 0, as well as age (HR, 1.07; 95% CI, 1.05-1.08), diabetes (HR, 1.61; 95% CI, 1.13-2.30), current smoking (HR, 2.62; 95% CI, 1.67-4.10), and statin use (HR, 0.32; 95% CI, 0.14-0.70). Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR, 14.2; 95% CI, 3.38-59.68) and stage 4 (HR, 51.5; 95% CI, 9.87-269.2) compared with stage 0, were associated significantly with the events. Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis. CONCLUSIONS: In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events. C1 [Angulo, Paul] Univ Kentucky, Med Ctr, Div Digest Dis & Nutr, Lexington, KY USA. [Kleiner, David E.] Natl Canc Inst, Pathol Lab, Bethesda, MD 20892 USA. [Dam-Larsen, Sanne] Koege Univ Hosp, Dept Med, Koege, Denmark. [Adams, Leon A.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Bjornsson, Einar S.] Univ Iceland, Natl Univ Hosp, Fac Med, Sect Gastroenterol & Hepatol, Reykjavik, Iceland. [Charatcharoenwitthaya, Phunchai] Mahidol Univ, Siriraj Hosp, Fac Med, Bangkok 10700, Thailand. [Mills, Peter R.; Lafferty, Heather D.] Gartnavel Royal Hosp, Glasgow, Lanark, Scotland. [Keach, Jill C.; Stahler, Alisha] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Haflidadottir, Svanhildur] Oslo Univ Hosp, Rikshosp, Dept Pediat, Oslo, Norway. [Bendtsen, Flemming] Univ Copenhagen, Hvidovre Hosp, Dept Gastroenterol, Copenhagen, Denmark. [Bendtsen, Flemming] Univ Copenhagen, Hvidovre Hosp, Fac Hlth Sci, Copenhagen, Denmark. RP Kleiner, DE (reprint author), Natl Canc Inst, Pathol Lab, Bldg 10,Room 2S235,MSC 1500,10 Ctr Dr, Bethesda, MD 20892 USA. EM kleinerd@mail.nih.gov FU National Institute of Health [R01 DK82426]; National Institutes of Health, National Cancer Institute FX Supported by a National Institute of Health R01 DK82426 grant. This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The sponsor played no role in the study design or the collection, analysis, and interpretation of data. NR 26 TC 129 Z9 130 U1 10 U2 18 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 2015 VL 149 IS 2 BP 389 EP + DI 10.1053/j.gastro.2015.04.043 PG 19 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CN4VX UT WOS:000358429600032 PM 25935633 ER PT J AU Ji, JL Eggert, T Budhu, A Forgues, M Takai, A Dang, H Ye, QH Lee, JS Kim, JH Greten, TF Wang, XW AF Ji, Juling Eggert, Tobias Budhu, Anuradha Forgues, Marshonna Takai, Atsushi Dang, Hien Ye, Qinghai Lee, Ju-Seog Kim, Ji Hoon Greten, Tim F. Wang, Xin Wei TI Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma SO HEPATOLOGY LA English DT Article ID SUPPRESSOR-CELLS; GENE-EXPRESSION; LIVER FIBROSIS; IMMUNE-RESPONSE; CANCER; METASTASIS; PREDICTION; SURVIVAL; MICROENVIRONMENT; PROTEIN-1 AB Hepatocellular carcinoma (HCC) patients suffer from a poor survival rate and a high incidence of postoperative recurrence. The hepatic microenvironment plays a significant role in the initiation, progression, and recurrence of HCC; however, the causal mechanisms of these phenomena are unclear. Given the predominant underlying fibrotic and cirrhotic conditions of the liver prone to HCC and its recurrence, alterations of components of the inflammatory milieu have been suggested as factors that promote HCC development. In particular, activated hepatic stellate cells (A-HSCs), which play a key role in liver fibrosis and cirrhosis, have been suggested as contributors to the HCC-prone microenvironment. Here, we have identified and validated an A-HSC-specific gene expression signature among nontumor tissues of 319 HCC patients that is significantly and independently associated with HCC recurrence and survival. Peritumoral, rather than tumor tissue-related, A-HSC-specific gene expression is associated with recurrence and poor survival. Analyses of A-HSC-specific gene signatures and further immunohistochemical validation in an additional 143 HCC patients have revealed that A-HSCs preferentially affect monocyte populations, shifting their gene expression from an inflammatory to an immunosuppressive signature. In addition, the interaction between A-HSCs and monocytes induces protumorigenic and progressive features of HCC cells by enhancing cell migration and tumor sphere formation. Conclusion: A-HSCs play a significant role in promoting HCC progression through interaction with and alteration of monocyte activities within the liver microenvironment; thus, disrupting the interactions and signaling events between the inflammatory milieu and components of the microenvironment may be useful therapeutic strategies for preventing HCC tumor relapse. (Hepatology 2015;62:481-495 C1 [Ji, Juling; Budhu, Anuradha; Forgues, Marshonna; Takai, Atsushi; Dang, Hien; Wang, Xin Wei] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Ji, Juling] Nantong Univ, Sch Med, Dept Pathol, Nantong, Peoples R China. [Eggert, Tobias; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Ye, Qinghai] Fudan Univ, Liver Canc Inst, Shanghai 200032, Peoples R China. [Lee, Ju-Seog] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Kim, Ji Hoon] Korea Univ, Coll Med, Dept Internal Med, Div Gastroenterol & Hepatol, Seoul 136705, South Korea. RP Wang, XW (reprint author), NCI, 37 Convent Dr,Bldg 37,Rm 3044A, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI Wang, Xin/B-6162-2009 FU Intramural NIH HHS [Z01 BC010313-09, Z01 BC010313-10]; NCI NIH HHS [P30 CA016672, Z01 BC010313, Z01 BC010876, Z01 BC010877, Z01-BC 010313, Z01-BC010877] NR 46 TC 9 Z9 10 U1 2 U2 17 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 2015 VL 62 IS 2 BP 481 EP 495 DI 10.1002/hep.27822 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CN5EX UT WOS:000358453700020 PM 25833323 ER PT J AU Chakraborty, M Fullerton, AM Semple, K Chea, LS Proctor, WR Bourdi, M Kleiner, DE Zeng, XB Ryan, PM Dagur, PK Berkson, JD Reilly, TP Pohl, LR AF Chakraborty, Mala Fullerton, Aaron M. Semple, Kenrick Chea, Lynette S. Proctor, William R. Bourdi, Mohammed Kleiner, David E. Zeng, Xiangbin Ryan, Pauline M. Dagur, Pradeep K. Berkson, Julia D. Reilly, Timothy P. Pohl, Lance R. TI Drug-induced allergic hepatitis develops in mice when myeloid-derived suppressor cells are depleted prior to halothane treatment SO HEPATOLOGY LA English DT Article ID INDUCED LIVER-INJURY; ANTIBODIES; PATHOGENESIS; ACTIVATION; EOSINOPHILS; NEUTROPHILS; ADDUCTS; MEDIATE; MODELS; ASTHMA AB Clinical evidence suggests that many cases of serious idiosyncratic drug-induced liver injury are mediated by the adaptive immune system in response to hepatic drug-protein adducts, also referred to as drug-induced allergic hepatitis; but detailed mechanistic proof has remained elusive due to the lack of animal models. We have hypothesized that drug-induced allergic hepatitis is as rare in animals as it is in humans due at least in part to the tolerogenic nature of the liver. We provide evidence that immune tolerance can be overcome in a murine model of halothane-induced liver injury initiated by trifluoroacetylated protein adducts of halothane formed in the liver. Twenty-four hours after female Balb/cJ mice were initially treated with halothane, perivenous necrosis and an infiltration of CD11b(+)Gr-1(high) cells were observed in the liver. Further study revealed a subpopulation of myeloid-derived suppressor cells within the CD11b(+)Gr-1(high) cell fraction that inhibited the proliferation of both CD4(+) and CD8(+) T cells. When CD11b(+)Gr-1(high) cells were depleted from the liver with Gr-1 antibody treatment, enhanced liver injury was observed at 9 days after halothane rechallenge. Toxicity was associated with increased serum levels of interleukin-4 and immunoglobulins G1 and E directed against hepatic trifluoroacetylated protein adducts, as well as increased hepatic infiltration of eosinophils and CD4(+) T cells, all features of an allergic reaction. When hepatic CD4(+) T cells were depleted 5 days after halothane rechallenge, trifluoroacetylated protein adduct-specific serum immunoglobulin and hepatotoxicity were reduced. Conclusion: Our data provide a rational approach for developing animal models of drug-induced allergic hepatitis mediated by the adaptive immune system and suggest that impaired liver tolerance may predispose patients to this disease. (Hepatology 2015;62:546-557 C1 [Chakraborty, Mala; Fullerton, Aaron M.; Semple, Kenrick; Chea, Lynette S.; Proctor, William R.; Bourdi, Mohammed; Zeng, Xiangbin; Ryan, Pauline M.; Berkson, Julia D.; Pohl, Lance R.] NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Dagur, Pradeep K.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Reilly, Timothy P.] Bristol Myers Squibb Co, Exploratory Clin & Translat Res, Princeton, NJ USA. RP Pohl, LR (reprint author), NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, Bldg 10,Room 8N110,10 Ctr Dr, Bethesda, MD 20892 USA. EM pohll@nhlbi.nih.gov NR 37 TC 8 Z9 8 U1 0 U2 5 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 2015 VL 62 IS 2 BP 546 EP 557 DI 10.1002/hep.27764 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CN5EX UT WOS:000358453700025 PM 25712247 ER PT J AU Tashima, KT Mollan, KR Na, L Gandhi, RT Klingman, KL Fichtenbaum, CJ Andrade, A Johnson, VA Eron, JJ Smeaton, L Haubrich, RH AF Tashima, Karen T. Mollan, Katie R. Na, Lumine Gandhi, Rajesh T. Klingman, Karin L. Fichtenbaum, Carl J. Andrade, Adriana Johnson, Victoria A. Eron, Joseph J. Smeaton, Laura Haubrich, Richard H. TI Regimen selection in the OPTIONS trial of HIV salvage therapy: drug resistance, prior therapy, and race-ethnicity determine the degree of regimen complexity SO HIV CLINICAL TRIALS LA English DT Article DE HIV drug resistance; Treatment-experienced; Phenotypic susceptibility score; Tropism; cPSS; Antiretroviral therapy ID TREATMENT-EXPERIENCED PATIENTS; SOCIETY-USA PANEL; PHENOTYPIC SUSCEPTIBILITY; PROTEASE INHIBITORS; INFECTION; EFFICACY; LAMIVUDINE; RITONAVIR; SAFETY; RECOMMENDATIONS AB Background: Regimen selection for highly treatment-experienced patients is complicated. Methods: Using a web-based utility, study team members reviewed antiretroviral (ARV) history and resistance data and recommended individual ARV regimens and nucleoside reverse transcriptase inhibitor (NRTI) options for treatment-experienced participants consisting of 3-4 of the following agents: raltegravir (RAL), darunavir (DRV)/ritonavir, tipranavir (TPV)/ritonavir, etravirine (ETR), maraviroc (MVC), and enfuvirtide (ENF). We evaluated team recommendations and site selection of regimen and NRTIs. Associations between baseline factors and the selection of a complex regimen (defined as including four ARV agents or ENF) were explored with logistic regression. Results: A total of 413 participants entered the study. Participants initiated the first or second recommended regimen 86% of the time and 21% of participants started a complex regimen. In a multivariable model, ARV resistance to NRTI (odds ratio [OR] =2.2), non-nucleoside reverse transcriptase inhibitor (NNRTI, OR=6.2) or boosted protease inhibitor (PI, OR=6.6), prior use of integrase strand transfer inhibitor (INSTI, OR=25), and race-ethnicity (all P <= 0.01) were associated with selection of a complex regimen. Black non-Hispanic (OR=0.5) and Hispanic participants from the continental US (OR=0.2) were less likely to start a complex regimen, compared to white non-Hispanics. Conclusions: In this multi-center trial, we developed a web-based utility that facilitated treatment recommendations for highly treatment-experienced patients. Drug resistance, prior INSTI use, and race-ethnicity were key factors in decisions to select a more complex regimen. C1 [Tashima, Karen T.] Brown Univ, Warren Alpert Med Sch, Miriam Hosp, Providence, RI 02906 USA. [Mollan, Katie R.; Na, Lumine; Smeaton, Laura] Harvard Univ, TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Mollan, Katie R.] Univ N Carolina, Chapel Hill, NC USA. [Gandhi, Rajesh T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gandhi, Rajesh T.] Ragon Inst, Boston, MA USA. [Klingman, Karin L.] NIAID, HIV Res Branch TRP, DAIDS, NIH, Bethesda, MD 20892 USA. [Fichtenbaum, Carl J.] Univ Cincinnati, Cincinnati, OH 45267 USA. [Andrade, Adriana] Johns Hopkins Univ, Baltimore, MD USA. [Johnson, Victoria A.] Birmingham VA Med Ctr, Birmingham, AL USA. [Johnson, Victoria A.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Eron, Joseph J.] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Haubrich, Richard H.] Gilead Sci Inc, Foster City, CA USA. [Haubrich, Richard H.] Univ Calif San Diego, La Jolla, CA 92093 USA. RP Tashima, KT (reprint author), Brown Univ, Warren Alpert Med Sch, Miriam Hosp, 164 Summit Ave, Providence, RI 02906 USA. EM ktashima@lifespan.org; fichtecj@ucmail.uc.edu FU National Institute of Allergy and Infectious Diseases (NIAID) [UM1AI068636]; National Institute of Mental Health (NIMH); National Institute of Dental and Craniofacial Research (NIDCR); NIAID [AI68634]; National Institutes of Health (NIH) [UM1 AI 069412, P30 AI042853, P30 AI50410, AI 064086, AI 069432, AI 36214, K24, R01 AI066992-04A1]; AIDS Clinical Trials Group [NIH U01 AI 694722, UM1 AI069501]; Harvard University Center for AIDS Research [NIH 2P30 AI060354-06] FX The project described was supported by Award Number UM1AI068636 from the National Institute of Allergy and Infectious Diseases (NIAID) and supported by National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID or the National Institutes of Health. The work was also supported by the Statistical and Data Management Center (SDMC) grant [AI68634] from the NIAID. Boehringer-Ingelheim, Hoffmann-La Roche, Janssen, Merck, and Pfizer provided study medications and Monogram Biosciences provided HIV genotype and phenotype resistance and HIV tropism testing. KTT: UM1 AI 069412 and P30 AI042853 (Lifespan/Tufts/Brown CFAR), P30 AI50410 (UNC-KM), AI 064086 (K24 to RH), AI 069432 (UCSD ACTU), AI 36214 (UCSD CFAR Clinical Investigation and Biostatistics Core) RTG is supported by National Institutes of Health (NIH) [R01 AI066992-04A1] and by grants to the AIDS Clinical Trials Group (NIH U01 AI 694722) and the Harvard University Center for AIDS Research (NIH 2P30 AI060354-06). CJF is supported by UM1 AI069501 from the AIDS Clinical Trials Group. NR 20 TC 1 Z9 1 U1 0 U2 15 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1528-4336 EI 1945-5771 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD AUG PY 2015 VL 16 IS 4 BP 147 EP 156 DI 10.1179/1945577115Y.0000000001 PG 10 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA CN8ZB UT WOS:000358733700004 PM 26212575 ER PT J AU Resnik, DB AF Resnik, David B. TI Retracting Inconclusive Research: Lessons from the S,ralini GM Maize Feeding Study SO JOURNAL OF AGRICULTURAL & ENVIRONMENTAL ETHICS LA English DT Article DE Genetically modified foods; Retraction; Peer review; Ethics; Scientific methodology ID GENETICALLY-MODIFIED MAIZE; LONG-TERM TOXICITY; SPRAGUE-DAWLEY RATS; SERALINI ET-AL.; ROUNDUP HERBICIDE; CORN AB In September 2012, Gilles-Eric S,ralini and seven coauthors published an article in Food and Chemical Toxicology claiming that rats fed RoundupA (c)-resistant genetically modified maize alone, genetically modified maize with RoundupA (c), or RoundupA (c) for 2 years had a higher percentage of tumors and kidney and liver damage than normal controls. Shortly after this study was published, numerous scientists and several scientific organizations criticized the research as methodologically and ethically flawed. In January 2014, the journal retracted the article without the authors' consent on the grounds that the research was inconclusive. In June 2014, Environmental Sciences Europe published a slightly modified version of the retracted paper. The publication, retraction and subsequent republication of the S,ralini study raise important scientific and ethical issues for journal editors. Decisions to retract an article should be made on the basis of well-established policies. Articles should be retracted only for serious errors that undermine the reliability of the data or results, or for serious ethical lapses, such as research misconduct or mistreatment of animal or human subjects. Inconclusiveness, by itself, is not a sufficient reason for retracting an article, though a flawed study design might be. Retracted articles that are submitted for republication should undergo scientific review to ensure that they meet appropriate standards. Republished articles should be linked to the original, retracted publication. Journals that are reviewing studies with significant scientific and social implications should take special care to ensure that peer review is rigorous and fair. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, 111 Alexander Dr,Box 12233,Mail Drop CU 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health FX This research was supported by the Intramural Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 45 TC 2 Z9 2 U1 8 U2 48 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1187-7863 EI 1573-322X J9 J AGR ENVIRON ETHIC JI J. Agric. Environ. Ethics PD AUG PY 2015 VL 28 IS 4 BP 621 EP 633 DI 10.1007/s10806-015-9546-y PG 13 WC Agriculture, Multidisciplinary; Ethics; Environmental Sciences; History & Philosophy Of Science SC Agriculture; Social Sciences - Other Topics; Environmental Sciences & Ecology; History & Philosophy of Science GA CN7GE UT WOS:000358601500002 PM 26251636 ER PT J AU Lewis, R Guha, R Korcsmaros, T Bender, A AF Lewis, Richard Guha, Rajarshi Korcsmaros, Tamas Bender, Andreas TI Synergy Maps: exploring compound combinations using network-based visualization SO JOURNAL OF CHEMINFORMATICS LA English DT Article DE Compound combinations; Mixtures; Synergy; Visualization; Network; Dimensionality reduction ID DRUG-COMBINATIONS; SYSTEMS; PAIRS; EXPLORATION; PREDICTION; TARGET AB Background: The phenomenon of super-additivity of biological response to compounds applied jointly, termed synergy, has the potential to provide many therapeutic benefits. Therefore, high throughput screening of compound combinations has recently received a great deal of attention. Large compound libraries and the feasibility of all-pairs screening can easily generate large, information-rich datasets. Previously, these datasets have been visualized using either a heat-map or a network approach-however these visualizations only partially represent the information encoded in the dataset. Results: A new visualization technique for pairwise combination screening data, termed "Synergy Maps", is presented. In a Synergy Map, information about the synergistic interactions of compounds is integrated with information about their properties (chemical structure, physicochemical properties, bioactivity profiles) to produce a single visualization. As a result the relationships between compound and combination properties may be investigated simultaneously, and thus may afford insight into the synergy observed in the screen. An interactive web app implementation, available at http://richlewis42.github.io/synergy-maps, has been developed for public use, which may find use in navigating and filtering larger scale combination datasets. This tool is applied to a recent all-pairs dataset of anti-malarials, tested against Plasmodium falciparum, and a preliminary analysis is given as an example, illustrating the disproportionate synergism of histone deacetylase inhibitors previously described in literature, as well as suggesting new hypotheses for future investigation. Conclusions: Synergy Maps improve the state of the art in compound combination visualization, by simultaneously representing individual compound properties and their interactions. The web-based tool allows straightforward exploration of combination data, and easier identification of correlations between compound properties and interactions. C1 [Lewis, Richard; Bender, Andreas] Univ Cambridge, Dept Chem, Ctr Mol Informat, Cambridge CB2 1EW, England. [Guha, Rajarshi] Natl Ctr Advancing Translat Sci, Rockville, MD 20850 USA. [Korcsmaros, Tamas] Genome Anal Ctr, IGAC, Norwich, Norfolk, England. [Korcsmaros, Tamas] Inst Food Res, Gut Hlth & Food Safety Programme, Norwich NR4 7UA, Norfolk, England. RP Bender, A (reprint author), Univ Cambridge, Dept Chem, Ctr Mol Informat, Lensfield Rd, Cambridge CB2 1EW, England. EM ab454@cam.ac.uk RI Bender, Andreas/C-6942-2009; OI Bender, Andreas/0000-0002-6683-7546; Lewis, Rich/0000-0001-6642-5771 FU EPSRC; BBSRC; Genome Analysis Centre; European Research Commission (ERC) FX Azedine Zoufir, Yasaman Kalandar Motamedi, Dan Mason and Krishna Bulusu are thanked for their advice and work in the area, and the rest of the Bender Group for helpful feedback on the layout and design of the software. RL thanks EPSRC for funding. TK is supported by a fellowship in computational biology at The Genome Analysis Centre, in partnership with the Institute of Food Research, and strategically supported by BBSRC. AB thanks the European Research Commission for funding (ERC Starting Grant 2013 MIXTURE). NR 47 TC 5 Z9 5 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD AUG 1 PY 2015 VL 7 AR 36 DI 10.1186/s13321-015-0090-6 PG 11 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA CO0IF UT WOS:000358832900001 PM 26236402 ER PT J AU Vaisar, T Tang, CR Babenko, I Hutchins, P Wimberger, J Suffredini, AF Heinecke, JW AF Vaisar, Tomas Tang, Chongren Babenko, Ilona Hutchins, Patrick Wimberger, Jake Suffredini, Anthony F. Heinecke, Jay W. TI Inflammatory remodeling of the HDL proteome impairs cholesterol efflux capacity SO JOURNAL OF LIPID RESEARCH LA English DT Article DE atherosclerosis; apolipoproteins; high density lipoprotein; inflammation; mass spectrometry; proteomics ID HIGH-DENSITY-LIPOPROTEIN; ACUTE-PHASE RESPONSE; APOLIPOPROTEIN-A-I; CORONARY-HEART-DISEASE; APOA-I; ANTIINFLAMMATORY PROPERTIES; MYELOPEROXIDASE IMPAIRS; METHIONINE OXIDATION; SHOTGUN PROTEOMICS; PHOSPHOLIPASE A(2) AB Recent studies demonstrate that HDL's ability to promote cholesterol efflux from macrophages associates strongly with cardioprotection in humans independently of HDL-cholesterol (HDL-C) and apoA-I, HDL's major protein. However, the mechanisms that impair cholesterol efflux capacity during vascular disease are unclear. Inflammation, a well-established risk factor for cardiovascular disease, has been shown to impair HDL's cholesterol efflux capacity. We therefore tested the hypothesis that HDL's impaired efflux capacity is mediated by specific changes of its protein cargo. Humans with acute inflammation induced by low-level endotoxin had unchanged HDL-C levels, but their HDL-C efflux capacity was significantly impaired. Proteomic analyses demonstrated that HDL's cholesterol efflux capacity correlated inversely with HDL content of serum amyloid A (SAA) 1 and SAA2. In mice, acute inflammation caused a marked impairment of HDL-C efflux capacity that correlated with a large increase in HDL SAA. In striking contrast, the efflux capacity of mouse inflammatory HDL was preserved with genetic ablation of SAA1 and SAA2.Jlr Our observations indicate that the inflammatory impairment of HDL-C efflux capacity is due in part to SAA-mediated remodeling of HDL's protein cargo. C1 [Vaisar, Tomas; Tang, Chongren; Babenko, Ilona; Hutchins, Patrick; Wimberger, Jake; Heinecke, Jay W.] Univ Washington, Dept Med, Seattle, WA 98105 USA. [Suffredini, Anthony F.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Vaisar, T (reprint author), Univ Washington, Dept Med, Seattle, WA 98105 USA. EM tvaisar@u.washington.edu FU National Institutes of Health [HL112625, HL108897, DK035816, DK002456, HL086798, HL089504]; American Heart Association [0830231N] FX This research was supported by National Institutes of Health Grants HL112625, HL108897, DK035816, DK002456, HL086798, and HL089504. T.V. was supported by the American Heart Association (0830231N). NR 80 TC 18 Z9 19 U1 1 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD AUG PY 2015 VL 56 IS 8 BP 1519 EP 1530 DI 10.1194/jlr.M059089 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CN8CT UT WOS:000358666000014 PM 25995210 ER PT J AU Bachmann-Gagescu, R Dempsey, JC Phelps, IG O'Roak, BJ Knutzen, DM Rue, TC Ishak, GE Isabella, CR Gorden, N Adkins, J Boyle, EA de Lacy, N O'Day, D Alswaid, A Ramadevi, AR Lingappa, L Lourenco, C Martorell, L Garcia-Cazorla, A Ozyurek, H Haliloglu, G Tuysuz, B Topcu, M Chance, P Parisi, MA Glass, IA Shendure, J Doherty, D AF Bachmann-Gagescu, R. Dempsey, J. C. Phelps, I. G. O'Roak, B. J. Knutzen, D. M. Rue, T. C. Ishak, G. E. Isabella, C. R. Gorden, N. Adkins, J. Boyle, E. A. de Lacy, N. O'Day, D. Alswaid, A. Ramadevi, Radha A. Lingappa, L. Lourenco, C. Martorell, L. Garcia-Cazorla, A. Ozyurek, H. Haliloglu, G. Tuysuz, B. Topcu, M. Chance, P. Parisi, M. A. Glass, I. A. Shendure, J. Doherty, D. CA Univ Washington TI Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID ABNORMAL EYE-MOVEMENTS; MECKEL-GRUBER-SYNDROME; EPISODIC HYPERPNEA; CEREBELLAR VERMIS; TRANSITION ZONE; COACH SYNDROME; PRIMARY CILIUM; MUTATIONS; CILIOPATHIES; SPECTRUM AB Background Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS. Methods We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next-generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion algorithm with an optimised score cut-off. Results We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a 'pure JS' phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS subtypes. Conclusions This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future. C1 [Bachmann-Gagescu, R.] Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland. [Bachmann-Gagescu, R.] Univ Zurich, Inst Med Genet, Zurich, Switzerland. [Dempsey, J. C.; Phelps, I. G.; Isabella, C. R.; O'Day, D.; Chance, P.; Glass, I. A.; Doherty, D.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [O'Roak, B. J.] Oregon Hlth & Sci Univ, Mol & Med Genet, Portland, OR 97201 USA. [Knutzen, D. M.] Franciscan Hlth Syst, Dept Oncol, Tacoma, WA USA. [Rue, T. C.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Ishak, G. E.] Univ Washington, Seattle Childrens Hosp, Dept Radiol, Seattle, WA 98195 USA. [Gorden, N.] Univ Colorado, Sch Med, Dept Internal Med, Aurora, CO USA. [Adkins, J.] Translat Genom Res Inst, Div Integrated Canc Genom, Phoenix, AZ USA. [Boyle, E. A.; Shendure, J.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [de Lacy, N.] Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. [Alswaid, A.] King Abdul Aziz Med City, Dept Pediat, Riyadh, Saudi Arabia. [Ramadevi, Radha A.] Rainbow Childrens Hosp, Hyderabad, Andhra Pradesh, India. [Lingappa, L.] Rainbow Children Hosp, Dept Child Neurol, Hyderabad, Andhra Pradesh, India. [Lourenco, C.] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Neurosci & Behav Neurosci, Sao Paulo, Brazil. [Martorell, L.] Hosp St Joan de Deu, Dept Genet Mol, Barcelona, Spain. [Garcia-Cazorla, A.] Hosp St Joan de Deu, Neurometab Unit, Dept Neurol, Barcelona, Spain. [Garcia-Cazorla, A.] ISCIII, CIBERER, Barcelona, Spain. [Ozyurek, H.] Ondokuz Mayis Univ, Dept Pediat Neurol, Fac Med, Samsun, Turkey. [Haliloglu, G.; Topcu, M.] Hacettepe Univ, Childrens Hosp, Dept Pediat Neurol, Ankara, Turkey. [Tuysuz, B.] Istanbul Univ, Cerrahpasa Med Sch, Dept Pediat Genet, Istanbul, Turkey. [Parisi, M. A.] NICHHD, NIH, Bethesda, MD 20892 USA. [Glass, I. A.; Doherty, D.] Seattle Childrens Res Inst, Seattle, WA USA. RP Doherty, D (reprint author), Univ Washington, 1959 NE Pacific St,Room RR247,Box 356320, Seattle, WA 98195 USA. EM ddoher@uw.edu RI Bachmann-Gagescu, Ruxandra/A-8444-2016; OI Bachmann-Gagescu, Ruxandra/0000-0002-3571-5271; O'Roak, Brian/0000-0002-4141-0095 FU Swiss NSF [PZ00P3_142404/1]; National Institutes of Health [K23NS45832, K24HD046712, R01NS064077]; March of Dimes Basil O'Connor Starter Scholar Research Award; Arc of Washington Trust Fund; University of Washington Intellectual and Developmental Disabilities Research Center Genetics Core (National Institutes of Health) [U54HD083091]; National Human Genome Research Institute; National Heart, Lung and Blood Institute [1U54HG006493] FX RB-G was supported by a Swiss NSF grant Ambizione-SCORE PZ00P3_142404/1. The following authors received support from the National Institutes of Health: M.A.P. K23NS45832, I.A.G. K24HD046712, D.D R01NS064077. D.D. also received funding from a March of Dimes Basil O'Connor Starter Scholar Research Award, The Arc of Washington Trust Fund, and private donations from families of children with Joubert syndrome. The work was also supported by the University of Washington Intellectual and Developmental Disabilities Research Center Genetics Core (National Institutes of Health U54HD083091). Sequencing was provided by the University of Washington Center for Mendelian Genomics (UW CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grant 1U54HG006493 to Drs Debbie Nickerson, JS and Michael Bamshad. NR 53 TC 19 Z9 20 U1 3 U2 11 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD AUG PY 2015 VL 52 IS 8 BP 514 EP 522 DI 10.1136/jmedgenet-2015-103087 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA CN5BG UT WOS:000358443800002 PM 26092869 ER PT J AU Mujtaba, G Schultz, JM Imtiaz, A Morell, RJ Friedman, TB Naz, S AF Mujtaba, Ghulam Schultz, Julie M. Imtiaz, Ayesha Morell, Robert J. Friedman, Thomas B. Naz, Sadaf TI A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID FACTOR/SCATTER FACTOR; LATERAL-LINE; GENES; IMPAIRMENT; REGION AB Background Hearing loss is a heterogeneous neurosensory disorder. Mutations of 56 genes are reported to cause recessively inherited non-syndromic deafness. Objective We sought to identify the genetic lesion causing hearing loss segregating in a large consanguineous Pakistani family. Methods and results Mutations of GJB2 and all other genes reported to underlie recessive deafness were ruled out as the cause of the phenotype in the affected members of the participating family. Homozygosity mapping with a dense array of one million SNP markers allowed us to map the gene for recessively inherited severe hearing loss to chromosome 7q31.2, defining a new deafness locus designated DFNB97 (maximum logarithm of the odds score of 4.8). Whole-exome sequencing revealed a novel missense mutation c.2521T>G (p.F841V) in MET (mesenchymal epithelial transition factor), which encodes the receptor for hepatocyte growth factor. The mutation cosegregated with the hearing loss phenotype in the family and was absent from 800 chromosomes of ethnically matched control individuals as well as from 136 602 chromosomes in public databases of nucleotide variants. Analyses by multiple prediction programmes indicated that p.F841V likely damages MET function. Conclusions We identified a missense mutation of MET, encoding the hepatocyte growth factor receptor, as a likely cause of hearing loss in humans. C1 [Mujtaba, Ghulam; Imtiaz, Ayesha; Naz, Sadaf] Univ Punjab, Sch Biol Sci, Lahore 54590, Pakistan. [Schultz, Julie M.; Morell, Robert J.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Lab Mol Genet, NIH, Bethesda, MD USA. RP Naz, S (reprint author), Univ Punjab, Sch Biol Sci, Lahore 54590, Pakistan. EM naz.sbs@pu.edu.pk OI Naz, Sadaf/0000-0002-1912-0235; Morell, Robert/0000-0003-1537-7356 FU Fogarty International Center [R01TW007608]; National Institute of Deafness and other Communication Disorders, National Institutes of Health, USA; National Institutes of Health from the National Institute on Deafness and Other Communication Disorders [DC000039-18] FX The work was supported by funds (Grant number R01TW007608) from the Fogarty International Center and National Institute of Deafness and other Communication Disorders, National Institutes of Health, USA, to SN. This work was also supported by National Institutes of Health intramural funds from the National Institute on Deafness and Other Communication Disorders DC000039-18 to T.B.F. NR 20 TC 5 Z9 6 U1 1 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD AUG PY 2015 VL 52 IS 8 BP 548 EP 552 DI 10.1136/jmedgenet-2015-103023 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA CN5BG UT WOS:000358443800006 PM 25941349 ER PT J AU Liu, D Zhang, YQ Gharavi, R Park, HR Lee, J Siddiqui, S Telljohann, R Nassar, MR Cutler, RG Becker, KG Mattson, MP AF Liu, Dong Zhang, Yongqing Gharavi, Robert Park, Hee Ra Lee, Jaewon Siddiqui, Sana Telljohann, Richard Nassar, Matthew R. Cutler, Roy G. Becker, Kevin G. Mattson, Mark P. TI The mitochondrial uncoupler DNP triggers brain cell mTOR signaling network reprogramming andCREB pathway up-regulation SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE 2; 4-dinitrophenol; autophagy; BDNF; CREB; insulin signaling; mTOR ID ACTIVATED PROTEIN-KINASE; ALZHEIMERS-DISEASE; ENERGY-METABOLISM; OXIDATIVE STRESS; MOUSE MODEL; CEREBRAL-ISCHEMIA; CALORIC RESTRICTION; COGNITIVE DEFICITS; EXPRESSION PROFILE; INSULIN-RESISTANCE AB Mitochondrial metabolism is highly responsive to nutrient availability and ongoing activity in neuronal circuits. The molecular mechanisms by which brain cells respond to an increase in cellular energy expenditure are largely unknown. Mild mitochondrial uncoupling enhances cellular energy expenditure in mitochondria and can be induced with 2,4-dinitrophenol (DNP), a proton ionophore previously used for weight loss. We found that DNP treatment reduces mitochondrial membrane potential, increases intracellular Ca2+ levels and reduces oxidative stress in cerebral cortical neurons. Gene expression profiling of the cerebral cortex of DNP-treated mice revealed reprogramming of signaling cascades that included suppression of the mammalian target of rapamycin (mTOR) and insulin - PI3K - MAPK pathways, and up-regulation of tuberous sclerosis complex 2, a negative regulator of mTOR. Genes encoding proteins involved in autophagy processes were up-regulated in response to DNP. CREB (cAMP-response element-binding protein) signaling, Arc and brain-derived neurotrophic factor, which play important roles in synaptic plasticity and adaptive cellular stress responses, were up-regulated in response to DNP, and DNP-treated mice exhibited improved performance in a test of learning and memory. Immunoblot analysis verified that key DNP-induced changes in gene expression resulted in corresponding changes at the protein level. Our findings suggest that mild mitochondrial uncoupling triggers an integrated signaling response in brain cells characterized by reprogramming of mTOR and insulin signaling, and up-regulation of pathways involved in adaptive stress responses, molecular waste disposal, and synaptic plasticity. C1 [Liu, Dong; Gharavi, Robert; Siddiqui, Sana; Telljohann, Richard; Nassar, Matthew R.; Cutler, Roy G.; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Intramural Res Program, Baltimore, MD 21224 USA. [Park, Hee Ra; Lee, Jaewon] Pusan Natl Univ, Coll Pharm, Mol Inflammat Res Ctr Aging Intervent, Dept Pharm, Busan, South Korea. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov OI nassar, matthew/0000-0002-5397-535X FU National Institute on Aging; Financial Supporting Project of Long-term Overseas Dispatch of PNU's Tenure-track Faculty FX The authors thank W. Wood III for help with microarray processing, P. Ghosh, J. Lim, and J. Licata for providing antibodies, and Mark Wilson for technical support. This research was supported in part by the Intramural Research Program of the National Institute on Aging, and the Financial Supporting Project of Long-term Overseas Dispatch of PNU's Tenure-track Faculty. The authors declare no competing interests. NR 106 TC 9 Z9 9 U1 0 U2 8 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 2015 VL 134 IS 4 BP 677 EP 692 DI 10.1111/jnc.13176 PG 16 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CN8KI UT WOS:000358688700008 PM 26010875 ER PT J AU Taylor, IC Hutt-Cabezas, M Brandt, WD Kambhampati, M Nazarian, J Chang, HT Warren, KE Eberhart, CG Raabe, EH AF Taylor, Isabella C. Huett-Cabezas, Marianne Brandt, William D. Kambhampati, Madhuri Nazarian, Javad Chang, Howard T. Warren, Katherine E. Eberhart, Charles G. Raabe, Eric H. TI Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article ID GAMMA-SECRETASE INHIBITOR; NEURAL STEM-CELLS; ACUTE LYMPHOBLASTIC-LEUKEMIA; BRAIN-TUMORS; THERAPEUTIC TARGET; HISTONE H3.3; PHASE-I; GLIOBLASTOMA; REVEALS; PATHWAY AB NOTCH regulates stem cells during normal development and stemlike cells in cancer, but the roles of NOTCH in the lethal pediatric brain tumor diffuse intrinsic pontine glioma (DIPG) remain unknown. Because DIPGs express stem cell factors such as SOX2 and MYCN, we hypothesized that NOTCH activity would be critical for DIPG growth. We determined that primary DIPGs expressed high levels of NOTCH receptors, ligands, and downstream effectors. Treatment of the DIPG cell lines JHH-DIPG1 and SF7761 with the gamma-secretase inhibitor MRK003 suppressed the level of the NOTCH effectors HES1, HES4, and HES5; inhibited DIPG growth by 75%; and caused a 3-fold induction of apoptosis. Short hairpin RNAs targeting the canonical NOTCH pathway caused similar effects. Pretreatment of DIPG cells with MRK003 suppressed clonogenic growth by more than 90% and enhanced the efficacy of radiation therapy. The high level of MYCN in DIPG led us to test sequential therapy with the bromodomain inhibitor JQ1 and MRK003, and we found that JQ1 and MRK003 inhibited DIPG growth and induced apoptosis. Together, these results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a gamma-secretase inhibitor during radiation therapy may be efficacious initially or during reirradiation. C1 [Taylor, Isabella C.; Huett-Cabezas, Marianne; Brandt, William D.; Eberhart, Charles G.; Raabe, Eric H.] Johns Hopkins Univ, Bloomberg Childrens Hosp, Div Neuropathol, Baltimore, MD USA. [Taylor, Isabella C.; Huett-Cabezas, Marianne; Brandt, William D.; Eberhart, Charles G.; Raabe, Eric H.] Johns Hopkins Univ, Bloomberg Childrens Hosp, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Taylor, Isabella C.; Raabe, Eric H.] Johns Hopkins Univ, Bloomberg Childrens Hosp, Div Pediat Oncol, Baltimore, MD USA. [Kambhampati, Madhuri; Nazarian, Javad] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Kambhampati, Madhuri; Nazarian, Javad] George Washington Univ, Sch Med & Hlth Sci, Washington, DC USA. [Chang, Howard T.] Michigan State Univ, Dept Neurol & Ophthalmol, E Lansing, MI 48824 USA. [Chang, Howard T.] Sparrow Hlth Syst, Lansing, MI USA. [Warren, Katherine E.] Natl Inst Hlth, Natl Canc Inst, Pediat Oncol Branch, Bethesda, MD USA. RP Raabe, EH (reprint author), Bloomberg Childrens Hosp, Div Pediat Oncol, Johns Hopkins Sch Med, Room 11379 1800 Orleans St, Baltimore, MD 21287 USA. EM eraabe2@jhmi.edu FU Matthew Larson Foundation; National Cancer Institute [SKCCC P30 CA006973] FX Supported by the Matthew Larson Foundation (Eric H. Raabe); National Cancer Institute Core Grant to the Johns Hopkins SKCCC P30 CA006973; Eric H. Raabe is a St. Baldrick's Scholar. NR 47 TC 0 Z9 0 U1 1 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD AUG PY 2015 VL 74 IS 8 BP 778 EP 790 DI 10.1097/NEN.0000000000000216 PG 13 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA CN8AB UT WOS:000358657300003 PM 26115193 ER PT J AU Sadowski, SM Millo, C Cottle-Delisle, C Merkel, R Yang, LA Herscovitch, P Pacak, K Simonds, WF Marx, SJ Kebebew, E AF Sadowski, Samira M. Millo, Corina Cottle-Delisle, Candice Merkel, Roxanne Yang, Lily A. Herscovitch, Peter Pacak, Karel Simonds, William F. Marx, Stephen J. Kebebew, Electron TI Results of (68)Gallium-DOTATATE PET/CT Scanning in Patients with Multiple Endocrine Neoplasia Type 1 SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID METASTATIC NEUROENDOCRINE TUMORS; GA-68-DOTATATE PET/CT; NONFUNCTIONING TUMORS; GUIDELINES; MANAGEMENT; DIAGNOSIS; THERAPY; SYSTEM; IMPACT; MEN1 AB BACKGROUND: Screening for neuroendocrine tumors (NETs) in patients with multiple endocrine neoplasia type 1 (MEN1) is recommended to detect primary and metastatic tumors, which can result in significant morbidity and mortality. The utility of somatostatin receptor imaging (68)Gallium-DOTATATE PET/CT in patients with MEN1 is not known. The aim of this study was to prospectively determine the accuracy of (68)Gallium-DOTATATE PET/CT vs In-111-pentetreotide single-photon emission CT (SPECT)/CT and anatomic imaging in patients with MEN1. STUDY DESIGN: We performed a prospective study comparing (68)Gallium-DOTATATE PET/CT, In-111-pentetreotide SPECT/CT, and triphasic CT scan to clinical, biochemical, and pathologic data in 26 patients with MEN1. RESULTS: (68)Gallium-DOTATATE PET/CT detected 107 lesions; In-111-pentetreotide SPECT/CT detected 33 lesions; and CT scan detected 48 lesions. Lesions detected on (68)Gallium-DOTATATE PET/CT had high standard uptake value (SUV)(max) (median SUVmax = 72.8 [range 19 to 191]). In 7 of the 26 patients (27%), 68Gallium-DOTATATE PET/CT was positive, with a negative In-111-pentetreotide SPECT/CT, and in 10 patients (38.5%), additional metastases were detected (range 0.3 cm to 1.5 cm). In 8 of the 26 patients (31%), there was a change in management recommendations as a result of the findings on (68)Gallium-DOTATATE PET/CT that were not seen on In-111-pentetreotide SPECT/CT and CT scan. CONCLUSIONS: (68)Gallium-DOTATATE PET/CT is more sensitive for detecting NETs than In-111-pentetreotide SPECT/CT and CT scan in patients with MEN1. This imaging technique should be integrated into radiologic screening and surveillance of patients with MEN1 because it can significantly alter management recommendations. (C) 2015 by the American College of Surgeons C1 [Sadowski, Samira M.; Cottle-Delisle, Candice; Merkel, Roxanne; Yang, Lily A.; Kebebew, Electron] NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. [Millo, Corina; Herscovitch, Peter] NIH, Positron Emiss Tomog Dept, Warren Grant Magnusson Clin Ctr, Bethesda, MD 20892 USA. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Simonds, William F.; Marx, Stephen J.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Sadowski, SM (reprint author), NCI, Endocrine Oncol Branch, NIH, Clin Res Ctr, Bldg 10-CRC,Room 3W-5840, Bethesda, MD 20892 USA. EM samira.sadowskiveuthey@nih.gov FU Center for Cancer Research, National Cancer Institute [1 ZIA BC011275 05, 1 ZIA BC011286 05, 1 ZID BC011534 01]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This research was supported by the intramural research programs of the Center for Cancer Research, National Cancer Institute (grant nos. 1 ZIA BC011275 05, 1 ZIA BC011286 05, and 1 ZID BC011534 01), and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 26 TC 13 Z9 13 U1 1 U2 7 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 2015 VL 221 IS 2 BP 509 EP 517 DI 10.1016/j.jamcollsurg.2015.04.005 PG 9 WC Surgery SC Surgery GA CN4EZ UT WOS:000358384400037 PM 26206648 ER PT J AU Fabbri, E Zoli, M Gonzalez-Freire, M Salive, ME Studenski, SA Ferrucci, L AF Fabbri, Elisa Zoli, Marco Gonzalez-Freire, Marta Salive, Marcel E. Studenski, Stephanie A. Ferrucci, Luigi TI Aging and Multimorbidity: New Tasks, Priorities, and Frontiers for Integrated Gerontological and Clinical Research SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Review DE Multimorbidity; multiple morbidities; aging; chronic disease ID MULTIPLE CHRONIC CONDITIONS; HEALTH-CARE UTILIZATION; DWELLING OLDER-ADULTS; CHRONIC DISEASE; PRACTICE GUIDELINES; GENERAL-PRACTICE; ELDERLY POPULATION; PHYSICAL-ACTIVITY; COMPLEX PATIENTS; RISK-FACTORS AB Aging is characterized by rising susceptibility to development of multiple chronic diseases and, therefore, represents the major risk factor for multimorbidity. From a gerontological perspective, the progressive accumulation of multiple diseases, which significantly accelerates at older ages, is a milestone for progressive loss of resilience and age-related multisystem homeostatic dysregulation. Because it is most likely that the same mechanisms that drive aging also drive multiple age-related chronic diseases, addressing those mechanisms may reduce the development of multimorbidity. According to this vision, studying multimorbidity may help to understand the biology of aging and, at the same time, understanding the underpinnings of aging may help to develop strategies to prevent or delay the burden of multimorbidity. As a consequence, we believe that it is time to build connections and dialogue between the clinical experience of general practitioners and geriatricians and the scientists who study aging, so as to stimulate innovative research projects to improve the management and the treatment of older patients with multiple morbidities. Published by Elsevier Inc. on behalf of AMDA - The Society for Post-Acute and Long-Term Care Medicine. C1 [Fabbri, Elisa; Gonzalez-Freire, Marta; Studenski, Stephanie A.; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Longitudinal Study Sect, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Fabbri, Elisa; Zoli, Marco] Univ Bologna, Dept Med & Surg Sci, Bologna, Italy. [Salive, Marcel E.] NIA, Div Geriatr & Clin Gerontol, Bethesda, MD 20892 USA. RP Ferrucci, L (reprint author), Harbor Hosp, NIA, NIH, 3001 Hanover St,5th Floor, Baltimore, MD 21225 USA. EM ferrucilu@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000015-49] NR 114 TC 22 Z9 22 U1 5 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 EI 1538-9375 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD AUG 1 PY 2015 VL 16 IS 8 BP 640 EP 647 DI 10.1016/j.jamda.2015.03.013 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CN4TP UT WOS:000358423400004 PM 25958334 ER PT J AU Simon, SL Bouville, A AF Simon, Steven L. Bouville, Andre TI Health effects of nuclear weapons testing SO LANCET LA English DT Editorial Material ID RADIOACTIVE FALLOUT; CANCER-RISKS; TEST-SITE; EXPOSURE; WORLDWIDE; LEUKEMIA C1 [Simon, Steven L.; Bouville, Andre] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Simon, SL (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM ssimon@mail.nih.gov NR 20 TC 0 Z9 0 U1 2 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD AUG 1 PY 2015 VL 386 IS 9992 BP 407 EP 409 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CN9IY UT WOS:000358761700005 PM 26251378 ER PT J AU Galassi, A Challinor, J AF Galassi, Annette Challinor, Julia CA Key Stakeholder Grp Oncol Nursing TI Strengthening the oncology nurse workforce in low-income and middle-income countries SO LANCET ONCOLOGY LA English DT Editorial Material C1 [Galassi, Annette] US Natl Canc Inst, Bethesda, MD 20892 USA. [Challinor, Julia] Int Network Canc Treatment & Res, Brussels, Belgium. RP Galassi, A (reprint author), US Natl Canc Inst, Bethesda, MD 20892 USA. EM agalassi57@gmail.com NR 9 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD AUG PY 2015 VL 16 IS 8 BP 887 EP 888 PG 2 WC Oncology SC Oncology GA CN6OS UT WOS:000358554700036 PM 26248831 ER PT J AU Harford, JB AF Harford, Joe B. TI Barriers to overcome for effective cancer control in Africa SO LANCET ONCOLOGY LA English DT Article ID SUB-SAHARAN AFRICA; MIDDLE-INCOME COUNTRIES; BREAST-CANCER; INDIGENOUS AFRICANS; PALLIATIVE CARE; WOMEN; CHALLENGES; NIGERIA AB Cancer control in Africa is complicated due to large differences in cancer incidence between countries caused by differences in exposure to known risk factors. For example, substantial differences are seen when selected cancers in north Africa are compared with those in sub-Saharan Africa. In the future, population growth and demographic shifts are likely to have profound effects on the prevalence of cancer across the continent. Likewise, many factors outside of health care such as language differences, conflict, and poverty can affect cancer control efforts. Although cooperation in cancer control efforts is desirable, differences in cultural and geopolitical factors that characterise African countries and their populations, together with the sheer size of the continent, present unique challenges to effective cancer control. This Series paper discusses factors related to the size, diversity, and conditions within Africa that present barriers to optimal collaboration in cancer control efforts across the continent. C1 [Harford, Joe B.] NCI, Ctr Global Hlth, Bethesda, MD 20892 USA. RP Harford, JB (reprint author), Capac Bldg Innovat & Transformat LLC, 10244 Democracy Blvd, Potomac, MD 20854 USA. EM harfordjb@gmail.com NR 52 TC 5 Z9 5 U1 5 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD AUG PY 2015 VL 16 IS 8 BP E385 EP E393 PG 9 WC Oncology SC Oncology GA CN6OS UT WOS:000358554700021 PM 26248846 ER PT J AU Volkow, ND Koob, G AF Volkow, Nora D. Koob, George TI Brain disease model of addiction: why is it so controversial? SO LANCET PSYCHIATRY LA English DT Editorial Material ID STIMULATION C1 [Volkow, Nora D.] NIDA, NIH, Bethesda, MD 20892 USA. [Koob, George] NIAAA, NIH, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, NIH, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov RI koob, george/P-8791-2016 FU Intramural NIH HHS [Z99 DA999999] NR 9 TC 10 Z9 10 U1 1 U2 33 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 2015 VL 2 IS 8 BP 677 EP 679 PG 4 WC Psychiatry SC Psychiatry GA CN9CH UT WOS:000358743200010 PM 26249284 ER PT J AU Becker, RE Seeman, MV Greig, NH Lahiri, DK AF Becker, Robert E. Seeman, Mary V. Greig, Nigel H. Lahiri, Debomoy K. TI What can triumphs and tribulations from drug research in Alzheimer's disease tell us about the development of psychotropic drugs in general? SO LANCET PSYCHIATRY LA English DT Editorial Material ID ASTERISK-D REPORT; CLINICAL-TRIALS; 2ND-GENERATION ANTIPSYCHOTICS; ATYPICAL ANTIPSYCHOTICS; PLACEBO-RESPONSE; ANIMAL-MODELS; AMYLOID-BETA; SCHIZOPHRENIA; PSYCHIATRY; CLOZAPINE AB Drug development for psychiatric disorders has almost ground to a halt. Some newer drugs are better tolerated or safer than older ones, but none is more effective. Years of failure in preventing or delaying the onset of illness, ameliorating symptoms, lowering suicide rates, or improving quality of life has put the commercial investments that had previously funded drug development at risk. To promote the development of psychiatric drugs with greater efficacy, we need to improve the way we bring potentially beneficial drugs to market. We need to acknowledge, as has been done in other specialties, that people differ in their response to drugs. Psychiatric drug research needs to be grounded in a better understanding of molecular brain mechanisms, neural circuits, and their relations to clinical disease. With this understanding, drugs need to be more precisely directed at specific brain targets. In psychiatric drug development, government, industry, regulatory bodies, and academia should realign to ensure medical science is used in the best interests of patients. C1 [Becker, Robert E.] Aristea Translat Med, Park City, UT USA. [Greig, Nigel H.] NIA, Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Seeman, Mary V.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Lahiri, Debomoy K.] Indiana Univ Sch Med, Dept Psychiat, Neurosci Res Ctr, Indianapolis, IN 46202 USA. [Lahiri, Debomoy K.] Indiana Univ Sch Med, Dept Med & Mol Genet, Neurosci Res Ctr, Indianapolis, IN 46202 USA. RP Greig, NH (reprint author), NIA, NIH, Translat Gerontol Branch, Baltimore, MD 21224 USA. EM greign@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health (NHG); National Institutes of Health [NIA-R01, NIA-R21]; Alzheimer's Association (IIRG) FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NHG), and by grants from the National Institutes of Health (NIA-R01 and -R21) and Alzheimer's Association (IIRG; DKL). We thank Jimmy Burril, Visual Media Services, Intramural Research Program, National Institute on Aging, in relation to figures 1 and 2. NR 74 TC 3 Z9 3 U1 2 U2 11 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 2015 VL 2 IS 8 BP 756 EP 764 PG 9 WC Psychiatry SC Psychiatry GA CN9CH UT WOS:000358743200027 PM 26249306 ER PT J AU Scott, AD Ferreira, PFADC Nielles-Vallespin, S Gatehouse, P McGill, LA Kilner, P Pennell, DJ Firmin, DN AF Scott, Andrew D. Ferreira, Pedro F. A. D. C. Nielles-Vallespin, Sonia Gatehouse, Peter McGill, Laura-Ann Kilner, Philip Pennell, Dudley J. Firmin, David N. TI Optimal diffusion weighting for in vivo cardiac diffusion tensor imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE DTI; diffusion weighting; b-value; cardiac diffusion; microvascular perfusion ID MAGNETIC-RESONANCE; HYPERTROPHIC CARDIOMYOPATHY; MYOCARDIAL MICROSTRUCTURE; WATER DIFFUSION; B-VALUE; MRI; STRAIN; MOTION; NOISE; HEART AB PurposeTo investigate the influence of the diffusion weighting on in vivo cardiac diffusion tensor imaging (cDTI) and obtain optimal parameters. MethodsTen subjects were scanned using stimulated echo acquisition mode echo planar imaging with six b-values, from 50 to 950 smm(-2), plus b=15 smm(-2) reference. The relationship between b-value and both signal loss and signal-to-noise ratio measures was investigated. Mean diffusivity, fractional anisotropy, and helical angle maps were calculated using all possible b-value pairs to investigate the effects of diffusion weighting on the main and reference data. ResultsSignal decay at low b-values was dominated by processes with high apparent diffusion coefficients, most likely microvascular perfusion. This effect could be avoided by diffusion weighting of the reference images. Parameter maps were improved with increased b-value until the diffusion-weighted signal approached the noise floor. For the protocol used in this study, b=750 smm(-2) combined with 150 smm(-2) diffusion weighting of the reference images proved optimal. ConclusionMean diffusivity, fractional anisotropy, and helical angle from cDTI are influenced by the b-value of the main and reference data. Using optimal values improves parameter maps and avoids microvascular perfusion effects. This optimized protocol should provide greater sensitivity to pathological changes in parameter maps. Magn Reson Med 74:420-430, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Scott, Andrew D.; Ferreira, Pedro F. A. D. C.; Nielles-Vallespin, Sonia; Gatehouse, Peter; McGill, Laura-Ann; Kilner, Philip; Pennell, Dudley J.; Firmin, David N.] Royal Brompton Hosp, NIHR Cardiovasc Biomed Res Unit, London SW3 6NP, England. [Scott, Andrew D.; Ferreira, Pedro F. A. D. C.; Gatehouse, Peter; McGill, Laura-Ann; Kilner, Philip; Pennell, Dudley J.; Firmin, David N.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Nielles-Vallespin, Sonia] NHLBI, NIH, Bethesda, MD 20892 USA. RP Scott, AD (reprint author), Royal Brompton Hosp, NIHR Cardiovasc Biomed Res Unit, London SW3 6NP, England. EM a.scott@rbht.nhs.uk OI Gatehouse, Peter/0000-0002-0260-4719 FU National Institute for Health Research Cardiovascular Biomedical Research Unit at The Royal Brompton Hospital and Imperial College London FX Grant sponsor: National Institute for Health Research Cardiovascular Biomedical Research Unit at The Royal Brompton Hospital and Imperial College London. NR 44 TC 9 Z9 9 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD AUG PY 2015 VL 74 IS 2 BP 420 EP 430 DI 10.1002/mrm.25418 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN7IK UT WOS:000358607700015 PM 25154715 ER PT J AU Pulitzer, MP Brannon, AR Berger, MF Louis, P Scott, SN Jungbluth, AA Coit, DG Brownell, I Busam, KJ AF Pulitzer, Melissa P. Brannon, A. Rose Berger, Michael F. Louis, Peter Scott, Sasinya N. Jungbluth, Achim A. Coit, Daniel G. Brownell, Isaac Busam, Klaus J. TI Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma SO MODERN PATHOLOGY LA English DT Article ID LARGE T-ANTIGEN; POLYOMAVIRUS INFECTION; TRABECULAR CARCINOMA; P63 EXPRESSION; IN-SITU; PROGNOSTIC MARKER; SKIN; ASSOCIATION; FEATURES; ECCRINE AB Cutaneous neuroendocrine (Merkel cell) carcinoma most often arises de novo in the background of a clonally integrated virus, the Merkel cell polyomavirus, and is notable for positive expression of retinoblastoma 1 (RB1) protein and low expression of p53 compared with the rare Merkel cell polyomavirus-negative Merkel cell carcinomas. Combined squamous and Merkel cell tumors are consistently negative for Merkel cell polyomavirus. Little is known about their immunophenotypic or molecular profile. Herein, we studied 10 combined cutaneous squamous cell and neuroendocrine carcinomas for immunohistochemical expression of p53, retinoblastoma 1 protein, neurofilament, p63, and cytokeratin 20 (CK20). We compared mutation profiles of five combined Merkel cell carcinomas and seven 'pure' Merkel cell carcinomas using targeted next-generation sequencing. Combined tumors were from the head, trunk, and leg of Caucasian males and one female aged 52-89. All cases were highly p53- and p63-positive and neurofilament-negative in the squamous component, whereas RB1-negative in both components. Eight out of 10 were p53-positive, 3/10 p63-positive, and 3/10 focally neurofilament-positive in the neuroendocrine component. Six out of 10 were CK20-positive in any part. By next-generation sequencing, combined tumors were highly mutated, with an average of 48 mutations per megabase compared with pure tumors, which showed 1.25 mutations per megabase. RB1 and p53 mutations were identified in all five combined tumors. Combined tumors represent an immunophenotypically and genetically distinct variant of primary cutaneous neuroendocrine carcinomas, notable for a highly mutated genetic profile, significant p53 expression and/or mutation, absent RB1 expression in the context of increased RB1 mutation, and minimal neurofilament expression. C1 [Pulitzer, Melissa P.; Brannon, A. Rose; Berger, Michael F.; Louis, Peter; Scott, Sasinya N.; Jungbluth, Achim A.; Busam, Klaus J.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Coit, Daniel G.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Brownell, Isaac] NCI, Dermatol Branch, NIH, Washington, DC USA. RP Pulitzer, MP (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. EM pulitzem@mskcc.org FU Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute [P30CA008748] FX The authors declare no conflict of interest. Research reported in this publication was supported by The Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 66 TC 9 Z9 9 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD AUG PY 2015 VL 28 IS 8 BP 1023 EP 1032 DI 10.1038/modpathol.2015.60 PG 10 WC Pathology SC Pathology GA CO0LD UT WOS:000358841800002 PM 26022453 ER PT J AU Bergeron, SA Carrier, N Li, GH Ahn, S Burgess, HA AF Bergeron, S. A. Carrier, N. Li, G. H. Ahn, S. Burgess, H. A. TI Gsx1 expression defines neurons required for prepulse inhibition SO MOLECULAR PSYCHIATRY LA English DT Article ID ACOUSTIC STARTLE RESPONSE; PEDUNCULOPONTINE TEGMENTAL NUCLEUS; INFORMATION-PROCESSING DEFICITS; PONTINE RETICULAR-FORMATION; SLEEPING-BEAUTY TRANSPOSON; FUNCTIONAL GROUND PLAN; LARVAL ZEBRAFISH; SCHIZOPHRENIC-PATIENTS; GABAERGIC NEURONS; NERVOUS-SYSTEM AB In schizophrenia, cognitive overload is thought to reflect an inability to suppress non-salient information, a process which is studied using prepulse inhibition (PPI) of the startle response. PPI is reduced in schizophrenia and routinely tested in animal models and preclinical trials of antipsychotic drugs. However, the underlying neuronal circuitry is not well understood. We used a novel genetic screen in larval zebrafish to reveal the molecular identity of neurons that are required for PPI in fish and mice. Ablation or optogenetic silencing of neurons with developmental expression of the transcription factor genomic screen homeobox 1 (gsx1) produced profound defects in PPI in zebrafish, and PPI was similarly impaired in Gsx1 knockout mice. Gsx1-expressing neurons reside in the dorsal brainstem and form synapses closely apposed to neurons that initiate the startle response. Surprisingly, brainstem Gsx1 neurons are primarily glutamatergic despite their role in a functionally inhibitory pathway. As Gsx1 has an important role in regulating interneuron development in the forebrain, these findings reveal a molecular link between control of interneuron specification and circuits that gate sensory information across brain regions. C1 [Bergeron, S. A.; Carrier, N.; Li, G. H.; Ahn, S.; Burgess, H. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD 20892 USA. RP Burgess, HA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, 6 Ctr Dr,Bldg 6B,Room 3B308, Bethesda, MD 20892 USA. EM burgessha@mail.nih.gov OI Bergeron, Sadie/0000-0002-1238-8730 FU Intramural Research Program of the NICHD FX We thank Jennifer Strykowski for zebrafish support and Victoria Carter and Daniel Abebe for mouse support. We also thank Andres Buonanno for assistance and useful discussions. This work was supported by the Intramural Research Program of the NICHD. NR 97 TC 3 Z9 3 U1 4 U2 10 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 2015 VL 20 IS 8 BP 974 EP 985 DI 10.1038/mp.2014.106 PG 12 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CN6EP UT WOS:000358527100006 PM 25224259 ER PT J AU Harrison, DM Oh, J Roy, S Wood, ET Whetstone, A Seigo, MA Jones, CK Pham, D van Zijl, P Reich, DS Calabresi, PA AF Harrison, Daniel M. Oh, Jiwon Roy, Snehashis Wood, Emily T. Whetstone, Anna Seigo, Michaela A. Jones, Craig K. Pham, Dzung van Zijl, Peter Reich, Daniel S. Calabresi, Peter A. TI Thalamic lesions in multiple sclerosis by 7T MRI: Clinical implications and relationship to cortical pathology SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE MRI; multiple sclerosis ID DEEP GRAY-MATTER; INTRACORTICAL LESIONS; INVERSION-RECOVERY; IN-VIVO; DEMYELINATION; INFLAMMATION; NEURODEGENERATION; ATROPHY; MS; HIPPOCAMPAL AB Objective: Pathology in both cortex and deep gray matter contribute to disability in multiple sclerosis (MS). We used the increased signal-to-noise ratio of 7-tesla (7T) MRI to visualize small lesions within the thalamus and to relate this to clinical information and cortical lesions. Methods: We obtained 7T MRI scans on 34 MS cases and 15 healthy volunteers. Thalamic lesion number and volume were related to demographic data, clinical disability measures, and lesions in cortical gray matter. Results: Thalamic lesions were found in 24/34 of MS cases. Two lesion subtypes were noted: discrete, ovoid lesions, and more diffuse lesional areas lining the periventricular surface. The number of thalamic lesions was greater in progressive MS compared to relapsing-remitting (mean SD, 10.7 +/- 0.7 vs. 3.0 +/- 0.7, respectively, p < 0.001). Thalamic lesion burden (count and volume) correlated with EDSS score and measures of cortical lesion burden, but not with white matter lesion burden or white matter volume. Conclusions: Using 7T MRI allows identification of thalamic lesions in MS, which are associated with disability, progressive disease, and cortical lesions. Thalamic lesion analysis may be a simpler, more rapid estimate of overall gray matter lesion burden in MS. C1 [Harrison, Daniel M.; Oh, Jiwon; Whetstone, Anna; Seigo, Michaela A.; Reich, Daniel S.; Calabresi, Peter A.] Johns Hopkins Univ, Sch Med, Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD 21287 USA. [Roy, Snehashis; Pham, Dzung] Uniformed Serv Univ Hlth Sci, Henry Jackson Fdn, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Wood, Emily T.; Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, NIH, Bethesda, MD 20892 USA. [Wood, Emily T.; van Zijl, Peter] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD USA. [Jones, Craig K.; van Zijl, Peter] Kennedy Krieger Inst, FM Kirby Res Ctr Funct Brain Imaging, Baltimore, MD USA. [Jones, Craig K.; van Zijl, Peter; Reich, Daniel S.] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. RP Harrison, DM (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Sch Med, Dept Neurol,Pathol 622A, 600 N Wolfe St, Baltimore, MD 21287 USA. EM dharri90@jhmi.edu RI Reich, Daniel/E-5701-2010; OI Reich, Daniel/0000-0002-2628-4334; Wood, Emily/0000-0003-0395-4849; Roy, Snehashis/0000-0002-7997-3993 FU NIH [5P41 RR15241-09S1, 5P41EB15909]; Bayer Schering Pharma; NINDS; NIH Mentored Grant [K23NS072366] FX This study was supported in part by NIH Supplemental Grants 5P41 RR15241-09S1 and 5P41EB15909 (van Zijl) and Bayer Schering Pharma (Calabresi). Dr Reich and Ms Wood are supported by the Intramural Research Program of NINDS. Time for data analysis was supported by an NIH Mentored Grant K23NS072366 (Harrison). NR 35 TC 5 Z9 5 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD AUG PY 2015 VL 21 IS 9 BP 1139 EP 1150 DI 10.1177/1352458514558134 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CN6IF UT WOS:000358537400007 PM 25583851 ER PT J AU Case, LB Waterman, CM AF Case, Lindsay B. Waterman, Clare M. TI Integration of actin dynamics and cell adhesion by a three-dimensional, mechanosensitive molecular clutch SO NATURE CELL BIOLOGY LA English DT Review ID OUT SIGNAL-TRANSDUCTION; FOCAL ADHESIONS; RETROGRADE FLOW; NASCENT ADHESIONS; MIGRATING CELLS; STRESS FIBERS; LEADING-EDGE; INTEGRIN ACTIVATION; MATRIX ADHESIONS; ALPHA-ACTININ AB During cell migration, the forces generated in the actin cytoskeleton are transmitted across transmembrane receptors to the extracellular matrix or other cells through a series of mechanosensitive, regulable protein-protein interactions termed the molecular clutch. In integrin-based focal adhesions, the proteins forming this linkage are organized into a conserved three-dimensional nano-architecture. Here we discuss how the physical interactions between the actin cytoskeleton and focal-adhesion-associated molecules mediate force transmission from the molecular clutch to the extracellular matrix. C1 [Case, Lindsay B.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Case, LB (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. EM Watermancm@nhibi.nih.gov OI Waterman, Clare/0000-0001-6142-6775 FU Division of Intramural Research, NHLBI FX The authors thank Michelle Baird and Michael Davidson (Florida State University) for assistance with figure design and members of the Waterman Lab for helpful discussions. Funding was provided by the Division of Intramural Research, NHLBI (L.B.C. and C.M.W.). NR 147 TC 31 Z9 31 U1 8 U2 60 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD AUG PY 2015 VL 17 IS 8 BP 955 EP 963 DI 10.1038/ncb3191 PG 9 WC Cell Biology SC Cell Biology GA CO0NE UT WOS:000358847700001 PM 26121555 ER PT J AU Eleveld, TF Oldridge, DA Bernard, V Koster, J Daage, LC Diskin, SJ Schild, L Bentahar, NB Bellini, A Chicard, M Lapouble, E Combaret, V Legoix-Ne, P Michon, J Pugh, TJ Hart, LS Rader, J Attiyeh, EF Wei, JS Zhang, SL Naranjo, A Gastier-Foster, JM Hogarty, MD Asgharzadeh, S Smith, MA Auvil, JMG Watkins, TBK Zwijnenburg, DA Ebus, ME van Sluis, P Hakkert, A van Wezel, E van der Schoot, CE Westerhout, EM Schulte, JH Tytgat, GA Dolman, MEM Janoueix-Lerosey, I Gerhard, DS Caron, HN Delattre, O Khan, J Versteeg, R Schleiermacher, G Molenaar, JJ Maris, JM AF Eleveld, Thomas F. Oldridge, Derek A. Bernard, Virginie Koster, Jan Daage, Leo Colmet Diskin, Sharon J. Schild, Linda Bentahar, Nadia Bessoltane Bellini, Angela Chicard, Mathieu Lapouble, Eve Combaret, Valerie Legoix-Ne, Patricia Michon, Jean Pugh, Trevor J. Hart, Lori S. Rader, JulieAnn Attiyeh, Edward F. Wei, Jun S. Zhang, Shile Naranjo, Arlene Gastier-Foster, Julie M. Hogarty, Michael D. Asgharzadeh, Shahab Smith, Malcolm A. Auvil, Jaime M. Guidry Watkins, Thomas B. K. Zwijnenburg, Danny A. Ebus, Marli E. van Sluis, Peter Hakkert, Anne van Wezel, Esther van der Schoot, C. Ellen Westerhout, Ellen M. Schulte, Johannes H. Tytgat, Godelieve A. Dolman, M. Emmy M. Janoueix-Lerosey, Isabelle Gerhard, Daniela S. Caron, Huib N. Delattre, Olivier Khan, Javed Versteeg, Rogier Schleiermacher, Gudrun Molenaar, Jan J. Maris, John M. TI Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations SO NATURE GENETICS LA English DT Article ID SEQUENCING DATA; CHROMOSOME 1P; ALK MUTATIONS; HUMAN CANCER; THERAPY; COMBINATION; PROGRESSION; ASSOCIATION; SENSITIVITY; CRIZOTINIB AB The majority of patients with neuroblastoma have tumors that initially respond to chemotherapy, but a large proportion will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole-genome sequencing of 23 paired diagnostic and relapse neuroblastomas showed clonal evolution from the diagnostic tumor, with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK pathway. Seven of these events were detected only in the relapse tumor, whereas the others showed clonal enrichment. In neuroblastoma cell lines, we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18; 61%), and these lesions predicted sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastomas and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease. C1 [Eleveld, Thomas F.; Koster, Jan; Schild, Linda; Zwijnenburg, Danny A.; Ebus, Marli E.; van Sluis, Peter; Hakkert, Anne; Westerhout, Ellen M.; Dolman, M. Emmy M.; Versteeg, Rogier; Molenaar, Jan J.] Univ Amsterdam, Acad Med Ctr, Dept Oncogen, NL-1105 AZ Amsterdam, Netherlands. [Oldridge, Derek A.; Diskin, Sharon J.; Hart, Lori S.; Rader, JulieAnn; Attiyeh, Edward F.; Hogarty, Michael D.; Maris, John M.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Oldridge, Derek A.; Diskin, Sharon J.; Hart, Lori S.; Rader, JulieAnn; Attiyeh, Edward F.; Hogarty, Michael D.; Maris, John M.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. [Oldridge, Derek A.; Diskin, Sharon J.; Attiyeh, Edward F.; Hogarty, Michael D.; Maris, John M.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Bernard, Virginie; Daage, Leo Colmet; Bentahar, Nadia Bessoltane; Legoix-Ne, Patricia] Inst Curie, ICGEX Platform, Paris, France. [Daage, Leo Colmet; Bellini, Angela; Chicard, Mathieu; Schleiermacher, Gudrun] Inst Curie, Transfer Dept, Lab RTOP, Paris, France. [Lapouble, Eve] Inst Curie, Unite Genet Somat, Paris, France. [Combaret, Valerie] Ctr Leon Berard, Lab Rech Translat Lyon, F-69373 Lyon, France. [Michon, Jean; Schleiermacher, Gudrun] Inst Curie, Dept Pediat, Paris, France. [Pugh, Trevor J.] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Pugh, Trevor J.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Wei, Jun S.; Zhang, Shile; Khan, Javed] NIH, Pediat Oncol Branch, Oncogen Sect, Ctr Canc Res, Gaithersburg, MD USA. [Naranjo, Arlene] Univ Florida, Dept Biostat, COG, Gainesville, FL USA. [Gastier-Foster, Julie M.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Gastier-Foster, Julie M.; Gerhard, Daniela S.] Nationwide Childrens Hosp, Biopathol Ctr, Columbus, OH USA. [Asgharzadeh, Shahab] Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA. [Asgharzadeh, Shahab] Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA. [Asgharzadeh, Shahab] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Auvil, Jaime M. Guidry] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Watkins, Thomas B. K.] Canc Res UK, Translat Canc Therapeut Lab, London, England. [van Wezel, Esther; van der Schoot, C. Ellen] Sanquin Res, Dept Expt Immunohematol, Amsterdam, Netherlands. [van Wezel, Esther; van der Schoot, C. Ellen] Univ Amsterdam, Acad Med Ctr, Landsteiner Lab, NL-1105 AZ Amsterdam, Netherlands. [Schulte, Johannes H.] Charite, Dept Pediat Oncol & Hematol, D-13353 Berlin, Germany. [Schulte, Johannes H.] German Consortium Translat Canc Res DKTK, Heidelberg, Germany. [Schulte, Johannes H.] Univ Childrens Hosp Essen, Dept Pediat Oncol & Hematol, Essen, Germany. [Schulte, Johannes H.] Univ Hosp Essen, West German Canc Ctr WTZ, Translat Neurooncol, Essen, Germany. [Tytgat, Godelieve A.; Caron, Huib N.] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Dept Pediat Oncol, NL-1105 AZ Amsterdam, Netherlands. [Janoueix-Lerosey, Isabelle; Delattre, Olivier; Schleiermacher, Gudrun] Inst Curie, Lab Genet & Biol Canc, INSERM U830, Paris, France. RP Schleiermacher, G (reprint author), Inst Curie, Transfer Dept, Lab RTOP, Paris, France. EM gudrun.schleiermacher@curie.fr; j.j.molenaar@amc.uva.nl; maris@chop.edu RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU US National Institutes of Health [RC1MD004418, HHSN261200800001E]; University of Pennsylvania Genome Frontiers Institute; National Cancer Institute; Annenberg Foundation; Nelia and Amadeo Barletta Foundation; SiRIC/INCa [INCa-DGOS-4654]; Comite d'Evaluation et Suivi des Projets de Recherche de Transfert (CEST) of Institut Curie; Associations Enfants et Sante; Association Hubert Gouin Enfance et Cancer; Les Bagouz a Manon; Les Amis de Claire; EQUIPEX Investissements d'Avenir program [ANR-10-EQPX-03]; Agence Nationale de le Recherche [ANR10-INBS-09-08]; Canceropole Ile-de-France; Villa Joep Foundation; Kinderen Kankervrij Foundation; Netherlands Cancer Foundation FX The authors would like to thank N. Ross for sample preparation and quality control. This study was supported in part by US National Institutes of Health grants RC1MD004418 to the TARGET consortium and CA98543 and CA98413 to the Children's Oncology Group and was supported in part by a grant throughout the University of Pennsylvania Genome Frontiers Institute. In addition, this project was funded in part with federal funds from the National Cancer Institute, US National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services nor does mention of trade names, commercial products or organizations imply endorsement by the US government. The binimetinib xenograft studies were supported through a research collaborative agreement between the Children's Hospital of Philadelphia and Novartis Pharmaceuticals. In France, this study was supported by the Annenberg Foundation and the Nelia and Amadeo Barletta Foundation. Funding was also obtained from SiRIC/INCa (grant INCa-DGOS-4654) and from the Comite d'Evaluation et Suivi des Projets de Recherche de Transfert (CEST) of Institut Curie. This study was also funded by the Associations Enfants et Sante, Association Hubert Gouin Enfance et Cancer, Les Bagouz a Manon and Les Amis de Claire. Deep sequencing experiments were conducted on the ICGex next-generation sequencing platform at the Institut Curie funded by the EQUIPEX Investissements d'Avenir program (ANR-10-EQPX-03) and ANR10-INBS-09-08 from the Agence Nationale de le Recherche and by the Canceropole Ile-de-France. In the Netherlands, this study was supported by grants from the Villa Joep Foundation, the Kinderen Kankervrij Foundation and the Netherlands Cancer Foundation. NR 42 TC 57 Z9 57 U1 1 U2 17 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 2015 VL 47 IS 8 BP 864 EP + DI 10.1038/ng.3333 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CN8FG UT WOS:000358674100008 PM 26121087 ER PT J AU Kelemen, LE Lawrenson, K Tyrer, J Li, Q Lee, JM Seo, JH Phelan, CM Beesley, J Chen, XQ Spindler, TJ Aben, KKH Anton-Culver, H Antonenkova, N Baker, H Bandera, EV Bean, Y Beckmann, MW Bisogna, M Bjorge, L Bogdanova, N Brinton, LA Brooks-Wilson, A Bruinsma, F Butzow, R Campbell, IG Carty, K Chang-Claude, J Chen, YA Chen, ZH Cook, LS Cramer, DW Cunningham, JM Cybulski, C Dansonka-Mieszkowska, A Dennis, J Dicks, E Doherty, JA Dicks, E Doherty, JA Dork, T du Bois, A Durst, M Eccles, D Easton, DT Edwards, RP Eilber, U Ekici, AB Engelholm, SA Fasching, PA Fridley, BL Gao, YT Gentry-Maharaj, A Giles, GG Glasspool, R Goode, EL Goodman, MT Grownwald, J Harrington, P Harter, P Hasmad, HN Hein, A Heitz, F Hildebrandt, MAT Hillemanns, P Hogdall, E Hogdall, C Hosono, S Iversen, ES Jakubowska, A Jensen, A Ji, BT Karlan, BY Kellar, M Kelley, JL Kiemeney, LA Krakstad, C Kjaer, SK Kupryjanczyk, J Lambrechts, D Lambrechts, S Le, ND Lee, AW Lele, S Leminen, A Lester, J Levine, DA Liang, D Lissowska, J Lu, KR Lubinski, J Lundvall, L Massuger, LFAG Matsuo, K McGuire, V McLaughlin, JR McNeish, I Menon, U Modugno, F Moes-Sosnowska, J Moysich, KB Narod, SA Nedergaard, L Ness, RB Nevanlinna, H Adenan, NAM Odunsi, K Olson, SH Orlow, I Orsulic, S Weber, RP Paul, J Pearce, CL Pejovic, T Pelttari, LM Permuth-Wey, J Pike, MC Poole, EM Ramus, SJ Risch, HA Rosen, B Rossing, MA Rothstein, JH Rudolph, A Runnebaum, IB Rzepecka, IK Salvesen, HB Schildkraut, JM Schwaab, I Shu, XO Shvetsov, YB Siddiqui, N Sieh, W Song, HL Southey, MC Sucheston, L Tangen, IL Teo, SH Terry, KL Thompson, PJ Tworoger, SS van Altena, AM Van Nieuwenhuysen, E Vergote, I Vierkant, RA Wang-Gohrke, S Walsh, C Wentzensen, N Whittemore, AS Wicklund, KG Wilkens, LR Sawicki, W Woo, YL Wu, XF Wu, AH Yang, H Zheng, W Ziogas, A Sellers, TA Freedman, ML Chenevix-Trench, G Pharoah, PDP Gayther, SA Berchuck, A AF Kelemen, Linda E. Lawrenson, Kate Tyrer, Jonathan Li, Qiyuan Lee, Janet M. Seo, Ji-Heui Phelan, Catherine M. Beesley, Jonathan Chen, Xiaoqing Spindler, Tassja J. Aben, Katja K. H. Anton-Culver, Hoda Antonenkova, Natalia Baker, Helen Bandera, Elisa V. Bean, Yukie Beckmann, Matthias W. Bisogna, Maria Bjorge, Line Bogdanova, Natalia Brinton, Louise A. Brooks-Wilson, Angela Bruinsma, Fiona Butzow, Ralf Campbell, Ian G. Carty, Karen Chang-Claude, Jenny Chen, Y. Ann Chen, Zhihua Cook, Linda S. Cramer, Daniel W. Cunningham, Julie M. Cybulski, Cezary Dansonka-Mieszkowska, Agnieszka Dennis, Joe Dicks, Ed Doherty, Jennifer A. Dicks, Ed Doherty, Jennifer A. Doerk, Thilo du Bois, Andreas Duerst, Matthias Eccles, Diana Easton, Douglas T. Edwards, Robert P. Eilber, Ursula Ekici, Arif B. Engelholm, Svend Aage Fasching, Peter A. Fridley, Brooke L. Gao, Yu-Tang Gentry-Maharaj, Aleksandra Giles, Graham G. Glasspool, Rosalind Goode, Ellen L. Goodman, Marc T. Grownwald, Jacek Harrington, Patricia Harter, Philipp Hasmad, Hanis Nazihah Hein, Alexander Heitz, Florian Hildebrandt, Michelle A. T. Hillemanns, Peter Hogdall, Estrid Hogdall, Claus Hosono, Satoyo Iversen, Edwin S. Jakubowska, Anna Jensen, Allan Ji, Bu-Tian Karlan, Beth Y. Kellar, Melissa Kelley, Joseph L. Kiemeney, Lambertus A. Krakstad, Camilla Kjaer, Susanne K. Kupryjanczyk, Jolanta Lambrechts, Diether Lambrechts, Sandrina Le, Nhu D. Lee, Alice W. Lele, Shashi Leminen, Arto Lester, Jenny Levine, Douglas A. Liang, Dong Lissowska, Jolanta Lu, Karen Lubinski, Jan Lundvall, Lene Massuger, Leon F. A. G. Matsuo, Keitaro McGuire, Valerie McLaughlin, John R. McNeish, Iain Menon, Usha Modugno, Francesmary Moes-Sosnowska, Joanna Moysich, Kirsten B. Narod, Steven A. Nedergaard, Lotte Ness, Roberta B. Nevanlinna, Heli Adenan, Noor Azmi Mat Odunsi, Kunle Olson, Sara H. Orlow, Irene Orsulic, Sandra Weber, Rachel Palmieri Paul, James Pearce, Celeste Leigh Pejovic, Tanja Pelttari, Liisa M. Permuth-Wey, Jennifer Pike, Malcolm C. Poole, Elizabeth M. Ramus, Susan J. Risch, Harvey A. Rosen, Barry Rossing, Mary Anne Rothstein, Joseph H. Rudolph, Anja Runnebaum, Ingo B. Rzepecka, Iwona K. Salvesen, Helga B. Schildkraut, Joellen M. Schwaab, Ira Shu, Xiao-Ou Shvetsov, Yurii B. Siddiqui, Nadeem Sieh, Weiva Song, Honglin Southey, Melissa C. Sucheston, Lara Tangen, Ingvild L. Teo, Soo-Hwang Terry, Kathryn L. Thompson, Pamela J. Tworoger, Shelley S. van Altena, Anne M. Van Nieuwenhuysen, Els Vergote, Ignace Vierkant, Robert A. Wang-Gohrke, Shan Walsh, Christine Wentzensen, Nicolas Whittemore, Alice S. Wicklund, Kristine G. Wilkens, Lynne R. Sawicki, Wlodzimierz Woo, Yin-Ling Wu, Xifeng Wu, Anna H. Yang, Hannah Zheng, Wei Ziogas, Argyrios Sellers, Thomas A. Freedman, Matthew L. Chenevix-Trench, Georgia Pharoah, Paul D. P. Gayther, Simon A. Berchuck, Andrew CA Australian Canc Study Australian Ovarian Canc Study Grp Ovarian Canc Assoc Consortium TI Genome-wide significant risk associations for mucinous ovarian carcinoma SO NATURE GENETICS LA English DT Article ID IDENTIFIES SUSCEPTIBILITY LOCI; BREAST-CANCER RISK; COLORECTAL-CANCER; MOLECULAR CHARACTERIZATION; ANALYSES REVEAL; FALLOPIAN-TUBE; HEPATITIS-C; CELL-TYPE; TUMORS; GENES AB Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 x 10(-8)), rs711830 at 2q31.1 (P = 7.5 x 10(-12)) and rs688187 at 19q13.2 (P = 6.8 x 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 x 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease. C1 [Kelemen, Linda E.] Med Univ S Carolina, Coll Med, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Lawrenson, Kate; Lee, Janet M.; Spindler, Tassja J.; Lee, Alice W.; Pearce, Celeste Leigh; Pike, Malcolm C.; Ramus, Susan J.; Wu, Anna H.; Gayther, Simon A.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Tyrer, Jonathan; Harrington, Patricia; Song, Honglin; Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Li, Qiyuan] Xiamen Univ, Coll Med, Xiamen, Peoples R China. [Li, Qiyuan; Seo, Ji-Heui; Freedman, Matthew L.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Dept Med Oncol, Boston, MA 02115 USA. [Phelan, Catherine M.; Permuth-Wey, Jennifer; Sellers, Thomas A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Beesley, Jonathan; Chen, Xiaoqing; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Canc Genet, Brisbane, Qld, Australia. [Aben, Katja K. H.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands. [Aben, Katja K. H.] Comprehens Canc Ctr Netherlands, Utrecht, Netherlands. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Genet Epidemiol Res Inst, Dept Epidemiol, Irvine, CA 92717 USA. [Antonenkova, Natalia] Byelorussian Inst Oncol & Med Radiol Aleksandrov, Minsk, Byelarus. [Baker, Helen; Dennis, Joe; Dicks, Ed; Easton, Douglas T.; Song, Honglin; Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Bandera, Elisa V.] Rutgers State Univ, Canc Inst New Jersey, Canc Prevent & Control Program, New Brunswick, NJ 08903 USA. [Bean, Yukie; Kellar, Melissa; Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Bean, Yukie; Kellar, Melissa; Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Beckmann, Matthias W.; Fasching, Peter A.; Hein, Alexander] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Bisogna, Maria; Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Bjorge, Line; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway. [Bjorge, Line; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway. [Bogdanova, Natalia; Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Brinton, Louise A.; Ji, Bu-Tian; Wentzensen, Nicolas; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Brooks-Wilson, Angela] British Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Bruinsma, Fiona; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Australia. [Butzow, Ralf] Univ Helsinki, Dept Pathol, Helsinki, Finland. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Helsinki Univ Hosp, Helsinki, Finland. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Campbell, Ian G.] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, East Melbourne, Vic, Australia. [Campbell, Ian G.; Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Campbell, Ian G.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia. [Carty, Karen; Glasspool, Rosalind; Paul, James] Beatson West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland. [Chang-Claude, Jenny; Eilber, Ursula; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chen, Y. Ann; Chen, Zhihua] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat, Tampa, FL USA. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Cramer, Daniel W.; Poole, Elizabeth M.; Terry, Kathryn L.; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstetr & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol, Rochester, MN USA. [Cybulski, Cezary; Grownwald, Jacek; Jakubowska, Anna; Lubinski, Jan] West Pomeranian Univ Technol, Int Hereditary Canc Ctr, Dept Genet & Pathol, PL-70310 Szczecin, Poland. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Moes-Sosnowska, Joanna; Rzepecka, Iwona K.] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Pathol & Lab Diagnost, Warsaw, Poland. [Doherty, Jennifer A.] Geisel Sch Med, Dept Epidemiol, Lebanon, NH USA. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, Essen, Germany. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [Duerst, Matthias; Runnebaum, Ingo B.] Univ Jena, Jena Univ Hospital, Dept Gynecol, Jena, Germany. [Eccles, Diana] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Edwards, Robert P.; Kelley, Joseph L.; Modugno, Francesmary] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Div Gynecol Oncol, Pittsburgh, PA USA. [Edwards, Robert P.; Kelley, Joseph L.; Modugno, Francesmary] Univ Pittsburgh, Ovarian Canc Ctr Excellence, Pittsburgh, PA USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Ctr Comprehens Canc, Inst Human Genet, D-91054 Erlangen, Germany. [Engelholm, Svend Aage] Univ Copenhagen, Rigshosp, Dept Radiat Oncol, DK-2100 Copenhagen, Denmark. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Inst Womens Hlth, Gynaecol Canc Res Ctr, Dept Womens Canc, London, England. [Giles, Graham G.] Univ Melbourne, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Community & Populat Hlth Res Inst, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Hasmad, Hanis Nazihah; Teo, Soo-Hwang] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya, Malaysia. [Hildebrandt, Michelle A. T.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Hillemanns, Peter] Hannover Med Sch, Clin Obstet & Gynaecol, Hannover, Germany. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Copenhagen, Denmark. [Hogdall, Estrid; Jensen, Allan; Kjaer, Susanne K.] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Hogdall, Claus; Kjaer, Susanne K.; Lundvall, Lene; Nedergaard, Lotte] Univ Copenhagen, Rigshosp, Dept Gynaecol, DK-2100 Copenhagen, Denmark. [Hosono, Satoyo] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra; Walsh, Christine] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Lambrechts, Diether] Univ Leuven, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Lambrechts, Sandrina; Van Nieuwenhuysen, Els; Vergote, Ignace] Univ Hosp Leuven, Dept Obstet & Gynaecol, Div Gynecol Oncol, Leuven, Belgium. [Lambrechts, Sandrina; Van Nieuwenhuysen, Els; Vergote, Ignace] Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. [Le, Nhu D.] British Columbia Canc Agcy, Canc Control Res, Vancouver, BC V5Z 4E6, Canada. [Lele, Shashi; Moysich, Kirsten B.; Sucheston, Lara] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Liang, Dong] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lu, Karen] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Massuger, Leon F. A. G.; van Altena, Anne M.] Radboud Univ Nijmegen, Med Ctr, Dept Obstet & Gynecol, NL-6525 ED Nijmegen, Netherlands. [Matsuo, Keitaro; Rothstein, Joseph H.] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Nagoya, Aichi, Japan. [McGuire, Valerie; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [McLaughlin, John R.] Publ Hlth Ontario, Toronto, ON, Canada. [McNeish, Iain] Univ Glasgow, Wolfson Wohl Canc Res Ctr, Beatson Inst Canc Res, Inst Canc Sci, Glasgow, Lanark, Scotland. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Adenan, Noor Azmi Mat; Woo, Yin-Ling] Univ Malaya, Med Ctr, Dept Obstet & Gynaecol, Kuala Lumpur, Malaysia. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Olson, Sara H.; Orlow, Irene; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Weber, Rachel Palmieri; Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC USA. [Pearce, Celeste Leigh] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Univ, Sch Med, Boston, MA USA. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Rosen, Barry] Univ Toronto, Dept Obstet & Gynecol, Toronto, ON, Canada. [Rossing, Mary Anne; Wicklund, Kristine G.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Schildkraut, Joellen M.] Duke Canc Inst, Durham, NC USA. [Schwaab, Ira] Praxis Humangenet, Wiesbaden, Germany. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Dept Med,Div Epidemiol, Nashville, TN 37212 USA. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Shvetsov, Yurii B.; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland. [Teo, Soo-Hwang; Woo, Yin-Ling] Univ Malaya, Fac Med, Med Ctr, Canc Res Inst, Kuala Lumpur, Malaysia. [Vierkant, Robert A.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, D-89069 Ulm, Germany. [Sawicki, Wlodzimierz] Med Univ Warsaw, Fac Med 2, Dept Obstet Gynecol & Oncol, Warsaw, Poland. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. RP Gayther, SA (reprint author), Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. EM simon.gayther@med.usc.edu RI salvesen, Helga/C-1187-2017; Bjorge, Line/C-1307-2017; Hein, Alexander/F-6999-2010; Massuger, Leon/H-8072-2014; Kiemeney, Lambertus/D-3357-2009; Brooks-Wilson, Angela/E-9399-2012; van Altena, Anne/B-9824-2016; Dork, Thilo/J-8620-2012; Teo, Soo-hwang/H-2353-2014; Aben, Katja/G-9686-2016; Bowtell, David/H-1007-2016; Woo, Yin Ling/B-5198-2010 OI salvesen, Helga/0000-0002-4438-8831; Glasspool, Rosalind/0000-0002-5000-1680; Kjaer, Susanne/0000-0002-8347-1398; Ramus, Susan/0000-0003-0005-7798; McNeish, Iain/0000-0002-9387-7586; Orlow, Irene/0000-0001-6234-6961; Krakstad, Camilla/0000-0002-0174-8139; Giles, Graham/0000-0003-4946-9099; Matsuo, Keitaro/0000-0003-1761-6314; Bjorge, Line/0000-0002-0240-2770; Hein, Alexander/0000-0003-2601-3398; Kiemeney, Lambertus/0000-0002-2368-1326; Brooks-Wilson, Angela/0000-0003-1009-6408; Aben, Katja/0000-0002-0214-2147; Bowtell, David/0000-0001-9089-7525; Woo, Yin Ling/0000-0003-1742-1066 FU European Commission [223175-HEALTH-F2-2009-223175]; Ovarian Cancer Research Fund [PPD/RPCI.07]; Genetic Associations and Mechanisms in Oncology (GAME-ON); National Cancer Institute Cancer Post-GWAS Initiative [U19-CA148112]; Wellcome Trust [076113] FX We thank all the individuals who took part in this study and all the researchers, clinicians, and technical and administrative staff who made possible the many studies contributing to this work (a full list is provided in the Supplementary Note). The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement 223175-HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were supported in part by Genetic Associations and Mechanisms in Oncology (GAME-ON) and a National Cancer Institute Cancer Post-GWAS Initiative (U19-CA148112). Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control Consortium; funding for the project was provided by the Wellcome Trust under award 076113. A full list of the investigators who contributed to the generation of the data is available from the consortium website (see URLs). The results published here are based in part on data generated by The Cancer Genome Atlas (TCGA) Pilot Project established by the National Cancer Institute and National Human Genome Research Institute; information about TCGA and the investigators and institutions who constitute the TCGA research network can be found on the project website (see URLs). NR 71 TC 8 Z9 8 U1 3 U2 25 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 2015 VL 47 IS 8 BP 888 EP 897 DI 10.1038/ng.3336 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CN8FG UT WOS:000358674100012 PM 26075790 ER PT J AU Childs, EJ Mocci, E Campa, D Bracci, PM Gallinger, S Goggins, M Li, DH Neale, RE Olson, SH Scelo, G Amundadottir, LT Bamlet, WR Bijlsma, MF Blackford, A Borges, M Brennan, P Brenner, H Bueno-de-Mesquita, HB Canzian, F Capurso, G Cavestro, GM Chaffee, KG Chanock, SJ Cleary, SP Cotterchio, M Foretova, L Fuchs, C Funel, N Gazouli, M Hassan, M Herman, JM Holcatova, I Holly, EA Hoover, RN Hung, RJ Janout, V Key, TJ Kupcinskas, J Kurtz, RC Landi, S Lu, LG Malecka-Panas, E Mambrini, A Mohelnikova-Duchonova, B Neoptolemos, JP Oberg, AL Orlow, I Pasquali, C Pezzilli, R Rizzato, C Saldia, A Scarpa, A Stolzenberg-Solomon, RZ Strobel, O Tavano, F Vashist, YK Vodicka, P Wolpin, BM Yu, H Petersen, GM Risch, HA Klein, AP AF Childs, Erica J. Mocci, Evelina Campa, Daniele Bracci, Paige M. Gallinger, Steven Goggins, Michael Li, Donghui Neale, Rachel E. Olson, Sara H. Scelo, Ghislaine Amundadottir, Laufey T. Bamlet, William R. Bijlsma, Maarten F. Blackford, Amanda Borges, Michael Brennan, Paul Brenner, Hermann Bueno-de-Mesquita, H. Bas Canzian, Federico Capurso, Gabriele Cavestro, Giulia M. Chaffee, Kari G. Chanock, Stephen J. Cleary, Sean P. Cotterchio, Michelle Foretova, Lenka Fuchs, Charles Funel, Niccola Gazouli, Maria Hassan, Manal Herman, Joseph M. Holcatova, Ivana Holly, Elizabeth A. Hoover, Robert N. Hung, Rayjean J. Janout, Vladimir Key, Timothy J. Kupcinskas, Juozas Kurtz, Robert C. Landi, Stefano Lu, Lingeng Malecka-Panas, Ewa Mambrini, Andrea Mohelnikova-Duchonova, Beatrice Neoptolemos, John P. Oberg, Ann L. Orlow, Irene Pasquali, Claudio Pezzilli, Raffaele Rizzato, Cosmeri Saldia, Amethyst Scarpa, Aldo Stolzenberg-Solomon, Rachael Z. Strobel, Oliver Tavano, Francesca Vashist, Yogesh K. Vodicka, Pavel Wolpin, Brian M. Yu, Herbert Petersen, Gloria M. Risch, Harvey A. Klein, Alison P. TI Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENOTYPE IMPUTATION; LUNG ADENOCARCINOMA; CIGARETTE-SMOKING; GENETIC-VARIATION; ALPHA-GENE; RISK; LOCI; POPULATION; MUTATIONS AB Pancreatic cancer is the fourth leading cause of cancer death in the developed world(1). Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM(3), PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A(7) and mismatch-repair genes(8) and low-penetrance loci are associated with increased risk(9-12). To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 x 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 x 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 x 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 x 10(-9)), a region with previous suggestive evidence in Han Chinese(12). We replicated previously reported associations at 9q34.2 (ABO)(9), 13q22.1 (KLF5)(10), 5p15.33 (TERT and CLPTM1)(10,11), 13q12.2 (PDX1)(11), 1q32.1 (NR5A2)(10), 7q32.3 (LINC-PINT)(11), 16q23.1 (BCAR1)(11) and 22q12.1 (ZNRF3)(11). Our study identifies new loci associated with pancreatic cancer risk. C1 [Childs, Erica J.] Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Mocci, Evelina; Blackford, Amanda; Klein, Alison P.] Sidney Kimmel Comprehens Canc Ctr, Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD 21218 USA. [Campa, Daniele] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Campa, Daniele] Univ Pisa, Dept Biol, Pisa, Italy. [Bracci, Paige M.; Holly, Elizabeth A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Gallinger, Steven; Hung, Rayjean J.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Goggins, Michael; Borges, Michael; Klein, Alison P.] Sol Goldman Pancreat Canc Res Ctr, Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. [Li, Donghui; Hassan, Manal] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Neale, Rachel E.] QIMR Berghofer Med Res Inst, Dept Populat Hlth, Kelvin Grove, Qld, Australia. [Olson, Sara H.; Orlow, Irene; Saldia, Amethyst] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Scelo, Ghislaine; Brennan, Paul] IARC, Lyon, France. [Amundadottir, Laufey T.; Chanock, Stephen J.; Hoover, Robert N.] NCI, Div Canc Epidemiol & Genet, US Natl Inst Hlth, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bamlet, William R.; Chaffee, Kari G.; Oberg, Ann L.; Petersen, Gloria M.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Bijlsma, Maarten F.] Univ Amsterdam, Acad Med Ctr, Lab Expt Oncol & Radiobiol, NL-1105 AZ Amsterdam, Netherlands. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Bueno-de-Mesquita, H. Bas] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur, Malaysia. [Canzian, Federico; Rizzato, Cosmeri] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Capurso, Gabriele] Univ Roma La Sapienza, Digest & Liver Dis Unit, I-00185 Rome, Italy. [Cavestro, Giulia M.] Univ Vita Salute San Raffaele, Milan, Italy. [Cavestro, Giulia M.] IRCCS, Osped San Raffaele, Milan, Italy. [Cleary, Sean P.] Univ Toronto, Dept Surg, Univ Hlth Network, Toronto, ON, Canada. [Cleary, Sean P.] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Cotterchio, Michelle] Univ Toronto, Canc Care Ontario, Toronto, ON, Canada. [Cotterchio, Michelle] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Foretova, Lenka] Masaryk Univ, Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Foretova, Lenka] Masaryk Univ, Fac Med, Brno, Czech Republic. [Fuchs, Charles; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Fuchs, Charles; Wolpin, Brian M.] Harvard Univ, Sch Med, Boston, MA USA. [Funel, Niccola] Univ Hosp Pisa, Unit Expt Surg Pathol, Dept Surg, Pisa, Italy. [Gazouli, Maria] Univ Athens, Sch Med, Biol Lab, Dept Med Sci, GR-11527 Athens, Greece. [Herman, Joseph M.] Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Radiat Oncol, Baltimore, MD USA. [Holcatova, Ivana] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Janout, Vladimir] Palacky Univ, Fac Med, Dept Prevent Med, CR-77147 Olomouc, Czech Republic. [Key, Timothy J.] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Kupcinskas, Juozas] Lithuanian Univ Hlth Sci, Dept Gastroenterol, Kaunas, Lithuania. [Kurtz, Robert C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Landi, Stefano] Univ Pisa, Genet Sect, Dept Biol, Pisa, Italy. [Lu, Lingeng; Risch, Harvey A.] Yale Univ, Sch Med, Dept Chron Dis Epidemiol, New Haven, CT USA. [Malecka-Panas, Ewa] Med Univ Lodz, Dept Digest Tract Dis, Lodz, Poland. [Mambrini, Andrea] Azienda USL 1 Massa Carrara, Dept Oncol, Massa Carrara, Italy. [Mohelnikova-Duchonova, Beatrice] Inst Publ Hlth, Lab Toxicogen, Prague, Czech Republic. [Neoptolemos, John P.] Univ Liverpool, NIHR, Pancreas Biomed Res Unit, Liverpool Clin Trials Unit, Liverpool L69 3BX, Merseyside, England. [Neoptolemos, John P.] Univ Liverpool, Canc Res UK Clin Trials Unit, Dept Mol & Clin Canc Med, Inst Translat Med, Liverpool L69 3BX, Merseyside, England. [Pasquali, Claudio] Univ Padua, Dept Surg Gastroenterol & Oncol, Padua, Italy. [Pezzilli, Raffaele] St Orsola Malpighi Hosp, Dept Digest Dis, Pancreas Unit, Bologna, Italy. [Scarpa, Aldo] Univ & Hosp Trust Verona, ARC NET Ctr Appl Res Canc, Verona, Italy. [Stolzenberg-Solomon, Rachael Z.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, US Natl Inst Hlth, Rockville, MD USA. [Strobel, Oliver] Univ Heidelberg Hosp, Dept Gen Surg, Heidelberg, Germany. [Tavano, Francesca] IRCCS Sci Inst, Div Gastroenterol & Res Lab, San Giovanni Rotondo, Italy. [Tavano, Francesca] Reg Gen Hosp Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. [Vashist, Yogesh K.] Univ Med Ctr Hamburg Eppendorf, Dept Gen Visceral & Thorac Surg, Hamburg, Germany. [Vodicka, Pavel] Acad Sci Czech Republic, Inst Expt Med, Dept Mol Biol Canc, Prague, Czech Republic. [Wolpin, Brian M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Yu, Herbert] Univ Hawaii, Ctr Canc, Epidemiol Program, Honolulu, HI 96822 USA. RP Klein, AP (reprint author), Sidney Kimmel Comprehens Canc Ctr, Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD 21218 USA. EM aklein1@jhmi.edu RI Hung, Rayjean/A-7439-2013; Janout, Vladimir/M-5133-2014; Gallinger, Steven/E-4575-2013; Campa, Daniele/K-1617-2016; Tavano, Francesca/K-2203-2016; scarpa, aldo/K-6832-2016; Brenner, Hermann/B-4627-2017; OI Neale, Rachel/0000-0001-7162-0854; Orlow, Irene/0000-0001-6234-6961; Campa, Daniele/0000-0003-3220-9944; Tavano, Francesca/0000-0002-8831-7349; scarpa, aldo/0000-0003-1678-739X; Brenner, Hermann/0000-0002-6129-1572; Funel, Niccola/0000-0002-5028-2363; Landi, Stefano/0000-0001-8364-6357 FU National Cancer Institute/US National Institutes of Health [RO1 CA154823, P30 CA008748]; US National Institutes of Health [HHSN268201100011I]; National Cancer Institute, US National Institutes of Health [R03 CA123546-02]; Ministry of Health of the Czech Republic [NR 9029-4/2006, NR9422-3, NR9998-3, MH CZ-DRO-MMCI 00209805]; National Cancer Institute [P50 CA62924, R01 CA97075]; Mayo Clinic Specialized Programs of Research Excellence (SPORE) in Pancreatic Cancer [P50 CA102701]; Geoffrey Beene Foundation; Arnold and Arlene Goldstein Family Foundation; Society of the Memorial Sloan Kettering Cancer Center; National Health and Medical Research Council of Australia (NHMRC) [442302, 1060183]; US National Institutes of Health/National Cancer Institute [R01 CA1009767, R01 CA109767-S1, 5R01 CA098870]; Joan Rombauer Pancreatic Cancer Fund; California Department of Public Health; National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program [HHSN261201000140C]; US Centers for Disease Control and Prevention (CDC) National Program of Cancer Registries [U58 DP003862-01]; Czech Science Foundation [P301/12/1734]; Internal Grant Agency of the Czech Ministry of Health [IGA NT 13 263]; Ministry of Research, Science and Arts of Baden-Wurttemberg state; Heidelberger EPZ Pancobank [01GS08114]; BMBH [01EY1101]; Dutch Cancer Society project [2012-5607]; Academic Medical Center Foundation; Italian government; Italian Ministry of Health [RC1203GA57, RC1303GA53, RC1303GA54, RC1303GA50]; Italian Association for Research on Cancer [AIRC 12182]; Italian Ministry of Research [FIRB-RBAP10AHJB]; Italian FIMP-Ministry of Health [CUP_J33G13000210001]; National Institute for Health Research (NIHR) Liverpool Pancreas Biomedical Research Unit, UK FX This work was supported by National Cancer Institute/US National Institutes of Health grant RO1 CA154823. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the US National Institutes of Health to the Johns Hopkins University, contract HHSN268201100011I.; The IARC/Central Europe study was supported by a grant from the National Cancer Institute, US National Institutes of Health (R03 CA123546-02) and by grants from the Ministry of Health of the Czech Republic (NR 9029-4/2006, NR9422-3, NR9998-3 and MH CZ-DRO-MMCI 00209805).; The work at Johns Hopkins University was supported by National Cancer Institute grants P50 CA62924 and R01 CA97075. Additional support was provided by Susan Wojcicki and Dennis Troper.; The Mayo Clinic Molecular Epidemiology of Pancreatic Cancer study is supported by the Mayo Clinic Specialized Programs of Research Excellence (SPORE) in Pancreatic Cancer (P50 CA102701).; The Memorial Sloan Kettering Cancer Center Pancreatic Tumor Registry is supported by National Cancer Institute/US National Institutes of Health grant P30 CA008748, the Geoffrey Beene Foundation, the Arnold and Arlene Goldstein Family Foundation and the Society of the Memorial Sloan Kettering Cancer Center.; The Queensland Pancreatic Cancer Study was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC; grant 442302). R.E.N. is supported by an NHMRC Senior Research Fellowship (1060183).; The University of California San Francisco (UCSF) pancreas study was supported by US National Institutes of Health/National Cancer Institute grants (R01 CA1009767 and R01 CA109767-S1) and the Joan Rombauer Pancreatic Cancer Fund. Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program; the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California (CPIC); and the US Centers for Disease Control and Prevention (CDC) National Program of Cancer Registries, under agreement U58 DP003862-01 awarded to the California Department of Public Health.; The Yale (Connecticut) pancreas study is supported by US National Institutes of Health/National Cancer Institute grant 5R01 CA098870. The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access is gratefully acknowledged. The Connecticut Pancreas Cancer Study was approved by the Department of Public Health Human Investigation Committee of the state of Connecticut. Certain data used in that study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data.; Studies included in PANDoRA were partly funded by the Czech Science Foundation (P301/12/1734) and the Internal Grant Agency of the Czech Ministry of Health (IGA NT 13 263); the Ministry of Research, Science and Arts of Baden-Wurttemberg state (H.B.), the Heidelberger EPZ Pancobank (M.W. Buchler and team; T. Hackert, N.A. Giese, Ch. Tjaden, E. Soyka and M. Meinhardt; Heidelberger Stiftung Chirurgie and BMBF, grant 01GS08114), the BMBH (P. Schirmacher; BMBF grant 01EY1101), Dutch Cancer Society project grant 2012-5607 and the Academic Medical Center Foundation (M.F.B.), the "5x1000" voluntary contribution of the Italian government, the Italian Ministry of Health (RC1203GA57, RC1303GA53, RC1303GA54 and RC1303GA50), the Italian Association for Research on Cancer (A. Scarpa; AIRC 12182), the Italian Ministry of Research (A. Scarpa; FIRB-RBAP10AHJB), the Italian FIMP-Ministry of Health (A. Scarpa; CUP_J33G13000210001) and the National Institute for Health Research (NIHR) Liverpool Pancreas Biomedical Research Unit, UK. We would like to acknowledge the contribution of F. Dijk and O. Busch (Academic Medical Center, Amsterdam). NR 64 TC 29 Z9 30 U1 6 U2 33 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 2015 VL 47 IS 8 BP 911 EP + DI 10.1038/ng.3341 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA CN8FG UT WOS:000358674100016 PM 26098869 ER PT J AU Shen, Y Bax, A AF Shen, Yang Bax, Ad TI Homology modeling of larger proteins guided by chemical shifts SO NATURE METHODS LA English DT Article ID SPARSE NMR DATA; STRUCTURE GENERATION; DISTANCE MATRICES; ROSETTA; PREDICTION; ALIGNMENT; SEQUENCE; INFORMATION; BACKBONE; ACCURATE AB We describe an approach to the structure determination of large proteins that relies on experimental NMR chemical shifts, plus sparse nuclear Overhauser effect (NOE) data if available. Our alignment method, POMONA (protein alignments obtained by matching of NMR assignments), directly exploits pre-existing bioinformatics algorithms to match experimental chemical shifts to values predicted for the crystallographic database. Protein templates generated by POMONA are subsequently used as input for chemical shift-based Rosetta comparative modeling (CS-RosettaCM) to generate reliable full-atom models. C1 [Shen, Yang; Bax, Ad] NIDDK, Chem Phys Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Shen, Y (reprint author), NIDDK, Chem Phys Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM shenyang@niddk.nih.gov; bax@nih.gov RI Shen, Yang/C-3064-2008 OI Shen, Yang/0000-0003-1408-8034 FU Intramural Research Program of the NIDDK, US National Institutes of Health (NIH) FX This work was funded by the Intramural Research Program of the NIDDK, US National Institutes of Health (NIH). We thank Y. Song, N. Sgourakis and D. Baker for help and advice on the use of RosettaCM. We also gratefully acknowledge use of the NIH high-performance computational Biowulf Linux cluster. NR 30 TC 5 Z9 5 U1 6 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD AUG PY 2015 VL 12 IS 8 BP 747 EP U77 DI 10.1038/NMETH.3437 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CN8ZW UT WOS:000358736100018 PM 26053889 ER PT J AU Kong, LJ Tang, JY Little, JP Yu, Y Lammermann, T Lin, CP Germain, RN Cuil, M AF Kong, Lingjie Tang, Jianyong Little, Justin P. Yu, Yang Laemmermann, Tim Lin, Charles P. Germain, Ronald N. Cuil, Meng TI Continuous volumetric imaging via an optical phase-locked ultrasound lens SO NATURE METHODS LA English DT Article ID IN-VIVO; NEURONAL-ACTIVITY; MICROSCOPY; CELLS; LIGHT AB In vivo imaging at high spatiotemporal resolution is key to the understanding of complex biological systems. We integrated an optical phase-locked ultrasound lens into a two-photon fluorescence microscope and achieved microsecond-scale axial scanning, thus enabling volumetric imaging at tens of hertz. We applied this system to multicolor volumetric imaging of processes sensitive to motion artifacts, including calcium dynamics in behaving mouse brain and transient morphology changes and trafficking of immune cells. C1 [Kong, Lingjie; Little, Justin P.; Yu, Yang; Cuil, Meng] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Tang, Jianyong; Laemmermann, Tim; Germain, Ronald N.] NIAID, NIH, Bethesda, MD 20892 USA. [Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellm Ctr Photomed, Boston, MA USA. [Lin, Charles P.] Harvard Stem Cell Inst, Cambridge, MA USA. RP Cuil, M (reprint author), Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. EM cuirn@janelia.hhmi.org RI Yu, Yang/D-4071-2015; kong, lingjie/G-5822-2012 OI Yu, Yang/0000-0002-4340-430X; kong, lingjie/0000-0003-1974-3245 FU Howard Hughes Medical Institute; Intramural Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (NIH); NIH [P41 E8015903-02S1] FX L.K. and M.C. thank W. Gan and H. Dana for many helpful discussions on cerebral cortex imaging, T.-W. Chen for help on data analysis in the visual cortex experiments, S. Peron and N.-L. Xu (Janelia Research Campus) for providing animals during system calibration, K. Ritola (Janelia Research Campus) for preparing GCaMP6 virus, K. Morris and J. Rouchard for virus injections, J. Liu for help on cluster computing, P. Keller for suggestions on data storage, B.-C. Chen and W. Legant for suggestions on data visualization, V. Iyer for support on ScanImage, D. Milkie for developing the custom Labview program, S. Sawtelle and L. Ramasamy for making the low-noise high-speed comparator, V. Goncharov for testing high-speed photodetectors, J. Freeman and F. Amat for help on data analysis and the Howard Hughes Medical Institute for funding the project. This work was supported in part by the Intramural Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (NIH) (to R.N.G.), and NIH grant P41 E8015903-02S1 (to C.P.L.). NR 27 TC 23 Z9 24 U1 8 U2 33 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD AUG PY 2015 VL 12 IS 8 BP 759 EP U166 DI 10.1038/NMETH.3476 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CN8ZW UT WOS:000358736100021 PM 26167641 ER PT J AU Takebe, N Miele, L Harris, PJ Jeong, W Bando, H Kahn, M Yang, S Ivy, SP AF Takebe, Naoko Miele, Lucio Harris, Pamela Jo Jeong, Woondong Bando, Hideaki Kahn, Michael Yang, SherryX. Ivy, S. Percy TI Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID GAMMA-SECRETASE INHIBITOR; ADVANCED SOLID TUMORS; METASTATIC COLORECTAL-CANCER; ACUTE LYMPHOBLASTIC-LEUKEMIA; TO-MESENCHYMAL TRANSITION; NEGATIVE BREAST-CANCER; PHASE-II TRIAL; BETA-CATENIN; SIGNALING PATHWAY; INITIATING CELLS AB During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents. C1 [Takebe, Naoko; Harris, Pamela Jo; Ivy, S. Percy] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag,NIH, Bethesda, MD 20892 USA. [Miele, Lucio] Louisiana State Univ, Hlth Sci Ctr, Stanley Scott Canc Ctr, Baton Rouge, LA 70803 USA. [Miele, Lucio] Louisiana Canc Res Consortium, New Orleans, LA USA. [Jeong, Woondong] Univ Texas, Canc Therapy & Res Ctr, Austin, TX USA. [Bando, Hideaki] Natl Canc Ctr Hosp East, Dept Gastroenterol & Gastrointestinal Oncol, Tokyo, Japan. [Kahn, Michael] Univ So Calif, Norris Comprehens Canc Res Ctr, San Francisco, CA USA. [Yang, SherryX.] NCI, Natl Clin Target Validat Lab, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Ivy, SP (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag,NIH, 9609 Med Ctr Dr MSC9739, Bethesda, MD 20892 USA. EM Takeben@mail.nih.gov; ivyp@ctep.nci.nih.gov FU NCI NIH HHS [P01 CA166009] NR 175 TC 124 Z9 133 U1 28 U2 87 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 2015 VL 12 IS 8 BP 445 EP 464 DI 10.1038/nrclinonc.2015.61 PG 20 WC Oncology SC Oncology GA CN8FO UT WOS:000358675100005 PM 25850553 ER PT J AU Basseville, A Bates, S Fojo, T AF Basseville, Agnes Bates, Susan Fojo, Tito TI Targeting KRAS and the vitamin D receptor via microtubules SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID PANCREATIC-CANCER; NAB-PACLITAXEL; GEMCITABINE; TRAFFICKING; RAS AB Pancreatic cancer remains a difficult-to-treat malignancy, yet nab-paclitaxel plus gemcitabine prolongs survival. Closer examination of the mechanism of action of nab-paclitaxel hints at a role for targeting KRAS. We discuss how nab-paclitaxel may be active in pancreatic cancer and how this informs the way forward to better treat patients with pancreatic cancer. C1 [Basseville, Agnes; Bates, Susan; Fojo, Tito] NCI, Med Oncol, Ctr Canc Res, Bethesda, MD 20892 USA. RP Fojo, T (reprint author), NCI, Med Oncol, Ctr Canc Res, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM fojot@mail.nih.gov NR 10 TC 1 Z9 1 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD AUG PY 2015 VL 12 IS 8 DI 10.1038/nrclinonc.2015.125 PG 2 WC Oncology SC Oncology GA CN8FO UT WOS:000358675100004 ER PT J AU Wouters, OJ O'Donoghue, DJ Ritchie, J Kanavos, PG Narva, AS AF Wouters, Olivier J. O'Donoghue, Donal J. Ritchie, James Kanavos, Panos G. Narva, Andrew S. TI Early chronic kidney disease: diagnosis, management and models of care SO NATURE REVIEWS NEPHROLOGY LA English DT Review ID GLOMERULAR-FILTRATION-RATE; STAGE RENAL-DISEASE; CLINICAL-PRACTICE GUIDELINE; IMPROVING PRIMARY-CARE; SERUM CYSTATIN-C; RISK-FACTORS; DIABETIC-NEPHROPATHY; CARDIOVASCULAR-DISEASE; COST-EFFECTIVENESS; AMERICAN-COLLEGE AB Chronic kidney disease (CKD) is prevalent in many countries, and the costs associated with the care of patients with end-stage renal disease (ESRD) are estimated to exceed US$1 trillion globally. The clinical and economic rationale for the design of timely and appropriate health system responses to limit the progression of CKD to ESRD is clear. Clinical care might improve if early-stage CKD with risk of progression to ESRD is differentiated from early-stage CKD that is unlikely to advance. The diagnostic tests that are currently used for CKD exhibit key limitations; therefore, additional research is required to increase awareness of the risk factors for CKD progression. Systems modelling can be used to evaluate the impact of different care models on CKD outcomes and costs. The US Indian Health Service has demonstrated that an integrated, system-wide approach can produce notable benefits on cardiovascular and renal health outcomes. Economic and clinical improvements might, therefore, be possible if CKD is reconceptualized as a part of primary care. This Review discusses which early CKD interventions are appropriate, the optimum time to provide clinical care, and the most suitable model of care to adopt. C1 [Wouters, Olivier J.; Kanavos, Panos G.] London Sch Econ & Polit Sci, LSE Hlth, London WC2A 2AE, England. [O'Donoghue, Donal J.; Ritchie, James] Salford Royal NHS Fdn Trust, Dept Renal Med, Salford M6 8HD, Lancs, England. [Narva, Andrew S.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. RP O'Donoghue, DJ (reprint author), London Sch Econ & Polit Sci, LSE Hlth, Cowdray House,Houghton St, London WC2A 2AE, England. EM donal.o'donoghue@srft.nhs.uk FU Intramural NIH HHS [Z99 DK999999] NR 163 TC 9 Z9 9 U1 3 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD AUG PY 2015 VL 11 IS 8 BP 491 EP 502 DI 10.1038/nrneph.2015.85 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA CN7IV UT WOS:000358608800008 PM 26055354 ER PT J AU Riddick, G Song, H Holbeck, SL Kopp, W Walling, J Ahn, S Zhang, W Fine, HA AF Riddick, G. Song, H. Holbeck, S. L. Kopp, W. Walling, J. Ahn, S. Zhang, W. Fine, H. A. TI An in silico screen links gene expression signatures to drug response in glioblastoma stem cells SO PHARMACOGENOMICS JOURNAL LA English DT Article ID PROLIFERATION; GLIOMA; ASTROCYTOMAS; SENSITIVITY; TUMORS AB Cancer stem cells (CSCs) are thought to promote resistance to chemotherapeutic drugs in glioblastoma, the most common and aggressive primary brain tumor. However, the use of high-throughput drug screens to discover novel small-molecule inhibitors for CSC has been hampered by their instability in long-term cell culture. We asked whether predictive models of drug response could be developed from gene expression signatures of established cell lines and applied to predict drug response in glioblastoma stem cells. Predictions for active compounds were confirmed both for 185 compounds in seven established glioma cell lines and 21 compounds in three glioblastoma stem cells. The use of established cell lines as a surrogate for drug response in CSC lines may enable the large-scale virtual screening of drug candidates that would otherwise be difficult or impossible to test directly in CSCs. C1 [Riddick, G.; Song, H.; Walling, J.; Ahn, S.; Zhang, W.] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. [Holbeck, S. L.; Kopp, W.] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Fine, H. A.] NYU, Bellevue Hosp, Langone Med Ctr,Canc Ctr, Brain Tumor Ctr,Laura & Isaac Perlmutter Canc Can, New York, NY 10016 USA. RP Fine, HA (reprint author), NYU, Bellevue Hosp, Langone Med Ctr,Canc Ctr, Brain Tumor Ctr,Laura & Isaac Perlmutter Canc Can, 522 First Ave,Smilow 1101, New York, NY 10016 USA. EM Howard.Fine@nyumc.org NR 20 TC 0 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X EI 1473-1150 J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PD AUG PY 2015 VL 15 IS 4 BP 347 EP 353 DI 10.1038/tpj.2014.61 PG 7 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA CN5CY UT WOS:000358448500009 PM 25446780 ER PT J AU Wang, C Sen, A Plegue, M Ruffin, MT O'Neill, SM Rubinstein, WS Acheson, LS Yoon, PW Valdez, R Irizarry-De La Cruz, M Khoury, MJ Jorgensen, C Scheuner, MT Rubinstein, WS O'Neill, SM Rothrock, N Beaumont, JL Khan, S Ali, D Ruffin, MT Nease, D Acheson, LS Zyzanski, SJ Wiesner, GL Werner, J Pace, WD Galliher, JM Brandt, E Wang, C Gramling, R Starzyk, EJ AF Wang, Catharine Sen, Ananda Plegue, Melissa Ruffin, Mack T. O'Neill, Suzanne M. Rubinstein, Wendy S. Acheson, Louise S. Yoon, Paula W. Valdez, Rodolfo Irizarry-De la Cruz, Margie Khoury, Muin J. Jorgensen, Cynthia Scheuner, Maren T. Rubinstein, Wendy S. O'Neill, Suzanne M. Rothrock, Nan Beaumont, Jennifer L. Khan, Shaheen Ali, Dawood Ruffin, Mack T. Nease, Donald Acheson, Louise S. Zyzanski, Stephen J. Wiesner, Georgia L. Werner, James Pace, Wilson D. Galliher, James M. Brandt, Elias Wang, Catharine Gramling, Robert Starzyk, Erin J. CA Family Healthware Impact Trial TI Impact of family history assessment on communication with family members and health care providers: A report from the Family Healthware (TM) Impact Trial (FHITr) SO PREVENTIVE MEDICINE LA English DT Article DE Family history assessment; Family communication; Provider communication; Dose effects; Chronic disease ID COMMON CHRONIC DISEASES; PATIENT BEHAVIOR; RISK-ASSESSMENT; PERCEIVED RISK; PUBLIC-HEALTH; CANCER; PERCEPTIONS; TOOL; OREGONIANS; PREVENTION AB Objective. This study examines the impact of Family Healthware (TM) on communication behaviors; specifically, communication with family members and health care providers about family health history. Methods. A total of 3786 participants were enrolled in the Family Healthware (TM) Impact Trial (FHITr) in the United States from 2005-7. The trial employed a two-arm cluster-randomized design, with primary care practices serving as the unit of randomization. Using generalized estimating equations (GEE), analyses focused on communication behaviors at 6 month follow-up, adjusting for age, site and practice clustering. Results. A significant interaction was observed between study arm and baseline communication status for the family communication outcomes (p's <.01), indicating that intervention had effects of different magnitude between those already communicating at baseline and those who were not. Among participants who were not communicating at baseline, intervention participants had higher odds of communicating with family members about family history risk (OR = 124, p = 0.042) and actively collecting family history information at follow-up (OR = 2.67, p = 0.026). Family Healthware (TM) did not have a significant effect on family communication among those already communicating at baseline, or on provider communication, regardless of baseline communication status. Greater communication was observed among those at increased familial risk for a greater number of diseases. Conclusion. Family Healthware (TM) prompted more communication about family history with family members, among those who were not previously communicating. Efforts are needed to identify approaches to encourage greater sharing of family history information, particularly with health care providers. (C) 2015 Elsevier Inc. All rights reserved. C1 [Yoon, Paula W.; Valdez, Rodolfo; Irizarry-De la Cruz, Margie; Khoury, Muin J.; Jorgensen, Cynthia] CDC, Atlanta, GA 30333 USA. [Scheuner, Maren T.] Univ Calif Los Angeles, Ctr Hlth Policy Res, Los Angeles, CA 90024 USA. [O'Neill, Suzanne M.] Northwestern Univ, Feinberg Sch Med, Evanston, IL 60208 USA. [Rothrock, Nan; Beaumont, Jennifer L.; Khan, Shaheen; Ali, Dawood] NorthShore Univ HealthSyst, Highland Pk, IL USA. [Ruffin, Mack T.] Univ Michigan, Ann Arbor, MI 48109 USA. [Nease, Donald] Univ Colorado Denver, Denver, CO USA. [Acheson, Louise S.; Zyzanski, Stephen J.; Wiesner, Georgia L.; Werner, James] Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH USA. [Pace, Wilson D.; Galliher, James M.; Brandt, Elias] Amer Acad Family Phys Natl Res Network, Leawood, KS USA. [Wang, Catharine] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Gramling, Robert] Univ Rochester, Rochester, NY 14627 USA. [Starzyk, Erin J.] Univ Illinois, Chicago, IL USA. [Wang, Catharine] Boston Univ, Sch Publ Hlth, Dept Community Hlth Sci, Boston, MA 02118 USA. [Sen, Ananda] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Plegue, Melissa] Univ Michigan, Ctr Stat Consultat & Res, Ann Arbor, MI 48109 USA. [Sen, Ananda; Plegue, Melissa; Ruffin, Mack T.] Univ Michigan, Dept Family Med, Ann Arbor, MI 48109 USA. [O'Neill, Suzanne M.] Northwestern Univ, Dept Med, Feinberg Sch Med, Evanston, IL USA. [Rubinstein, Wendy S.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Acheson, Louise S.] Case Western Reserve Univ, Dept Family Med & Community Hlth, Cleveland, OH 44106 USA. [Acheson, Louise S.] Case Western Reserve Univ, Dept Reprod Biol, Cleveland, OH 44106 USA. [Acheson, Louise S.] Univ Hosp Case Med Ctr, Case Comprehens Canc Ctr, Cleveland, OH USA. RP Wang, C (reprint author), Boston Univ, Sch Publ Hlth, Dept Community Hlth Sci, Crosstown Ctr, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA. EM clwang@bu.edu RI Nease, Donald/B-6206-2013; OI Nease, Donald/0000-0001-8323-3720; Wang, Catharine/0000-0001-8584-2781 FU CDC [U50/CCU300860 TS-1216]; Association for Prevention Teaching and Research (ENH) [U50/CCU300860 TS-1216]; American Association of Medical Colleges (UM) [U36/CCU319276 MM-0789]; American Association of Medical Colleges (CWR) [U36/CCU319276 MM0630]; National Cancer Institute [K07 CA086958, K07 CA131103] FX The Family Healthware (TM) Impact Trial (FHITr) was supported through cooperative agreements between the CDC and the Association for Prevention Teaching and Research (ENH-#U50/CCU300860 TS-1216) and the American Association of Medical Colleges (UM#U36/CCU319276 MM-0789 and CWR# U36/CCU319276 MM0630). Dr. Acheson received salary support from the National Cancer Institute (K07 CA086958). Dr. Wang is also supported by the National Cancer Institute (K07 CA131103) and a Peter T. Paul career development professorship from Boston University. Trial Registration: NCT00164658 'Evaluating Tools for Health Promotion and Disease Prevention'. NR 37 TC 2 Z9 2 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD AUG PY 2015 VL 77 BP 28 EP 34 DI 10.1016/j.ypmed.2015.04.007 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CN4HQ UT WOS:000358391600006 PM 25901453 ER PT J AU Ford, CL Godette, DC Mulatu, MS Gaines, TL AF Ford, Chandra L. Godette, Dionne C. Mulatu, Mesfin S. Gaines, Tommi L. TI Recent HIV Testing Prevalence, Determinants, and Disparities Among US Older Adult Respondents to the Behavioral Risk Factor Surveillance System SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID HEALTH-CARE SETTINGS; AGED 50; HIV/AIDS; STATES; DIAGNOSIS; AMERICANS; SERVICES; DISEASE; PEOPLE AB Background Although routine human immune deficiency virus (HIV) testing during health care visits is recommended for most adults, many older adults (i.e., ages 50-64 years) do not receive it. This study identified factors associated with HIV testing in the past 12 months (i.e., recent HIV testing) among US adults in the 3 categories of older adulthood (50-54, 55-59, and 60-64 years) for which routine HIV testing is recommended. Method This was a cross-sectional analysis of data from US older adult respondents to the 2010 Behavioral Risk Factor Surveillance System. We calculated prevalence (proportions) of HIV testing by age category and race/ethnicity. Using multiple logistic regression, we identified predisposing, enabling, and need factors associated with recent HIV testing within and across age categories, by race/ethnicity and controlling for covariates. Results HIV testing prevalence was low (<5%), varied by race/ethnicity, and decreased with age. Within and across age categories, the odds of testing were highest among blacks (odds ratio [OR], 3.47; 95% confidence interval [CI], 2.82-4.25) and higher among Latinos (OR, 2.06; 95% CI, 1.50-2.84) and the oldest and youngest categories of American Indians/Alaska Natives (OR, 2.48; 95% CI, 1.11-5.55; OR, 2.98; 95% CI, 1.49-5.95) than among whites. Those reporting a recent doctor visit (OR, 2.32; 95% CI, 1.92-2.74) or HIV risk behaviors (OR, 3.50; 95% CI, 2.67-4.59) had higher odds of HIV testing. Conclusion Regardless of risk, the oldest older adults, whites, and older women may forego HIV testing. Doctor visits may facilitate HIV testing. Additional research is needed to understand why eligible older adults seen by providers may not be screened for HIV infection. C1 [Ford, Chandra L.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Community Hlth Sci, Los Angeles, CA 90095 USA. [Godette, Dionne C.] NIAAA, Div Epidemiol & Prevent Res, NIH, Rockville, MD 20852 USA. [Mulatu, Mesfin S.] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. [Gaines, Tommi L.] Univ Calif San Diego, Dept Med, Div Global Publ Hlth, San Diego, CA 92103 USA. RP Ford, CL (reprint author), Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Community Hlth Sci, Box 951772, Los Angeles, CA 90095 USA. EM clford@ucla.edu FU UCLA Faculty Career Development Award; Eunice Kennedy Schriver National Institute of Child Health and Human Development via UCLA California Center for Population Research [5R24HD041022]; National Institute on Drug Abuse [K01DA034523-01] FX Dr Ford received support from an UCLA Faculty Career Development Award and the Eunice Kennedy Schriver National Institute of Child Health and Human Development via the UCLA California Center for Population Research (5R24HD041022). Dr Gaines received support from the National Institute on Drug Abuse (K01DA034523-01). Dr Mulatu's participation represents a personal endeavor not conducted on behalf of the Centers for Disease Control and Prevention. NR 30 TC 3 Z9 3 U1 1 U2 5 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 2015 VL 42 IS 8 BP 405 EP 410 DI 10.1097/OLQ.0000000000000305 PG 6 WC Infectious Diseases SC Infectious Diseases GA CN2YW UT WOS:000358290300001 PM 26165428 ER PT J AU Watson, NF Badr, MS Belenky, G Bliwise, DL Buxton, OM Buysse, D Dinges, DF Gangwisch, J Grandner, MA Kushida, C Malhotra, RK Martin, JL Patel, SR Quan, SF Tasali, E Twery, M Croft, JB Maher, E Barrett, JA Thomas, SM Heald, JL AF Watson, Nathaniel F. Badr, M. Safwan Belenky, Gregory Bliwise, Donald L. Buxton, Orfeu M. Buysse, Daniel Dinges, David F. Gangwisch, James Grandner, Michael A. Kushida, Clete Malhotra, Raman K. Martin, Jennifer L. Patel, Sanjay R. Quan, Stuart F. Tasali, Esra Twery, Michael Croft, Janet B. Maher, Elise Barrett, Jerome A. Thomas, Sherene M. Heald, Jonathan L. TI Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion SO SLEEP LA English DT Article DE sleep duration; consensus; recommendation; adult; health ID BODY-MASS INDEX; CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; ALL-CAUSE MORTALITY; POPULATION-BASED COHORT; QUALITY-OF-LIFE; NUTRITION EXAMINATION SURVEY; ACUTE MYOCARDIAL-INFARCTION; IMPAIRED GLUCOSE-TOLERANCE; AMBULATORY BLOOD-PRESSURE AB The American Academy of Sleep Medicine and Sleep Research Society recently released a Consensus Statement regarding the recommended amount of sleep to promote optimal health in adults. This paper describes the methodology, background literature, voting process, and voting results for the consensus statement. In addition, we address important assumptions and challenges encountered during the consensus process. Finally, we outline future directions that will advance our understanding of sleep need and place sleep duration in the broader context of sleep health. C1 [Watson, Nathaniel F.] Univ Washington, Seattle, WA 98195 USA. [Badr, M. Safwan] Wayne State Univ, Detroit, MI USA. [Belenky, Gregory] Washington State Univ, Spokane, WA USA. [Bliwise, Donald L.] Emory Univ, Atlanta, GA 30322 USA. [Buxton, Orfeu M.] Penn State Univ, University Pk, PA USA. [Buysse, Daniel] Univ Pittsburgh, Pittsburgh, PA USA. [Dinges, David F.; Grandner, Michael A.] Univ Penn, Philadelphia, PA 19104 USA. [Gangwisch, James] Columbia Univ, New York, NY USA. [Kushida, Clete] Stanford Univ, Stanford, CA 94305 USA. [Malhotra, Raman K.] St Louis Univ, St Louis, MO 63103 USA. [Martin, Jennifer L.] Univ Calif Los Angeles, Los Angeles, CA USA. [Patel, Sanjay R.; Quan, Stuart F.] Harvard Univ, Sch Med, Boston, MA USA. [Tasali, Esra] Univ Chicago, Chicago, IL 60637 USA. [Twery, Michael] Blood Inst, Natl Heart, Lung, NIH, Bethesda, MD USA. [Croft, Janet B.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Maher, Elise] Sleep Disorders Inst, New York, NY USA. [Barrett, Jerome A.; Thomas, Sherene M.; Heald, Jonathan L.] Amer Acad Sleep Med, Darien, IL USA. RP Watson, NF (reprint author), 2510 N Frontage Rd, Darien, IL 60561 USA. EM research@aasmnet.org OI Patel, Sanjay/0000-0002-9142-5172 FU American Academy of Sleep Medicine; Centers for Disease Control and Prevention (CDC) [1U50DP004930-01]; NIH; Inspire Medical; ResMed; Jawbone; Cephalon; Aerial BioPharma; Impax Laboratories, Inc.; Equinox Fitness; American Sleep Medicine Foundation; ResMed Foundation; American College of Physicians; Sleep Research Society FX Funding for this project was provided by the American Academy of Sleep Medicine and Sleep Research Society, and supported by the cooperative agreement number 1U50DP004930-01 from the Centers for Disease Control and Prevention (CDC). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC.; The authors declare the following conflicts of interest: Dr. Watson has received grant/research support from NIH. He has also served on the Board of Directors for the AASM, ASMF, and ABSM. Dr. Badr has received grant/research support provided by Inspire Medical. Dr. Belenky has no conflicts of interest to disclose. Dr. Bliwise has served as a consultant for New England Research Institute, Ferring Pharmaceuticals, Morehouse School of Medicine, Vantia Therapeutics, Georgia Institute of Technology, and Merck. Dr. Buxton has no conflicts of interest to disclose. Dr. Buysse has served as a consultant for Merck, Purdue Pharm, Emmi, and Philips Respironics. He has also contributed towards CME educational program development for Medscape, CME Outfitters, and WebMD. Additionally he has received grant/research support provided by NIH. Dr. Dinges is a scientific advisor to MARS, Inc. He also receives salary as the Editor-in-Chief of SLEEP. Dr. Gangwisch has no conflicts of interest to disclose. Dr. Grandner has served as a consultant to Bayer and Nexalin. Dr. Kushida has received grant/research support provided by ResMed, Jawbone, Cephalon, Aerial BioPharma, and Impax Laboratories, Inc. He has also served as a consultant for Sephyr Sleep Technologies, Philips-Respironics, Morphy Smart Bed, and Nokia. Dr. Malhotra has served as a member of the speaker's bureau for Teva Pharmaceuticals. Dr. Martin has received grant/research support provided by Equinox Fitness and has served as a consultant to Equinox Fitness. Dr. Patel has received grant/research support provided by American Sleep Medicine Foundation, and ResMed Foundation. He has also received a stipend for chairing AASM Young Investigator Research Forum, and a stipend for authorship from the American College of Physicians. Dr. Quan has served as a consultant to Global Corporate Challenge. Dr Tasali has no conflicts of interest to disclose. NR 360 TC 22 Z9 22 U1 8 U2 27 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 2015 VL 38 IS 8 BP 1161 EP 1183 AR PII sp-00367-15 DI 10.5665/sleep.4886 PG 23 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CO0JV UT WOS:000358838100006 ER PT J AU Narayan, SM Varghese, M Hepburn, K Lewis, M Paul, I Bhimani, R AF Narayan, Suzanne M. Varghese, Mathew Hepburn, Kenneth Lewis, Marsha Paul, Isabel Bhimani, Rozina TI Caregiving Experiences of Family Members of Persons With Dementia in South India SO AMERICAN JOURNAL OF ALZHEIMERS DISEASE AND OTHER DEMENTIAS LA English DT Article DE dementia; caregiving experience; caregivers; family; qualitative research; South India ID ALZHEIMERS-DISEASE; MENTAL-HEALTH; DEVELOPING-COUNTRIES; SAVVY CAREGIVER; OLDER-ADULTS; IN-LAW; CARE; INTERVENTION; DEPRESSION; PROGRAM AB This study reports on the first phase of an investigation aimed at adapting The Savvy Caregiver program, a successful family caregiving curriculum developed in the United States, for application in South India. Thirty family members caring for a person with dementia were interviewed regarding their experiences as caregivers (CGs). Qualitative interviews were conducted with the family member at a geriatric clinic, while other diagnostic procedures were being carried out with the person with dementia. Findings from the study revealed that although family members understood the term CG, none could identify a word for CG in his or her language. There was little understanding of dementia as an illness. Family CGs reported feeling distressed, overwhelmed, and frustrated with caregiving. Caregivers were interested in an educational program, but many had unrealistic expectations for what they wanted to learn. The findings provide directions for adapting The Savvy Caregiver curriculum for Indian family CGs. C1 [Narayan, Suzanne M.] Metropolitan State Univ, Sch Nursing, St Paul, MN USA. [Varghese, Mathew] Natl Inst Mental Hlth & Neurosci, Bangalore 560029, Karnataka, India. [Hepburn, Kenneth] Emory Univ, Nell Hodgson Woodruff Sch Nursing, Atlanta, GA 30322 USA. [Lewis, Marsha] SUNY Buffalo, Sch Nursing, Buffalo, NY 14260 USA. [Paul, Isabel] People Wellness, Bangalore, Karnataka, India. [Bhimani, Rozina] St Catherine Univ, Henrietta Schmoll Sch Hlth, St Paul, MN USA. RP Narayan, SM (reprint author), NIMH, Sch Nursing, 700 East Seventh St, St Paul, MN 55106 USA. EM suzanne.narayan@metrostate.edu RI Varghese, Mathew/M-9900-2016 OI Varghese, Mathew/0000-0001-5670-5710 FU Fogarty International Research Collaborative Award [7R03TW001498-04] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Fogarty International Research Collaborative Award (Grant #7R03TW001498-04). NR 61 TC 0 Z9 0 U1 2 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-3175 EI 1938-2731 J9 AM J ALZHEIMERS DIS JI Am. J. Alzheimers Dis. Other Dement. PD AUG PY 2015 VL 30 IS 5 BP 508 EP 516 DI 10.1177/1533317514567125 PG 9 WC Geriatrics & Gerontology; Clinical Neurology SC Geriatrics & Gerontology; Neurosciences & Neurology GA CN4PP UT WOS:000358412700011 PM 25735742 ER PT J AU Inker, LA Okparavero, A Tighiouart, H Aspelund, T Andresdottir, MB Eiriksdottir, G Harris, T Launer, L Nikulasdottir, H Sverrisdottir, JE Gudmundsdottir, H Noubary, F Mitchell, G Palsson, R Indridason, OS Gudnason, V Levey, AS AF Inker, Lesley A. Okparavero, Aghogho Tighiouart, Hocine Aspelund, Thor Andresdottir, Margret B. Eiriksdottir, Gudny Harris, Tamara Launer, Lenore Nikulasdottir, Hjalmfridur Sverrisdottir, Johanna Eyrun Gudmundsdottir, Hrefna Noubary, Farzad Mitchell, Gary Palsson, Runolfur Indridason, Olafur S. Gudnason, Vilmundur Levey, Andrew S. TI Midlife Blood Pressure and Late-Life GFR and Albuminuria: An Elderly General Population Cohort SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease (CKD); elderly; blood pressure; hypertension; measured glomerular filtration rate (mGFR); iohexol clearance; renal function; albuminuria; albumin-creatinine ratio (ACR); mid-life; aging; modifiable risk factor ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; STAGE RENAL-DISEASE; CYSTATIN-C; CARDIOVASCULAR-DISEASE; HEART-FAILURE; RISK-FACTOR; AGES-REYKJAVIK; OLDER-ADULTS; ALL-CAUSE AB Background: Chronic kidney disease (CKD) is common in the elderly, but the cause is often not identifiable. Some posit that age-related reductions in glomerular filtration rate (GFR) and increases in albuminuria are normal, whereas others suggest that they are a consequence of vascular disease. Study Design: Cross-sectional analysis of a substudy of a prospective cohort. Setting & Participants: AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study. Predictor: Exposure to higher blood pressure in midlife. Outcomes & Measurements: Measured GFR using plasma clearance of iohexol and urine albumin-creatinine ratio. Results: GFR was measured in 805 participants with mean age in midlife and late life of 51.0 +/- 5.8 and 80.8 +/- 4.0 (SD) years, respectively. Mean measured GFR was 62.4 +/- 16.5 mL/min/1.73 m(2) and median albuminuria was 8.0 (IQR, 5.4-16.5) mg/g. Higher midlife systolic and diastolic blood pressures were associated with lower later-life GFRs. Associations persisted after adjustment. Higher midlife systolic and diastolic blood pressures were also associated with higher albumin-creatinine ratios, and associations remained significant even after adjustment. Limitations: This is a study of survivors, and people who agreed to participate in this study were healthier than those who refused. Blood pressure may encompass effects of the other risk factors. Results may not be generalizable to populations of other races. We were not able to adjust for measured GFR or albuminuria at the midlife visit. Conclusions: Factors other than advanced age may account for the high prevalence of CKD in the elderly. Midlife factors are potential contributing factors to late-life kidney disease. Further studies are needed to identify and treat midlife modifiable factors to prevent the development of CKD. (C) 2015 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Inker, Lesley A.; Okparavero, Aghogho; Levey, Andrew S.] Tufts Univ, Tufts Med Ctr, Boston, MA 02111 USA. [Tighiouart, Hocine; Noubary, Farzad] Tufts Univ, Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA 02111 USA. [Tighiouart, Hocine] Tufts Univ, Tufts Clin & Translat Sci, Boston, MA 02111 USA. [Aspelund, Thor; Eiriksdottir, Gudny; Nikulasdottir, Hjalmfridur; Sverrisdottir, Johanna Eyrun; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor; Palsson, Runolfur; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Andresdottir, Margret B.; Gudmundsdottir, Hrefna; Palsson, Runolfur; Indridason, Olafur S.] Landspitali Natl Univ Hosp Iceland, Reykjavik, Iceland. [Harris, Tamara; Launer, Lenore] NIA, Bethesda, MD 20892 USA. [Mitchell, Gary] Cardiovasc Engn Inc, Norwood, MA USA. RP Inker, LA (reprint author), Tufts Med Ctr, Div Nephrol, 800 Washington St,Box 391, Boston, MA 02111 USA. EM linker@tuftsmedicalcenter.org RI Gudnason, Vilmundur/K-6885-2015; Aspelund, Thor/C-5983-2008 OI Gudnason, Vilmundur/0000-0001-5696-0084; Aspelund, Thor/0000-0002-7998-5433 FU NIH; National Kidney Foundation; Pharmalink AB; Gilead Sciences; Amgen FX Dr Inker reports funding to Tufts Medical Center for research and contracts with the NIH, National Kidney Foundation, Pharmalink AB, and Gilead Sciences; a consulting agreement with Otsuka; and has a provisional patent [Drs Coresh, Inker, and Levey] filed August 15, 2014-Precise estimation of glomerular filtration rate from multiple biomarkers (licensing under negotiations). Dr Mitchell is owner of Cardiovascular Engineering Inc, a company that develops and manufactures devices to measure vascular stiffness; serves as a consultant to and receives honoraria from Novartis and Merck; and is funded by research grants from the NIH. Dr Levey reports funding to Tufts Medical Center for research and contracts with the NIH, National Kidney Foundation, Amgen, Pharmalink AB, and Gilead Sciences and has a provisional patent [Drs Coresh, Inker and Levey] filed August 15, 2014-Precise estimation of glomerular filtration rate from multiple biomarkers (licensing under negotiations). Drs Harris and Launer work for the National Institute on Aging. The other authors declare that they have no other relevant financial interests. NR 50 TC 7 Z9 7 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 2015 VL 66 IS 2 BP 240 EP 248 DI 10.1053/j.ajkd.2015.03.030 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CN4ED UT WOS:000358382100019 PM 25987258 ER PT J AU Shah, R Matthews, GJ Shah, RY McLaughlin, C Chen, J Wolman, M Master, SR Chai, BY Xie, DW Rader, DJ Raj, DS Mehta, NN Budoff, M Fischer, MJ Go, AS Townsend, RR He, J Kusek, JW Feldman, HI Foulkes, AS Reilly, MP AF Shah, Rachana Matthews, Gregory J. Shah, Rhia Y. McLaughlin, Catherine Chen, Jing Wolman, Melanie Master, Stephen R. Chai, Boyang Xie, Dawei Rader, Daniel J. Raj, Dominic S. Mehta, Nehal N. Budoff, Matthew Fischer, Michael J. Go, Alan S. Townsend, Raymond R. He, Jiang Kusek, John W. Feldman, Harold I. Foulkes, Andrea S. Reilly, Muredach P. CA CRIC Study Investigators TI Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Cardiometabolic disease; chronic kidney disease (CKD); cardiovascular disease (CVD); atherosclerosis; metabolic syndrome; diabetes; fractalkine (CX3CL1); Chronic Renal Insufficiency Cohort ID CHRONIC KIDNEY-DISEASE; BASE-LINE CHARACTERISTICS; CORONARY-ARTERY-DISEASE; PLASMA CXCL12 LEVELS; BETA-CELL FUNCTION; RECEPTOR CX3CR1; UNSTABLE ANGINA; RISK-FACTOR; ASSOCIATION; MONOCYTES AB Background: Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD. Study Design: Cross-sectional and longitudinal observational analysis. Setting & Participants: Adults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. Predictor: Quartiles of plasma CX3CL1 levels at baseline. Outcomes: Baseline estimated glomerular filtration rate from a creatinine and cystatin C-based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A(1c) level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality. Results: Among 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P = 0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P < 0.001) in adjusted models. During a mean follow-up of 6 years, there were 352 deaths, 176 myocardial infarctions, and 484 composite outcomes. In fully adjusted models, 1-SD higher CX3CL1 level increased the hazard for all-cause mortality (1.11; 95% CI, 1.00-1.22; P = 0.02) and the composite outcome (1.09; 95% CI, 1.00-1.19; P = 0.04). Limitations: Study design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect. Conclusions: Circulating CX3CL1 level may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX3CL1 affects the pathogenesis of atherosclerosis and diabetes. (C) 2015 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Shah, Rachana] Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. [Matthews, Gregory J.; Foulkes, Andrea S.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Amherst, MA 01003 USA. [Shah, Rhia Y.; Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [McLaughlin, Catherine] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Chen, Jing; He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Wolman, Melanie; Chai, Boyang; Xie, Dawei] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Master, Stephen R.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Raj, Dominic S.] George Washington Univ, Washington, DC USA. [Mehta, Nehal N.] NHLBI, Bethesda, MD 20892 USA. [Budoff, Matthew] Los Angeles Biomed Res Inst, Torrance, CA USA. [Fischer, Michael J.] Jesse Brown VA Med Ctr, Med, Chicago, IL USA. [Fischer, Michael J.] Univ Hosp & Hlth Sci Syst, Chicago, IL USA. [Fischer, Michael J.] Edward Hines Jr VA Hosp, Ctr Innovat Complex Chron Healthcare, Hines, IL USA. [Go, Alan S.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Townsend, Raymond R.; Feldman, Harold I.] Univ Penn, Renal Elect & Hypertens Div, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kusek, John W.] NIDDK, Bethesda, MD USA. RP Shah, R (reprint author), Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. EM shahr@email.chop.edu; muredach@mail.med.upenn.edu OI Shah, Rachana/0000-0001-7866-557X FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) [R01-DK071224, R01-DK090505, K23-DK095913, K24-DK002651]; National Heart, Lung and Blood Institute of the NIH [R01-HL107196, K24-HL107643, U01-HL108636, R01-HL113147]; US Department of Veterans Affairs Health Services Research and Development Service Award; NIH Intramural Award [HL-Z0000]; NIDDK [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award (CTSA) NIH/National Center for Advancing Translational Sciences (NCATS) [UL1TR000003]; Johns Hopkins University [UL1 TR-000424]; University of Maryland [GCRC M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland from the NCATS component of the NIH [UL1TR000439]; NIH Roadmap for Medical Research; Michigan Institute for Clinical and Health Research (MICHR) [UL1TR000433]; University of Illinois at Chicago CTSA [UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser Permanente NIH/National Center for Research Resources [UCSF-CTSI UL1 RR-024131] FX Support: This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH; R01-DK071224 and R01-DK090505 to Mr Reilly, K23-DK095913 to Dr Shah, K24-DK002651 to Dr Feldman). The National Heart, Lung and Blood Institute of the NIH also provided support (R01-HL107196 to Dr Foulkes and K24-HL107643, U01-HL108636, and R01-HL113147 to Mr Reilly). The US Department of Veterans Affairs Health Services Research and Development Service Award supports Dr Fischer. Dr Mehta is supported by NIH Intramural Award [HL-Z0000]. Funding for the CRIC Study was obtained under a cooperative agreement from the NIDDK (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by the following: the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award (CTSA) NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the NCATS component of the NIH and NIH Roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) UL1TR000433, University of Illinois at Chicago CTSA UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, and Kaiser Permanente NIH/National Center for Research Resources UCSF-CTSI UL1 RR-024131. NR 33 TC 7 Z9 7 U1 0 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 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2015 VL 66 IS 2 BP 266 EP 273 DI 10.1053/j.ajkd.2015.01.021 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CN4ED UT WOS:000358382100022 PM 25795074 ER PT J AU Poncet, N Lamont, H Fulcher, L Shi, YB Taylor, PM AF Poncet, Nadege Lamont, Holly Fulcher, Luke Shi, Yun-Bo Taylor, Peter M. TI Tamoxifen-Cre induced knockout of the LAT1 (Slc7a5) amino acid exchanger in adult mice promotes stress signalling associated with reduction in the mass of peripheral tissues SO AMINO ACIDS LA English DT Meeting Abstract C1 [Poncet, Nadege; Lamont, Holly; Fulcher, Luke; Taylor, Peter M.] Univ Dundee, Coll Life Sci, Dundee DD1 5EH, Scotland. [Shi, Yun-Bo] NICHD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0939-4451 EI 1438-2199 J9 AMINO ACIDS JI Amino Acids PD AUG PY 2015 VL 47 IS 8 BP 1625 EP 1625 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CN1JH UT WOS:000358175100051 ER PT J AU Ding, J Mitchell, GF Bots, ML Sigurdsson, S Harris, TB Garcia, M Eiriksdottir, G van Buchem, MA Gudnason, V Launer, LJ AF Ding, Jie Mitchell, Gary F. Bots, Michiel L. Sigurdsson, Sigurdur Harris, Tamara B. Garcia, Melissa Eiriksdottir, Gudny van Buchem, Mark A. Gudnason, Vilmundur Launer, Lenore J. TI Carotid Arterial Stiffness and Risk of Incident Cerebral Microbleeds in Older People The Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE carotid arteries; cerebral small vessel diseases; incidence; vascular stiffness ID SMALL-VESSEL DISEASE; BLOOD-PRESSURE; AORTIC STIFFNESS; ROTTERDAM SCAN; WAVE REFLECTION; ISCHEMIC-STROKE; REYKJAVIK; METAANALYSIS; ASSOCIATION; PULSATILITY AB Objective Age and high blood pressure are major risk factors for cerebral microbleeds (CMBs). However, the underlying mechanisms remain unclear and arterial stiffness may be important. We investigated whether carotid arterial stiffness is associated with incidence and location of CMBs. Approach and Results In the prospective, population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik study, 2512 participants aged 66 to 93 years underwent a baseline brain MRI examination and carotid ultrasound in 2002 to 2006 and returned for a repeat brain MRI in 2007 to 2011. Common carotid arterial stiffness was assessed using a standardized protocol and expressed as carotid arterial strain, distensibility coefficient, and Young elastic modulus. Modified Poisson regression was applied to relate carotid arterial stiffness parameters to CMB incidence. During a mean follow-up of 5.2 years, 463 people (18.4%) developed new CMBs, of whom 292 had CMBs restricted to lobar regions and 171 had CMBs in a deep or infratentorial region. After adjusting for age, sex, and follow-up interval, arterial stiffness measures were associated with incident CMBs (risk ratio per SD decrease in carotid arterial strain, 1.11 [95% confidence interval, 1.01-1.21]; per SD decrease in natural log-transformed distensibility coefficient, 1.14 [1.05-1.24]; and per SD increase in natural log-transformed Young elastic modulus, 1.13 [1.04-1.23]). These measures were also significantly associated with incident deep CMBs (1.18 [1.02-1.37]; 1.24 [1.08-1.42]; and 1.23 [1.07-1.42]) but not with lobar CMBs. When further adjusted for blood pressure and other baseline vascular risk factors, carotid plaque, prevalent CMBs, subcortical infarcts, and white matter hyperintensities, the associations persisted. Conclusions Our findings support the hypothesis that localized increases in carotid arterial stiffness may contribute to the development of CMBs, especially in a deep location attributable to hypertension. C1 [Ding, Jie; Harris, Tamara B.; Garcia, Melissa; Launer, Lenore J.] NIA, Intramural Res Program, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20814 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Bots, Michiel L.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Sigurdsson, Sigurdur; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. RP Launer, LJ (reprint author), NIA, Intramural Res Program, 7201 Wisconsin Ave,Suite 3c-309, Bethesda, MD 20814 USA. EM LaunerL@nia.nih.gov RI Gudnason, Vilmundur/K-6885-2015; Ding, Jie/K-9943-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084; FU National Institutes of Health [N01-AG-12100]; National Institute on Aging; Icelandic Heart Association; Icelandic Parliament FX The AGES-Reykjavik study was funded by the National Institutes of Health (contract N01-AG-12100); the Intramural Research Program of the National Institute on Aging; the Icelandic Heart Association and the Icelandic Parliament. NR 30 TC 5 Z9 5 U1 1 U2 3 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 2015 VL 35 IS 8 BP 1889 EP 1895 DI 10.1161/ATVBAHA.115.305451 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CN2ZC UT WOS:000358291100019 PM 26112009 ER PT J AU Bachelerie, F Graham, GJ Locati, M Mantovani, A Murphy, PM Nibbs, R Rot, A Sozzani, S Thelen, M AF Bachelerie, Francoise Graham, Gerard J. Locati, Massimo Mantovani, Alberto Murphy, Philip M. Nibbs, Robert Rot, Antal Sozzani, Silvano Thelen, Marcus TI An atypical addition to the chemokine receptor nomenclature: IUPHAR Review 15 SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review ID CONCISE GUIDE; CELLS; PHARMACOLOGY; IMMUNE; BIOLOGY; SYSTEM; SDF-1 AB Chemokines and their receptors are essential regulators of in vivo leukocyte migration and, some years ago, a systematic nomenclature system was developed for the chemokine receptor family. Chemokine receptor biology and biochemistry was recently extensively reviewed. In this review, we also highlighted a new component to the nomenclature system that incorporates receptors previously known as scavenging', or decoy', chemokine receptors on the basis of their lack of classical signalling responses to ligand binding and their general ability to scavenge, or sequester, their cognate chemokine ligands. These molecules are now collectively referred to as atypical chemokine receptors', or ACKRs, and play fundamental roles in regulating in vivo responses to chemokines. This commentary highlights this new addition to the chemokine receptor nomenclature system and provides brief information on the four receptors currently covered by this nomenclature. C1 [Bachelerie, Francoise] Univ Paris 11, INSERM, UMR S996, Lab Excellence Res Medicat & Innovat Therapeut, Clamart, France. [Graham, Gerard J.; Nibbs, Robert] Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Glasgow Biomed Res Ctr, Glasgow, Lanark, Scotland. [Locati, Massimo; Mantovani, Alberto] Univ Milan, Dept Mol Biotechnol & Translat Med, Milan, Italy. [Locati, Massimo; Mantovani, Alberto; Sozzani, Silvano] Humanitas Univ, Ist Clin Humanitas, Milan, Italy. [Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Rot, Antal] Univ Birmingham, Inst Biomed Res, Sch Infect & Immun, Med Res Council Ctr Immune Regulat, Birmingham, W Midlands, England. [Sozzani, Silvano] Univ Brescia, Dept Mol & Translat Med, Brescia, Italy. [Thelen, Marcus] Inst Res Biomed, Bellinzona, Switzerland. RP Graham, GJ (reprint author), Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Glasgow Biomed Res Ctr, Glasgow, Lanark, Scotland. EM gerard.graham@glasgow.ac.uk RI BACHELERIE, FRANCOISE/F-8823-2013; OI Mantovani, Alberto/0000-0001-5578-236X; Locati, Massimo/0000-0003-3077-590X; Nibbs, Robert/0000-0002-8150-0044 FU Investissements d'Avenir; INSERM; ERA-Net for Research Programmes on Rare Diseases [E-Rare-013]; Italian Association for Cancer Research; European Commission; Italian Ministry of Education, Universities and Research; Italian Ministry of Health; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases; Medical Research Council [G0802838]; Wellcome Trust; Helmut Horten Foundation; Swiss National Science Foundation FX Work in the author's laboratories is supported by the following agencies: Investissements d'Avenir (supporting the Laboratory of Excellence in Research on Medication and Innovative Therapeutics of which F. B. is a member), INSERM (F. B.), ERA-Net for Research Programmes on Rare Diseases (E-Rare-013 to F. B.), the Italian Association for Cancer Research (A. M., M. L. and S. S.), European Commission (A. M. and M. L.), the Italian Ministry of Education, Universities and Research (A. M., M. L. and S. S.), the Italian Ministry of Health (A. M. and M. L.), the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (P. M. M.), the Medical Research Council (G. J. G. and R. N.; G0802838 to A. R.), the Wellcome Trust (G. J. G.), the Helmut Horten Foundation (M. T.) and the Swiss National Science Foundation (M. T.). NR 29 TC 2 Z9 3 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD AUG PY 2015 VL 172 IS 16 BP 3945 EP 3949 DI 10.1111/bph.13182 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CN5FB UT WOS:000358454100001 PM 25958743 ER PT J AU Morton, RA Baptista-Hon, DT Hales, TG Lovinger, DM AF Morton, Russell A. Baptista-Hon, Daniel T. Hales, Tim G. Lovinger, David M. TI Agonist- and antagonist-induced up-regulation of surface 5-HT(3)A receptors SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article ID SEROTONIN 5-HT3 RECEPTOR; NICOTINIC RECEPTORS; PHARMACOLOGICAL CHAPERONE; ACETYLCHOLINE-RECEPTORS; NERVOUS-SYSTEM; RAT-BRAIN; EXPRESSION; BINDING; DESENSITIZATION; ACTIVATION AB Background and PurposeThe 5-HT3 receptor is a member of the pentameric ligand-gated ion channel family and is pharmacologically targeted to treat irritable bowel syndrome and nausea/emesis. Furthermore, many antidepressants elevate extracellular concentrations of 5-HT. This study investigates the functional consequences of exposure of recombinant 5-HT(3)A receptors to agonists and antagonists. Experimental ApproachWe used HEK cells stably expressing recombinant 5-HT(3)A receptors and the ND7/23 (mouse neuroblastoma/dorsal root ganglion hybrid) cell line, which expresses endogenous 5-HT3 receptors. Surface expression of recombinant 5-HT(3)A receptors, modified to contain the bungarotoxin (BTX) binding sequence, was quantified using fluorescence microscopy to image BTX-conjugated fluorophores. Whole cell voltage-clamp electrophysiology was used to measure the density of current mediated by 5-HT(3)A receptors. Key Results5-HT(3)A receptors were up-regulated by the prolonged presence of agonists (5-HT and m-chlorophenylbiguanide) and antagonists (MDL-72222 and morphine). The up-regulation of 5-HT(3)A receptors by 5-HT and MDL-72222 was time- and concentration-dependent but was independent of newly translated receptors. The phenomenon was observed for recombinant rodent and human 5-HT(3)A receptors and for endogenous 5-HT3 receptors in neuronal ND7/23 cells. Conclusions and ImplicationsUp-regulation of 5-HT(3)A receptors, following exposure to either agonists or antagonists suggests that this phenomenon may occur in response to different therapeutic agents. Medications that elevate 5-HT levels, such as the antidepressant inhibitors of 5-HT reuptake and antiemetic inhibitors of 5-HT3 receptor function, may both raise receptor expression. However, this will require further investigation in vivo. C1 [Morton, Russell A.; Lovinger, David M.] NIAAA, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. [Morton, Russell A.; Hales, Tim G.; Lovinger, David M.] George Washington Univ, Dept Pharmacol & Physiol, Washington, DC USA. [Baptista-Hon, Daniel T.; Hales, Tim G.] Univ Dundee, Ninewells Hosp & Med Sch, Div Neurosci, Inst Acad Anaesthesia, Dundee DD1 9SY, Scotland. RP Lovinger, DM (reprint author), NIAAA, Lab Integrat Neurosci, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. EM lovindav@mail.nih.gov FU Tenovus Scotland; Division of Intramural Clinical and Biological Research, NIAAA FX The work of D. T. B.-H. and T.G. H. was supported by a grant from Tenovus Scotland. The work of R. A. M. and D. M. L. was supported by the Division of Intramural Clinical and Biological Research, NIAAA. NR 44 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD AUG PY 2015 VL 172 IS 16 BP 4066 EP 4077 DI 10.1111/bph.13197 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CN5FB UT WOS:000358454100010 PM 25989383 ER PT J AU Mattila, JT Maiello, P Sun, T Via, LE Flynn, JL AF Mattila, Joshua T. Maiello, Pauline Sun, Tao Via, Laura E. Flynn, JoAnne L. TI Granzyme B-expressing neutrophils correlate with bacterial load in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques SO CELLULAR MICROBIOLOGY LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; CD4 T-CELLS; SERINE PROTEASES; CATHEPSIN-G; POLYMORPHONUCLEAR NEUTROPHILS; ACTIVITY CONTRIBUTES; HUMAN KERATINOCYTES; BAL FLUID; IN-VIVO; PERFORIN AB The role of neutrophils in tuberculosis (TB), and whether neutrophils express granzyme B (grzB), a pro-apoptotic enzyme associated with cytotoxic T cells, is controversial. We examined neutrophils in peripheral blood (PB) and lung granulomas of Mycobacterium tuberculosis-infected cynomolgus macaques and humans to determine whether mycobacterial products or pro-inflammatory factors induce neutrophil grzB expression. We found large numbers of grzB-expressing neutrophils in macaque and human granulomas and these cells contained more grzB+ granules than T cells. Higher neutrophil, but not T cell, grzB expression correlated with increased bacterial load. Although unstimulated PB neutrophils lacked grzB expression, grzB expression increased upon exposure to M.tuberculosis bacilli, M.tuberculosis culture filtrate protein or lipopolysaccharide from Escherichia coli. Perforin is required for granzyme-mediated cytotoxicity by T cells, but was not observed in PB or granuloma neutrophils. Nonetheless, stimulated PB neutrophils secreted grzB as determined by enzyme-linked immunospot assays. Purified grzB was not bactericidal or bacteriostatic, suggesting secreted neutrophil grzB acts on extracellular targets, potentially enhancing neutrophil migration through extracellular matrix and regulating apoptosis or activation in other cell types. These data indicate mycobacterial products and the pro-inflammatory environment of granulomas up-regulates neutrophil grzB expression and suggests a previously unappreciated aspect of neutrophil biology in TB. C1 [Mattila, Joshua T.; Maiello, Pauline; Flynn, JoAnne L.] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA 15260 USA. [Sun, Tao; Flynn, JoAnne L.] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA. [Via, Laura E.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Mattila, JT (reprint author), Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA 15260 USA. EM jmattila@pitt.edu OI , Joshua/0000-0002-6384-1291 FU NIH [AI077183, HL110811, EB012579]; Bill and Melinda Gates Foundation; Heiser Program for Research Leprosy FX The authors gratefully acknowledge technical assistance provided by Mark Rodgers, Carolyn Bigbee, Chelsea Chedrick and the Flynn Lab veterinary staff. We are also grateful to the staff of the National Masan Hospital and the pathologist Dr Seokyong Eum of the International Tuberculosis Research Center for their assistance in tissue collection. Support for this study was provided by NIH grants AI077183 (J.T.M.), HL110811 (J.L.F.), EB012579 (J.L.F.); the Bill and Melinda Gates Foundation (J.L.F.); and the Heiser Program for Research Leprosy (J.T.M.). Support for human tissue collection was provided in part by the Division of Intramural Research, NIAID, NIH and the Korean Ministry of Health and Welfare through the Korean CDC (Clifton E. Barry 3rd and L.E.V.). NR 77 TC 6 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-5814 EI 1462-5822 J9 CELL MICROBIOL JI Cell Microbiol. PD AUG PY 2015 VL 17 IS 8 BP 1085 EP 1097 DI 10.1111/cmi.12428 PG 13 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA CN2LD UT WOS:000358251700002 PM 25653138 ER PT J AU Aramesh, K AF Aramesh, Kiarash TI A Brief History of Biomedical Research Ethics in Iran: Conflict of Paradigms SO DEVELOPING WORLD BIOETHICS LA English DT Article DE biomedical research ethics; history; Iran; paradigm shift; research oversight ID MEDICAL-ETHICS; SCIENCES AB During the past two decades, Iran has experienced a noteworthy growth in its biomedical research sector. At the same time, ethical concerns and debates resulting from this burgeoning enterprise has led to increasing attention paid to biomedical ethics. In Iran, Biomedical research ethics and research oversight passed through major periods during the past decades, separated by a paradigm shift. Period 1, starting from the early 1970s, is characterized by research paternalism and complete reliance on researchers as virtuous and caring physicians. This approach was in concordance with the paternalistic clinical practice of physicians outside of research settings during the same period. Period 2, starting from the late 1990s, was partly due to revealing of ethical flaws that occurred in biomedical research in Iran. The regulatory and funding bodies concluded that it was not sufficient to rely solely on the personal and professional virtues of researchers to safeguard human subjects' rights and welfare. The necessity for independent oversight, emphasized by international declarations, became obvious and undeniable. This paradigm shift led to the establishment of research ethics committees throughout the country, the establishment of academic research centers focusing on medical ethics (MEHR) and the compilation of the first set of national ethical guidelines on biomedical research-one of the first and most important projects conducted by and in the MEHR. Although not yet arrived, period 3' is on its way. It is predictable from the obvious trends toward performance of high-quality clinical research and the appearance of a highly educated new generation, especially among women. C1 [Aramesh, Kiarash] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Aramesh, Kiarash] Univ Tehran Med Sci, Med Eth & Hist Med Res Ctr, Tehran, Iran. RP Aramesh, K (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10-1C149, Bethesda, MD 20892 USA. EM Kiarash.aramesh@nih.gov FU NIH; Medical Ethics and History of Medicine Research Center of Tehran University of Medical Sciences FX This research was supported in part by the Intramural Research Program of the NIH and Medical Ethics and History of Medicine Research Center of Tehran University of Medical Sciences. I would like to express my many thanks to Christine Grady and David Wendler, NIH department of bioethics, for their so helpful comments. Also, I would like to thank Cindy Clark, NIH Library Writing Center, for manuscript editing assistance. NR 12 TC 0 Z9 0 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1471-8731 EI 1471-8847 J9 DEV WORLD BIOETH JI Dev. World Bioeth. PD AUG PY 2015 VL 15 IS 2 BP 107 EP 112 DI 10.1111/dewb.12053 PG 6 WC Ethics; Medical Ethics SC Social Sciences - Other Topics; Medical Ethics GA CN2NR UT WOS:000358259100007 PM 24720443 ER PT J AU Reinhardt, M Thearle, MS Ibrahim, M Hohenadel, MG Bogardus, C Krakoff, J Votruba, SB AF Reinhardt, Martin Thearle, Marie S. Ibrahim, Mostafa Hohenadel, Maximilian G. Bogardus, Clifton Krakoff, Jonathan Votruba, Susanne B. TI A Human Thrifty Phenotype Associated With Less Weight Loss During Caloric Restriction SO DIABETES LA English DT Article ID ENERGY-EXPENDITURE; BODY-WEIGHT; METABOLIC-RATE; GAIN; OBESITY; THERMOGENESIS; DETERMINANTS; INDIVIDUALS; RESISTANCE; DIET AB Successful weight loss is variable for reasons not fully elucidated. Whether effective weight loss results from smaller reductions in energy expenditure during caloric restriction is not known. We analyzed whether obese individuals with a "thrifty" phenotype, that is, greater reductions in 24-h energy expenditure during fasting and smaller increases with overfeeding, lose less weight during caloric restriction than those with a "spendthrift" phenotype. During a weight-maintaining period, 24-h energy expenditure responses to fasting and 200% overfeeding were measured in a whole-room indirect calorimeter. Volunteers then underwent 6 weeks of 50% caloric restriction. We calculated the daily energy deficit (kilocalories per day) during caloric restriction, incorporating energy intake and waste, energy expenditure, and daily activity. We found that a smaller reduction in 24-h energy expenditure during fasting and a larger response to overfeeding predicted more weight loss over 6 weeks, even after accounting for age, sex, race, and baseline weight, as well as a greater rate of energy deficit accumulation. The success of dietary weight loss efforts is influenced by the energy expenditure response to caloric restriction. Greater decreases in energy expenditure during caloric restriction predict less weight loss, indicating the presence of thrifty and spendthrift phenotypes in obese humans. C1 [Reinhardt, Martin; Thearle, Marie S.; Ibrahim, Mostafa; Hohenadel, Maximilian G.; Bogardus, Clifton; Krakoff, Jonathan; Votruba, Susanne B.] NIDDKD, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH,Dept Hlth & Human Serv, Phoenix, AZ 20892 USA. RP Reinhardt, M (reprint author), NIDDKD, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH,Dept Hlth & Human Serv, Phoenix, AZ 20892 USA. EM martin.reinhardt@nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 42 TC 10 Z9 10 U1 1 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD AUG PY 2015 VL 64 IS 8 BP 2859 EP 2867 DI 10.2337/db14-1881 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CN8EL UT WOS:000358671300024 PM 25964395 ER PT J AU Zhao, YG Tarbell, KV AF Zhao, Yongge Tarbell, Kristin V. TI pH of Drinking Water Influences the Composition of Gut Microbiome and Type 1 Diabetes Incidence. Diabetes 2014;63:632-644 SO DIABETES LA English DT Letter C1 [Zhao, Yongge; Tarbell, Kristin V.] NIDDK, NIH, Immune Tolerance Sect, Diabet Endocrinol & Obes Branch, Bethesda, MD 20892 USA. RP Tarbell, KV (reprint author), NIDDK, NIH, Immune Tolerance Sect, Diabet Endocrinol & Obes Branch, Bethesda, MD 20892 USA. EM tarbellk@niddk.nih.gov NR 2 TC 1 Z9 1 U1 1 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD AUG PY 2015 VL 64 IS 8 BP E19 EP E19 DI 10.2337/db15-0321 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CN8EL UT WOS:000358671300001 PM 26207042 ER PT J AU Yeskey, K Miller, A AF Yeskey, Kevin Miller, Aubrey TI Science Unpreparedness SO DISASTER MEDICINE AND PUBLIC HEALTH PREPAREDNESS LA English DT Editorial Material C1 [Yeskey, Kevin] MDB Inc, Washington, DC USA. [Yeskey, Kevin] Uniformed Serv Univ Hlth Sci, Dept Mil & Emergency Med, Bethesda, MD 20814 USA. [Miller, Aubrey] NIEHS, NIH, Bethesda, MD USA. RP Yeskey, K (reprint author), 1101 Connecticut Ave,Suite 550, Washington, DC 20036 USA. EM kyeskey@michaeldbaker.com NR 2 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 1935-7893 EI 1938-744X J9 DISASTER MED PUBLIC JI Dis. Med. Public Health Prep. PD AUG PY 2015 VL 9 IS 4 BP 444 EP 445 DI 10.1017/dmp.2015.53 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CN2YY UT WOS:000358290600018 PM 25898771 ER PT J AU Wang, JY Yu, IS Huang, CC Chen, CY Wang, WP Lin, SW Jeang, KT Chi, YH AF Wang, Jing-Ya Yu, I. -Shing Huang, Chien-Chi Chen, Chia-Yen Wang, Wan-Ping Lin, Shu-Wha Jeang, Kuan-Teh Chi, Ya-Hui TI Sun1 deficiency leads to cerebellar ataxia in mice SO DISEASE MODELS & MECHANISMS LA English DT Article DE Sun1; LINC complex; Cerebellar ataxia ID VESICULAR GLUTAMATE TRANSPORTERS; NUCLEAR-ENVELOPE; NEURONAL MIGRATION; BRAIN-DEVELOPMENT; PURKINJE-CELLS; LINC COMPLEX; PROTEIN SUN1; LAMIN B1; ROLES; EXPRESSION AB Migration and organization of the nucleus are essential for the proliferation and differentiation of cells, including neurons. However, the relationship between the positioning of the nucleus and cellular morphogenesis remains poorly understood. Inherited recessive cerebellar ataxia has been attributed to mutations in SYNE1, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. Regardless, Syne1-mutant mice present with normal cerebellar development. The Sad1-Unc-84 homology (SUN)-domain proteins are located at the inner nuclear membrane and recruit Syne proteins through the KASH domain to the outer nuclear membrane. Here, we report an unrecognized contribution of Sun1 and Sun2 to the postnatal development of murine cerebellum. Mice depleted of Sun1 showed a marked reduction in the cerebellar volume, and this phenotype is exacerbated with additional loss of a Sun2 allele. Consistent with these histological changes, Sun1(-/-) and Sun1(-/-) Sun2(+/-) mice exhibited defectivemotor coordination. Results of immunohistochemical analyses suggested that Sun1 is highly expressed in Purkinje cells and recruits Syne2 to the periphery of the nucleus. Approximately 33% of Purkinje cells in Sun1(-/-) mice and 66% of Purkinje cells in Sun1(-/-) Sun2(+/-) mice were absent from the surface of the internal granule layer (IGL), whereas the proliferation and migration of granule neurons were unaffected. Furthermore, the Sun1(-/-) Sun2(+/) Purkinje cells exhibited retarded primary dendrite specification, reduced dendritic complexity and aberrant patterning of synapses. Our findings reveal a cell-type-specific role for Sun1 and Sun2 innucleokinesis during cerebellar development, and we propose the use of Sun-deficient mice as a model for studying cerebellar ataxia that is associated with mutation of human SYNE genes or loss of Purkinje cells. C1 [Wang, Jing-Ya; Wang, Wan-Ping; Chi, Ya-Hui] Natl Hlth Res Inst, Inst Biotechnol & Pharmaceut Res, Zhunan 35053, Miaoli County, Taiwan. [Yu, I. -Shing; Lin, Shu-Wha] Natl Taiwan Univ Hosp, Dept Clin Lab Sci & Med Biotechnol, Taipei 10048, Taiwan. [Yu, I. -Shing; Lin, Shu-Wha] Natl Taiwan Univ, Coll Med, Natl Taiwan Univ Hosp, Ctr Genom Med, Taipei 10048, Taiwan. [Huang, Chien-Chi] Natl Hlth Res Inst, Inst Mol & Genom Med, Zhunan 35053, Miaoli County, Taiwan. [Chen, Chia-Yen; Jeang, Kuan-Teh] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Lin, Shu-Wha] Natl Taiwan Univ Hosp, Dept Lab Med, Taipei 10048, Taiwan. [Chi, Ya-Hui] China Med Univ, Grad Inst Basic Med Sci, Taichung 40402, Taiwan. RP Chi, YH (reprint author), Natl Hlth Res Inst, Inst Biotechnol & Pharmaceut Res, Zhunan 35053, Miaoli County, Taiwan. EM ychi@nhri.org.tw OI LIN, SHU-WHA/0000-0001-6748-5581 FU National Health Research Institutes, Taiwan [NHRI 01A1-CSPP13-014]; Ministry of Science and Technology, Taiwan [NSC101-2311-B-400-004-MY3]; National Institute of Allergy and Infectious (NIAID), National Institutes of Health; NIAID FX This work was supported by intramural grants to Y.-H.C. from the National Health Research Institutes, Taiwan [NHRI 01A1-CSPP13-014]; and Ministry of Science and Technology, Taiwan [NSC101-2311-B-400-004-MY3]; and by intramural funds of National Institute of Allergy and Infectious (NIAID), National Institutes of Health; and an NIAID contract to SoBran, Inc. NR 57 TC 2 Z9 2 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 PY 2015 VL 8 IS 8 BP 957 EP U344 DI 10.1242/dmm.019240 PG 19 WC Cell Biology; Pathology SC Cell Biology; Pathology GA CN3DD UT WOS:000358303200017 PM 26035387 ER PT J AU Liu, C Gates, KP Fang, LH Amar, MJ Schneider, DA Geng, HL Huang, W Kim, J Pattison, J Zhang, J Witztum, JL Remaley, AT Dong, PD Miller, YI AF Liu, Chao Gates, Keith P. Fang, Longhou Amar, Marcelo J. Schneider, Dina A. Geng, Honglian Huang, Wei Kim, Jungsu Pattison, Jennifer Zhang, Jian Witztum, Joseph L. Remaley, Alan T. Duc Dong, P. Miller, Yury I. TI Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia SO DISEASE MODELS & MECHANISMS LA English DT Article DE Zebrafish; Apolipoprotein C-II; APOC2; Lipoprotein lipase; Hyperlipidemia ID APOLIPOPROTEIN-C-II; VASCULAR LIPID-ACCUMULATION; LIPOPROTEIN-LIPASE ACTIVITY; HIGH-DENSITY-LIPOPROTEIN; SEVERE HYPERTRIGLYCERIDEMIA; IN-VIVO; HYPERCHOLESTEROLEMIC ZEBRAFISH; CARDIOVASCULAR-DISEASE; FUNCTION MUTATIONS; CLINICAL-FEATURES AB Apolipoprotein C-II (APOC2) is an obligatory activator of lipoprotein lipase. Human patients with APOC2 deficiency display severe hypertriglyceridemia while consuming a normal diet, often manifesting xanthomas, lipemia retinalis and pancreatitis. Hypertriglyceridemia is also an important risk factor for development of cardiovascular disease. Animal models to study hypertriglyceridemia are limited, with no Apoc2-knockout mouse reported. To develop a genetic model of hypertriglyceridemia, we generated an apoc2 mutant zebrafish characterized by the loss of Apoc2 function. apoc2 mutants show decreased plasma lipase activity and display chylomicronemia and severe hypertriglyceridemia, which closely resemble the phenotype observed in human patients with APOC2 deficiency. The hypertriglyceridemia in apoc2 mutants is rescued by injection of plasma from wild-type zebrafish or by injection of a human APOC2 mimetic peptide. Consistent with a previous report of a transient apoc2 knockdown, apoc2 mutant larvae have a minor delay in yolk consumption and angiogenesis. Furthermore, apoc2 mutants fed a normal diet accumulate lipid and lipid-laden macrophages in the vasculature, which resemble early events in the development of human atherosclerotic lesions. In addition, apoc2 mutant embryos show ectopic overgrowth of pancreas. Taken together, our data suggest that the apoc2 mutant zebrafish is a robust and versatile animal model to study hypertriglyceridemia and the mechanisms involved in the pathogenesis of associated human diseases. C1 [Liu, Chao; Fang, Longhou; Schneider, Dina A.; Geng, Honglian; Huang, Wei; Kim, Jungsu; Pattison, Jennifer; Witztum, Joseph L.; Miller, Yury I.] Univ Calif San Diego, Dept Med, Div Endocrinol & Metab, La Jolla, CA 92093 USA. [Gates, Keith P.; Duc Dong, P.] Sanford Childrens Hlth Res Ctr, Programs Genet Dis & Dev & Aging & Stem Cell & Re, Sanford Burnham Med Res Inst, La Jolla, CA USA. [Amar, Marcelo J.; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bethesda, MD 20892 USA. [Zhang, Jian] Chinese Acad Sci, State Key Lab Mol Dev Biol, Inst Genet & Dev Biol, Beijing, Peoples R China. RP Miller, YI (reprint author), Univ Calif San Diego, Dept Med, Div Endocrinol & Metab, La Jolla, CA 92093 USA. EM yumiller@ucsd.edu OI Schneider, Dina/0000-0002-5276-3304; Fang, Longhou/0000-0003-1653-5221 FU National Institutes of Health (NIH) [HL093767, HL055798, HL088093, DK098092]; UCSD Neuroscience Microscopy Facility [P30NS0471010] FX The project was supported by the National Institutes of Health (NIH) [grant numbers HL093767 to Y.I.M., HL055798 to Y.I.M., HL088093 to J.L.W. and DK098092 P.D.S.D.], as well as the UCSD Neuroscience Microscopy Facility [grant number P30NS0471010]. NR 64 TC 8 Z9 8 U1 0 U2 3 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 PY 2015 VL 8 IS 8 BP 989 EP 998 DI 10.1242/dmm.019836 PG 10 WC Cell Biology; Pathology SC Cell Biology; Pathology GA CN3DD UT WOS:000358303200020 PM 26044956 ER PT J AU Poudel, A Savari, O Striegel, DA Periwal, V Taxy, J Millis, JM Witkowski, P Atkinson, MA Hara, M AF Poudel, Ananta Savari, Omid Striegel, Deborah A. Periwal, Vipul Taxy, Jerome Millis, J. Michael Witkowski, Piotr Atkinson, Mark A. Hara, Manami TI Beta-cell destruction and preservation in childhood and adult onset type 1 diabetes SO ENDOCRINE LA English DT Article DE Type 1 diabetes; Childhood onset; Adult onset; Pancreatic islets; Beta-cells ID MELLITUS; REGENERATION; PREVALENCE; DIAGNOSIS; PANCREAS; ARCHITECTURE; MASS AB Previous studies describing the symptomatic onset of type 1 diabetes (T1D) and rate of beta-cell loss (C-peptide) support the notion that childhood onset T1D exhibits more severe beta-cell depletion compared to adult onset T1D. To test this notion, we performed whole pancreas analyses in two T1D cases, one of childhood onset (7-year old, onset at 1.5-year) along with an adult onset case (43-year old with onset at 27-year). Both cases were matched for age and gender with control subjects. Striking regional differences in beta-cell loss were observed in both T1D cases, with severity of loss in the order of tail > body > head regions. In contrast, pancreatic alpha- and delta-cell mass was similar in controls and T1D patients. In the childhood onset T1D case, no intra-islet beta-cells were detected while in the adult onset case, beta-cell containing islets were found, exclusively in the head region. In the latter case, considerable numbers of small cellular clusters negative for three major endocrine hormones were observed, in islets with or without beta-cells. Ultrastructural analysis suggests these cells correspond to degenerating beta-cells, with empty granular membranes and abnormal morphology of nuclei with intranuclear pseudo-inclusions, adjacent to healthy alpha- and delta-cells. These results support a hypothesis that during T1D development in childhood, beta-cells are more susceptible to autoimmune destruction or immune attack is more severe, while beta-cell death in the adult onset T1D may be more protracted and incomplete. In addition, T1D may be associated with the formation of "empty" beta-cells, an interesting population of cells that may represent a key facet to the disorder's pathogenesis. C1 [Poudel, Ananta; Hara, Manami] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Savari, Omid; Millis, J. Michael; Witkowski, Piotr] Univ Chicago, Dept Surg, Chicago, IL 60637 USA. [Striegel, Deborah A.; Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. [Taxy, Jerome] NorthShore Univ Hlth Syst, Dept Pathol & Lab Med, Evanston, IL USA. [Atkinson, Mark A.] Univ Florida, Dept Pathol, Gainesville, FL 32611 USA. RP Hara, M (reprint author), Univ Chicago, Dept Med, 5841 S Maryland Ave,MC1027, Chicago, IL 60637 USA. EM mhara@uchicago.edu FU US Public Health Service Grant [DK-020595, DK-072473, AG-042151] FX The study is supported by US Public Health Service Grant DK-020595 to the University of Chicago Diabetes Research and Training Center (Animal Models Core), DK-072473, AG-042151, and a gift from the Kovler Family Foundation. The authors would like to acknowledge the generosity and support of Dr. Martin Jendrisak and the entire team of the Gift of Hope Organ & Tissue Donor Network in Chicago for providing the human pancreas tissues used in the present study. NR 37 TC 3 Z9 4 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD AUG PY 2015 VL 49 IS 3 BP 693 EP 702 DI 10.1007/s12020-015-0534-9 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CN3NJ UT WOS:000358333300016 PM 25605478 ER PT J AU Nikolopoulou, E Mytilinaios, D Calogero, AE Kamilaris, TC Troupis, T Chrousos, GP Johnson, EO AF Nikolopoulou, Elena Mytilinaios, Dimitrios Calogero, Aldo E. Kamilaris, Themis C. Troupis, Theodore Chrousos, George P. Johnson, Elizabeth O. TI Modulation of central glucocorticoid receptors in short- and long-term experimental hyperthyroidism SO ENDOCRINE LA English DT Article DE Thyroid hormone; Glucocorticoid receptor (GR); Mineralocorticoid receptor (MR); Hyperthyroidism; Hippocampus; Anterior pituitary; HPA axis ID PITUITARY-ADRENAL AXIS; MESSENGER-RNA EXPRESSION; CORTICOTROPIN-RELEASING HORMONE; RATS IN-VITRO; THYROID-HORMONE; NEGATIVE FEEDBACK; DURATION HYPOTHYROIDISM; DIFFERENTIAL REGULATION; ADRENOCORTICAL AXIS; GENE-EXPRESSION AB Hyperthyroidism is associated with a significant increase in circulating glucocorticoid levels and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to examine whether the HPA axis hyperactivity observed in hyperthyroidism may be explained by a disturbed feedback inhibition of endogenous glucocorticoids through two specific intracellular receptors in the brain: the high affinity mineralocorticoid receptor (MR) and the lower affinity glucocorticoid receptor (GR). Cytosolic receptor binding and gene expression was assessed in rats with short (7 days) and long standing (60 days) eu- and hyperthyroidism. Glucocorticoid receptor number and binding affinity (Kd) in the hippocampus were measured using [H-3(2)]-dexamethasone radioreceptor assay. In situ hybridization was employed to examine the effects of hyperthyroidism on the GR and MR mRNA levels in the hippocampus and the pituitary. Both short- and long-term hyperthyroid rats showed pronounced reduction in the concentration of cytosolic GR in the hippocampus, without changes in binding affinity or changes in GR expression. In contrast, GR mRNA in the pituitary increased after 7 days and decreased after 60 days of thyroxin treatment. MR mRNA was moderately affected. Hyperthyroidism is associated with significant decreases in hippocampal GR levels supporting the hypothesis that hyperactivity of the HPA axis observed in experimentally induced hyperthyroidism may be attributed, at least in part, to decreased negative feedback at the level of the hippocampus. These findings further support the notion that a central locus is principally responsible for the hyperactivity of the HPA axis observed in hyperthyroidism. C1 [Nikolopoulou, Elena; Mytilinaios, Dimitrios; Troupis, Theodore; Johnson, Elizabeth O.] Univ Athens, Sch Med, Dept Anat, Athens 11572, Greece. [Calogero, Aldo E.] Univ Catania, Dept Med & Pediat Sci, Sect Endocrinol Androl & Internal Med, Catania, Italy. [Kamilaris, Themis C.] NICHHD, Dev Endocrinol Branch, Bethesda, MD 20892 USA. [Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, Athens 11572, Greece. RP Johnson, EO (reprint author), Univ Athens, Sch Med, Dept Anat, 75 Mikras Asias Str, Athens 11572, Greece. EM elizabethojohnson@gmail.com OI NIKOLOPOULOU, ELENA/0000-0001-9943-3655 NR 86 TC 1 Z9 1 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD AUG PY 2015 VL 49 IS 3 BP 828 EP 841 DI 10.1007/s12020-015-0528-7 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CN3NJ UT WOS:000358333300032 PM 25722011 ER PT J AU Tekola-Ayele, F Adeyemo, A Chen, GJ Hailu, E Aseffa, A Davey, G Newport, MJ Rotimi, CN AF Tekola-Ayele, Fasil Adeyemo, Adebowale Chen, Guanjie Hailu, Elena Aseffa, Abraham Davey, Gail Newport, Melanie J. Rotimi, Charles N. TI Novel genomic signals of recent selection in an Ethiopian population SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ACTIVATED RECEPTOR-ALPHA; FATTY-ACID OXIDATION; RECENT POSITIVE SELECTION; HIGH-ALTITUDE ADAPTATION; LEUKOCYTE ANTIGEN LOCI; TYPE-2 DIABETES LOCI; NATURAL-SELECTION; PPAR-ALPHA; BALANCING SELECTION; SOUTHERN ETHIOPIA AB The recent feasibility of genome-wide studies of adaptation in human populations has provided novel insights into biological pathways that have been affected by adaptive pressures. However, only a few African populations have been investigated using these genome-wide approaches. Here, we performed a genome-wide analysis for evidence of recent positive selection in a sample of 120 individuals of Wolaita ethnicity belonging to Omotic-speaking people who have inhabited the mid-and high-land areas of southern Ethiopia for millennia. Using the 11 HapMap populations as the comparison group, we found Wolaita-specific signals of recent positive selection in several human leukocyte antigen (HLA) loci. Notably, the selected loci overlapped with HLA regions that we previously reported to be associated with podoconiosis-a geochemical lymphedema of the lower legs common in the Wolaita area. We found selection signals in PPARA, a gene involved in energy metabolism during prolonged food deficiency. This finding is consistent with the dietary use of enset, a crop with high-carbohydrate and low-fat and -protein contents domesticated in Ethiopia subsequent to food deprivation 10 000 years ago, and with metabolic adaptation to highaltitude hypoxia. We observed novel selection signals in CDKAL1 and NEGR1, well-known diabetes and obesity susceptibility genes. Finally, the SLC24A5 gene locus known to be associated with skin pigmentation was in the top selection signals in the Wolaita, and the alleles of single-nucleotide polymorphisms rs1426654 and rs1834640 (SLC24A5) associated with light skin pigmentation in Eurasian populations were of high frequency (47.9%) in this Omotic-speaking indigenous Ethiopian population. C1 [Tekola-Ayele, Fasil; Adeyemo, Adebowale; Chen, Guanjie; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Hailu, Elena; Aseffa, Abraham] Armauer Hansen Res Inst, Addis Ababa, Ethiopia. [Davey, Gail; Newport, Melanie J.] Brighton & Sussex Med Sch, Brighton, E Sussex, England. RP Tekola-Ayele, F (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bldg 12A,Room 4047,12 South Dr, Bethesda, MD 20892 USA. EM ayeleft@mail.nih.gov RI Aseffa, Abraham/J-3248-2016; OI Aseffa, Abraham/0000-0002-8028-1150; Adeyemo, Adebowale/0000-0002-3105-3231; Davey, Gail/0000-0003-2796-7468; Tekola-Ayele, Fasil/0000-0003-4194-9370 FU Wellcome Trust [079791]; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, in the Center for Research on Genomics and Global Health (CRGGH); National Institute of Diabetes and Digestive and Kidney Diseases FX The research project was supported by the Wellcome Trust (grant #079791), and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, in the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is also supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank staff of the Mossy Foot Treatment and Prevention Association (now Mossy Foot International) for coordinating the fieldwork. NR 67 TC 2 Z9 2 U1 2 U2 49 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 2015 VL 23 IS 8 BP 1085 EP 1092 DI 10.1038/ejhg.2014.233 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CM9DH UT WOS:000358006100017 PM 25370040 ER PT J AU Kishimoto, S Bernardo, M Saito, K Koyasu, S Mitchell, JB Choyke, PL Krishna, MC AF Kishimoto, Shun Bernardo, Marcelino Saito, Keita Koyasu, Sho Mitchell, James B. Choyke, Peter L. Krishna, Murali C. TI Evaluation of oxygen dependence on in vitro and in vivo cytotoxicity of photoimmunotherapy using IR-700-antibody conjugates SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Photodynamic therapy; Photoimmunotherapy; Singlet oxygen; ROS; Hypoxia ID GROWTH-FACTOR RECEPTOR; PHOTODYNAMIC THERAPY; PHOTOSENSITIZED OXIDATION; PHTHALOCYANINE TETRASULFONATE; MAMMALIAN-CELLS; TUMOR; CANCER; MECHANISMS; MODEL; TOXICITY AB Photoimmunotherapy (PIT) using the near-infrared-absorbing photosensitizing phthalocyanine dye, IRDye 700DX (IR-700), conjugated with a tumor-targeting antibody such as panitumumab (Pan) has shown efficacy in in vitro studies and several preclinical models in mice with promise for clinical translation. PIT results in rapid necrotic cell death in vitro and tumor shrinkage in vivo. Photochemical studies with the Pan-IR-700 conjugate showed that this agent can support generation of singlet oxygen and also generate reactive oxygen species after exposure to near-infrared (NIR) light. Moreover, in vitro studies using A431 cells, singlet oxygen scavengers abrogated the efficacy of PIT with Pan-IR-700, while oxygen depletion to undetectable levels in the exposure chamber almost completely inhibited the cellular cytotoxicity of PIT. Survival of tumor bearing mice was prolonged in PIT-treated animals but mice whose tumors were made transiently hypoxic prior to PIT had no benefit from the treatment. The results from this study support a central role for molecular oxygen derived species in cell death caused by PIT. Published by Elsevier Inc. C1 [Kishimoto, Shun; Saito, Keita; Mitchell, James B.; Krishna, Murali C.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bernardo, Marcelino; Koyasu, Sho; Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM murali@helix.nih.gov FU intramural research program of NCI/NIH FX This work was supported by intramural research program of NCI/NIH. NR 58 TC 6 Z9 6 U1 6 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG PY 2015 VL 85 BP 24 EP 32 DI 10.1016/j.freebiomed.2015.03.038 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CN1RO UT WOS:000358198000003 PM 25862414 ER PT J AU Vallelian, F Garcia-Rubio, I Puglia, M Kahraman, A Deuel, JW Engelsberger, WR Mason, RP Buehler, PW Schaer, DJ AF Vallelian, Florence Garcia-Rubio, Ines Puglia, Michele Kahraman, Abdullah Deuel, Jeremy W. Engelsberger, Wolfgang R. Mason, Ronald P. Buehler, Paul W. Schaer, Dominik J. TI Spin trapping combined with quantitative mass spectrometry defines free radical redistribution within the oxidized hemoglobin: haptoglobin complex SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Hemoglobin; Haptoglobin; Radical; Spin trapping; Oxidative stress; Oxidation; Electron paramagnetic resonance (EPR); Mass spectrometry ID GUINEA-PIGS; CYSTEINE RESIDUE; IN-VIVO; PEROXIDE; IDENTIFICATION; THERAPEUTICS; MECHANISMS; DECREASES; HEMOLYSIS; PROTEINS AB Extracellular or free hemoglobin (Hb) accumulates during hemolysis, tissue damage, and inflammation. Heme-triggered oxidative reactions can lead to diverse structural modifications of lipids and proteins, which contribute to the propagation of tissue damage. One important target of Hb's peroxidase reactivity is its own globin structure. Amino acid oxidation and crosslinking events destabilize the protein and ultimately cause accumulation of proinflammatory and cytotoxic Hb degradation products. The Hb scavenger haptoglobin (Hp) attenuates oxidation induced Hb degradation. In this study we show that in the presence of hydrogen peroxide (H2O2), Hb and the Hb:Hp complex share comparable peroxidative reactivity and free radical generation. While oxidation of both free Hb and Hb:Hp complex generates a common tyrosine based free radical, the spin-trapping reaction with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) yields dissimilar paramagnetic products in Hb and Hb:Hp, suggesting that radicals are differently redistributed within the complex before reacting with the spin trap. With LC-MS2 mass spectrometry we assigned multiple known and novel DMPO adduct sites. Quantification of these adducts suggested that the Hb:Hp complex formation causes extensive delocalization of accessible free radicals with drastic reduction of the major tryptophan and cysteine modifications in the beta-globin chain of the Hb:Hp complex, including decreased beta Cys93 DMPO adduction. In contrast, the quantitative changes in DMPO adduct formation on Hb:Hp complex formation were less pronounced in the Hb alpha-globin chain. In contrast to earlier speculations, we found no evidence that free Hb radicals are delocalized to the Hp chain of the complex. The observation that Hb:Hp complex formation alters free radical distribution in Hb may help to better understand the structural basis for Hp as an antioxidant protein. (C) 2015 Elsevier Inc. All rights reseived, C1 [Vallelian, Florence; Puglia, Michele; Deuel, Jeremy W.; Engelsberger, Wolfgang R.; Schaer, Dominik J.] Univ Zurich Hosp, Div Internal Med, CH-8091 Zurich, Switzerland. [Garcia-Rubio, Ines] Swiss Fed Inst Technol, Lab Phys Chem, Zurich, Switzerland. [Garcia-Rubio, Ines] Ctr Univ Def, Zaragoza, Spain. [Puglia, Michele] Univ Zurich, Funct Genom Ctr, CH-8006 Zurich, Switzerland. [Kahraman, Abdullah] Univ Zurich, Inst Mol & Life Sci, CH-8006 Zurich, Switzerland. [Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Buehler, Paul W.] Food & Drug Adm, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Schaer, Dominik J.] Univ Zurich, Inst Evolutionary Med, CH-8006 Zurich, Switzerland. RP Schaer, DJ (reprint author), Univ Zurich Hosp, Div Internal Med, CH-8091 Zurich, Switzerland. EM dominik.schaer@usz.ch OI Deuel, Jeremy/0000-0002-5409-7712; Kahraman, Abdullah/0000-0003-3523-4467 FU Swiss National Science Foundation [310030/120658, 31003A/138500]; University of Zurich Research Priority Program "Integrative Human Physiology"; University of Zurich program "Research Time"; Swiss Federal Commission for Technology and Innovation (CTI) FX This work was supported by the Swiss National Science Foundation (Grants 310030/120658 and 31003A/138500 to D.J.S.), the University of Zurich Research Priority Program "Integrative Human Physiology," the University of Zurich program "Research Time," and the Swiss Federal Commission for Technology and Innovation (CTI). NR 33 TC 5 Z9 5 U1 11 U2 29 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG PY 2015 VL 85 BP 259 EP 268 DI 10.1016/j.freeradbiomed.2015.04.023 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CN1RO UT WOS:000358198000025 PM 25933590 ER PT J AU Avery, JA Kerr, KL Ingeholm, JE Burrows, K Bodurka, J Simmons, WK AF Avery, Jason A. Kerr, Kara L. Ingeholm, John E. Burrows, Kaiping Bodurka, Jerzy Simmons, W. Kyle TI A common gustatory and interoceptive representation in the human mid-insula SO HUMAN BRAIN MAPPING LA English DT Article DE gustation; interoception; insula ID FUNCTIONAL CONNECTIVITY; GASTRIC DISTENSION; BRAIN STRUCTURES; TASTE; STIMULATION; ACTIVATION; CORTICES; CORTEX; AREAS; FMRI AB The insula serves as the primary gustatory and viscerosensory region in the mammalian cortex. It receives visceral and gustatory afferent projections through dedicated brainstem and thalamic nuclei, which suggests a potential role as a site for homeostatic integration. For example, while human neuroimaging studies of gustation have implicated the dorsal mid-insular cortex as one of the primary gustatory regions in the insula, other recent studies have implicated this same region of the insula in interoception. This apparent convergence of gustatory and interoceptive information could reflect a common neural representation in the insula shared by both interoception and gustation. This idea finds support in translational studies in rodents, and may constitute a medium for integrating homeostatic information with feeding behavior. To assess this possibility, healthy volunteers were asked to undergo fMRI while performing tasks involving interoceptive attention to visceral sensations as well as a gustatory mapping task. Analysis of the unsmoothed, high-resolution fMRI data confirmed shared representations of gustatory and visceral interoception within the dorsal mid-insula. Group conjunction analysis revealed overlapping patterns of activation for both tasks in the dorsal mid-insula, and region-of-interest analyses confirmed that the dorsal mid-insula regions responsive for visceral interoception also exhibit strong responses to tastants. Hum Brain Mapp 36:2996-3006, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Avery, Jason A.; Kerr, Kara L.; Burrows, Kaiping; Bodurka, Jerzy; Simmons, W. Kyle] Laureate Inst Brain Res, Tulsa, OK 74136 USA. [Avery, Jason A.] Univ Tulsa, Dept Biol Sci, Tulsa, OK 74104 USA. [Kerr, Kara L.] Univ Tulsa, Dept Psychol, Tulsa, OK 74104 USA. [Ingeholm, John E.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Bodurka, Jerzy] Univ Oklahoma, Coll Engn, Norman, OK 73071 USA. [Bodurka, Jerzy] Univ Oklahoma, Ctr Biomed Engn, Norman, OK 73071 USA. [Simmons, W. Kyle] Univ Tulsa, Dept Community Med, Tulsa, OK 74104 USA. RP Simmons, WK (reprint author), Laureate Inst Brain Res, 6655 South Yale Ave, Tulsa, OK 74136 USA. EM wksimmons@laureateinstitute.org RI Simmons, William/K-8925-2015 OI Simmons, William/0000-0002-0399-9003 FU Oklahoma Center for the Advancement of Science and Technology [OCAST HR10-141]; NIMH [K01MH096175-01]; Brain and Behavior Foundation; NARSAD Young Investigator Award; Oklahoma Tobacco Research Center; Laureate Institute for Brain Research; William K. Warren Foundation; University of Tulsa; Wilfred A. Woobank Fellowship FX Contract grant sponsor: Oklahoma Center for the Advancement of Science and Technology; Contract grant number: OCAST HR10-141 (to W.K.S.); Contract grant sponsor: NIMH; Contract grant number: K01MH096175-01 (to W.K.S.); Contract grant sponsor: Brain and Behavior Foundation; NARSAD Young Investigator Award (to W.K.S.); Contract grant sponsor: Oklahoma Tobacco Research Center (to W.K.S.); Contract grant sponsors: Laureate Institute for Brain Research, and The William K. Warren Foundation; Contract grant sponsor: The University of Tulsa; Wilfred A. Woobank Fellowship (to J.A.A.) NR 40 TC 10 Z9 10 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD AUG PY 2015 VL 36 IS 8 BP 2996 EP 3006 DI 10.1002/hbm.22823 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CM8KP UT WOS:000357949900011 PM 25950427 ER PT J AU Tomasi, D Wang, GJ Volkow, ND AF Tomasi, Dardo Wang, Gene-Jack Volkow, Nora D. TI Balanced modulation of striatal activation from D-2/D-3 receptors in caudate and ventral striatum: Disruption in cannabis abusers SO HUMAN BRAIN MAPPING LA English DT Article DE raclopride; reward; dopamine; sensorimotor; reaction time; functional magnetic resonance imaging; positron emission tomography ID ADOLESCENT MARIJUANA USERS; WORKING-MEMORY TASKS; BASAL GANGLIA; FUNCTIONAL CONNECTIVITY; BRAIN ACTIVATION; COCAINE ABUSERS; REWARD; AVAILABILITY; ADDICTION; HUMANS AB Proper communication between dorsal caudate (CD) and ventral striatum (VS) is likely to be crucial for on-time responses and its disruption might result in impulsivity. Here, we used functional magnetic resonance imaging (fMRI) with a sensorimotor reaction time task and positron emission tomography (PET) with [C-11]raclopride in 14 healthy controls and 18 cannabis abusers to contrast the modulation of striatal fMRI responses by dopamine receptors (D-2/D3R) in CD and VS. In controls, we show that the fMRI signals in VS that occurs concomitantly with on-time responses showed opposite modulation from D-2/D3R in CD (inhibitory) and D-2/D3R in VS (stimulatory). In contrast, this modulation was not significant in cannabis abusers. Findings suggest that action speed requires balanced VS-inhibition from D-2/D3R in CD and VS-facilitation from D-2/D3R in VS. Hum Brain Mapp 36:3154-3166, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Tomasi, Dardo; Wang, Gene-Jack; Volkow, Nora D.] NIAAA, NIH, Bethesda, MD 20892 USA. [Volkow, Nora D.] NIDA, NIH, Bethesda, MD 20892 USA. RP Tomasi, D (reprint author), NIAAA, Bethesda, MD 20892 USA. EM tomasidg@mail.nih.gov RI Tomasi, Dardo/J-2127-2015 FU National Institute of Health's Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism [2RO1AA09481]; Infrastructure of Brookhaven National Laboratory [DE-AC02-98CH10886] FX Contract grant sponsor: The National Institute of Health's Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism; Contract grant number: 2RO1AA09481; Contract grant sponsor: Infrastructure of Brookhaven National Laboratory; Contract grant number: DE-AC02-98CH10886 NR 50 TC 3 Z9 3 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD AUG PY 2015 VL 36 IS 8 BP 3154 EP 3166 DI 10.1002/hbm.22834 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CM8KP UT WOS:000357949900022 PM 26058801 ER PT J AU Barbosa, L Johnson, CK Lambourn, DM Gibson, AK Haman, KH Huggins, JL Sweeny, AR Sundar, N Raverty, SA Grigg, ME AF Barbosa, Lorraine Johnson, Christine K. Lambourn, Dyanna M. Gibson, Amanda K. Haman, Katherine H. Huggins, Jessica L. Sweeny, Amy R. Sundar, Natarajan Raverty, Stephen A. Grigg, Michael E. TI A novel Sarcocystis neurona genotype XIII is associated with severe encephalitis in an unexpectedly broad range of marine mammals from the northeastern Pacific Ocean SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article DE Sarcocystis neurona; Marine mammal; Protozoal disease; Coccidia; Parasite; Genotype; SnSAG; Encephalitis ID ENHYDRA-LUTRIS-NEREIS; OPOSSUMS DIDELPHIS-VIRGINIANA; TOXOPLASMA-GONDII OOCYSTS; NEOSPORA-CANINUM INFECTIONS; PHOCA-VITULINA-RICHARDSI; SEA OTTERS; SURFACE-ANTIGEN; MOLECULAR CHARACTERIZATION; SEXUAL RECOMBINATION; DISTEMPER VIRUS AB Sarcocystis neurona is an important cause of protozoal encephalitis among marine mammals in the northeastern Pacific Ocean. To characterise the genetic type of S. neurona in this region, samples from 227 stranded marine mammals, most with clinical or pathological evidence of protozoal disease, were tested for the presence of coccidian parasites using a nested PCR assay. The frequency of S. neurona infection was 60% (1361227) among pinnipeds and cetaceans, including seven marine mammal species not previously known to be susceptible to infection by this parasite. Eight S. neurona fetal infections identified this coccidian parasite as capable of being transmitted transplacentally. Thirty-sevens. neurona-positive samples were multilocus sequence genotyped using three genetic markers: SnSAG1-5-6, SnSAG3 and SnSAG4. A novel genotype, referred to as Type XIII within the S. neurona population genetic structure, has emerged recently in the northeastern Pacific Ocean and is significantly associated with an increased severity of protozoal encephalitis and mortality among multiple stranded marine mammal species. Published by Elsevier Ltd. on behalf of Australian Society for Parasitology Inc. C1 [Barbosa, Lorraine; Johnson, Christine K.] Univ Calif Davis, Sch Vet Med, Wildlife Hlth Ctr, Davis, CA 95616 USA. [Barbosa, Lorraine; Gibson, Amanda K.; Haman, Katherine H.; Sweeny, Amy R.; Sundar, Natarajan; Grigg, Michael E.] NIAID, Mol Parasitol Sect, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. [Lambourn, Dyanna M.] Dept Fish & Wildlife, Olympia, WA 98501 USA. [Haman, Katherine H.; Raverty, Stephen A.; Grigg, Michael E.] Univ British Columbia, Dept Zool, Fisheries Ctr, Marine Mammal Res Unit, Vancouver, BC V6T 1Z4, Canada. [Huggins, Jessica L.] Cascadia Res Collect, Olympia, WA 98501 USA. [Raverty, Stephen A.] Minist Agr, Ctr Anim Hlth, Abbotsford, BC V3G 2M3, Canada. RP Grigg, ME (reprint author), NIAID, Mol Parasitol Sect, Lab Parasit Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM griggm@niaid.nih.gov FU National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID), US; John H. Prescott Marine Mammal Rescue Assistance Grant Program, USA; NOAA Prescott Marine Mammal Rescue Grants, USA; Washington Department of Fish and Wildlife, USA; Cascadia Research Collective, USA; Animal Health Center, British Columbia Ministry of Agriculture, Canada FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH) and National Institute of Allergy and Infectious Diseases (NIAID), US. MEG is a scholar of the Canadian Institute for Advanced Research (CIFAR) Program for Integrated Microbial Biodiversity, Canada. Specimens and support for carcass collection and sampling were provided by various Northwest Marine Mammal Stranding Network participants including staff, interns and volunteers from Washington Department of Fish and Wildlife, Cascadia Research Collective, Portland State University Mammal Stranding Network, Oregon State University, San Juan County Stranding Network, Port Townsend Marine Science Center, Central Puget Sound Stranding Network, Washington and Oregon State Parks, Wolf Hollow, PAWS Wildlife, Makah Tribe, U.S. Fish and Wildlife Service, National Marine Fisheries Service/National Marine Mammal Laboratory and National Oceanic and Atmospheric Administration (NOAA) NW Region Office of Protected Resources, USA that responded to the numerous marine mammal strandings in Oregon and Washington. Special thanks to Susan Berta, John Calambokidis, Deb Duffield, Joe Gaydos, Steven Jefferies, Harriet Huber, Deanna Lynch, Brent Norberg, Stephanie Norman, Jim Rice, Amy Traxler and Kristin Wilkinson. We also thank the Rocky Mountain Laboratories Genomics Unit, USA and its DNA Sequencing Center for providing sequence data, and Sandra Etheridge of the Animal Health Center, Canada for immunohistochemistry. Stranding response and diagnostic costs were supported by the John H. Prescott Marine Mammal Rescue Assistance Grant Program, USA; NOAA Prescott Marine Mammal Rescue Grants, USA; Washington Department of Fish and Wildlife, USA; the Cascadia Research Collective, USA; and the Animal Health Center, British Columbia Ministry of Agriculture, Canada. NR 56 TC 6 Z9 7 U1 4 U2 29 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-7519 EI 1879-0135 J9 INT J PARASITOL JI Int. J. Parasit. PD AUG PY 2015 VL 45 IS 9-10 BP 595 EP 603 DI 10.1016/j.ijpara.2015.02.013 PG 9 WC Parasitology SC Parasitology GA CN5IC UT WOS:000358462000004 PM 25997588 ER PT J AU Hsieh, JH Sedykh, A Huang, RL Xia, MH Tice, RR AF Hsieh, Jui-Hua Sedykh, Alexander Huang, Ruili Xia, Menghang Tice, Raymond R. TI A Data Analysis Pipeline Accounting for Artifacts in Tox21 Quantitative High-Throughput Screening Assays SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE qHTS data analysis; in vitro activity profiling; Tox21; concentration-response curve ID DRUG-SENSITIVITY; CHEMICALS; LIBRARIES AB A main goal of the U.S. Tox21 program is to profile a 10K-compound library for activity against a panel of stress-related and nuclear receptor signaling pathway assays using a quantitative high-throughput screening (qHTS) approach. However, assay artifacts, including nonreproducible signals and assay interference (e.g., autofluorescence), complicate compound activity interpretation. To address these issues, we have developed a data analysis pipeline that includes an updated signal noise-filtering/curation protocol and an assay interference flagging system. To better characterize various types of signals, we adopted a weighted version of the area under the curve (wAUC) to quantify the amount of activity across the tested concentration range in combination with the assay-dependent point-of-departure (POD) concentration. Based on the 32 Tox21 qHTS assays analyzed, we demonstrate that signal profiling using wAUC affords the best reproducibility (Pearson's r = 0.91) in comparison with the POD (0.82) only or the AC(50) (i.e., half-maximal activity concentration, 0.81). Among the activity artifacts characterized, cytotoxicity is the major confounding factor; on average, about 8% of Tox21 compounds are affected, whereas autofluorescence affects less than 0.5%. To facilitate data evaluation, we implemented two graphical user interface applications, allowing users to rapidly evaluate the in vitro activity of Tox21 compounds. C1 [Hsieh, Jui-Hua; Tice, Raymond R.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Sedykh, Alexander] MultiCASE Inc, Beachwood, OH USA. [Huang, Ruili; Xia, Menghang] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. RP Hsieh, JH (reprint author), NIEHS, Div Natl Toxicol Program, Mail Code K2-17, Res Triangle Pk, NC 27709 USA. EM jui-hua.hsieh@nih.gov FU National Institute of Environmental Health Sciences/National Toxicology Program [Y2-ES-7020-01] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported through an interagency agreement (IAG #Y2-ES-7020-01) from the National Institute of Environmental Health Sciences/National Toxicology Program to the National Center for Advancing Translational Sciences, National Institutes of Health. The views expressed in this article are those of the authors and do not necessarily reflect the statements, opinions, views, conclusions, or policies of the National Institute of Environmental Health Sciences (NIEHS), the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), or the United States government. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. NR 23 TC 7 Z9 7 U1 2 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 EI 1552-454X J9 J BIOMOL SCREEN JI J. Biomol. Screen PD AUG PY 2015 VL 20 IS 7 BP 887 EP 897 DI 10.1177/1087057115581317 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA CN2QF UT WOS:000358266100007 PM 25904095 ER PT J AU Malkov, S Cawthon, PM Peters, KW Cauley, JA Murphy, RA Visser, M Wilson, JP Harris, T Satterfield, S Cummings, S Shepherd, JA AF Malkov, Serghei Cawthon, Peggy M. Peters, Kathy Wilt Cauley, Jane A. Murphy, Rachel A. Visser, Marjolein Wilson, Joseph P. Harris, Tamara Satterfield, Suzanne Cummings, Steve Shepherd, John A. CA Hlth ABC Study TI Hip Fractures Risk in Older Men and Women Associated With DXA-Derived Measures of Thigh Subcutaneous Fat Thickness, Cross-Sectional Muscle Area, and Muscle Density SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE HIP FRACTURE; DUAL-ENERGY X-RAY ABSORPTIOMETRY; BODY COMPOSITION; OSTEOPOROSIS; SKELETAL MUSCLE ATTENUATION; AGING ID X-RAY ABSORPTIOMETRY; BODY-COMPOSITION MEASUREMENTS; TROCHANTERIC SOFT-TISSUES; SKELETAL-MUSCLE; COMPUTED-TOMOGRAPHY; LEG MUSCLE; HEALTH; MASS; ATTENUATION; STRENGTH AB Mid-thigh cross-sectional muscle area (CSA), muscle attenuation, and greater trochanter soft tissue thickness have been shown to be independent risk factors of hip fracture. Our aim was to determine whether muscle and adipose tissue measures derived from dual-energy X-ray absorptiometry (DXA) scans would have a similar risk association as those measured using other imaging methods. Using a case-cohort study design, we identified 169 incident hip fracture cases over an average of 13.5 years among participants from the Health ABC Study, a prospective study of 3075 individuals initially aged 70 to 79 years. We modeled the thigh 3D geometry and compared DXA and computed tomography (CT) measures. DXA-derived thigh CSA, muscle attenuation, and subcutaneous fat thickness were found to be highly correlated to their CT counterparts (Pearson's r=0.82, 0.45, and 0.91, respectively; p < 0.05). The fracture risk of men and women were calculated separately. We found that decreased subcutaneous fat, CT thigh muscle attenuation, and appendicular lean mass by height squared (ALM/Ht(2)) were associated with fracture risk in men; hazard ratios (HR)=1.44 (1.02, 2.02), 1.40 (1.05, 1.85), and 0.58 (0.36, 0.91), respectively, after adjusting for age, race, clinical site, body mass index (BMI), chronic disease, hip bone mineral density (BMD), self-reported health, alcohol use, smoking status, education, physical activity, and cognitive function. In a similar model for women, only decreases in subcutaneous fat and DXA CSA were associated with hip fracture risk; HR=1.39 (1.07, 1.82) and 0.78 (0.62, 0.97), respectively. Men with a high ALM/Ht(2) and low subcutaneous fat thickness had greater than 8 times higher risk for hip fracture compared with those with low ALM/Ht(2) and high subcutaneous fat. In women, ALM/Ht(2) did not improve the model when subcutaneous fat was included. We conclude that the DXA-derived subcutaneous fat thickness is a strong marker for hip fracture risk in both men and women, especially in men with high ALM/Ht(2). (c) 2015 American Society for Bone and Mineral Research. (c) 2015 American Society for Bone and Mineral Research C1 [Malkov, Serghei; Wilson, Joseph P.; Shepherd, John A.] Univ Calif San Francisco, Dept Radiol, Bone & Breast Dens Res Grp, San Francisco, CA 94143 USA. [Cawthon, Peggy M.; Peters, Kathy Wilt; Cummings, Steve] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Murphy, Rachel A.; Harris, Tamara] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Visser, Marjolein] Vrije Univ Amsterdam, Dept Hlth Sci, Amsterdam, Netherlands. [Visser, Marjolein] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. RP Shepherd, JA (reprint author), Univ Calif San Francisco, Dept Radiol & Bioimaging, Box 0628,MRSC AC122, San Francisco, CA 94143 USA. EM john.shepherd@ucsf.edu RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 FU Merck; National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute of Nursing Research [R01-NR-012459, R01-AG031827A]; National Institutes of Health, National Institute on Aging FX This study was funded by the Investigator Initiated Study from Merck. This research was supported by National Institute on Aging (contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106); National Institute on Aging (grant R01-AG028050); and National Institute of Nursing Research (grants R01-NR-012459 and R01-AG031827A). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 27 TC 8 Z9 8 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD AUG PY 2015 VL 30 IS 8 BP 1414 EP 1421 DI 10.1002/jbmr.2469 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CN1JL UT WOS:000358175500009 PM 25644748 ER PT J AU Merrick, MT Litrownik, AJ Margolis, B Wiley, TRA Everson, MD Dubowitz, H English, D AF Merrick, Melissa T. Litrownik, Alan J. Margolis, Benyamin Wiley, Tisha R. A. Everson, Mark D. Dubowitz, Howard English, Diana TI Sexualized Behaviors Partially Mediate the Link between Maltreatment and Delinquent Behaviors SO JOURNAL OF CHILD AND FAMILY STUDIES LA English DT Article DE Child maltreatment; Sexualized behaviors; Juvenile delinquency; Mediation ID CHILD MALTREATMENT; JUVENILE-DELINQUENCY; ADULT CRIMINALITY; FIT INDEXES; ABUSE; EPIDEMIOLOGY; EXPERIENCES; VIOLENCE; MODELS; IMPACT AB The link between child maltreatment and juvenile delinquency has been well established, yet the underlying mechanisms through which the relationship may be explained are not very well understood. Although sexualized behaviors have been most studied in the context of sexual abuse, increasing evidence suggests that a broader conceptualization is warranted. Therefore, the current study tested sexualized behaviors as a mediator in the relation between child maltreatment of any type and delinquent behaviors using structural equation modeling. This study used a multi-site prospective sample of 804 children who were at high-risk for experiencing maltreatment and part of the Longitudinal Studies of Child Abuse and Neglect consortium. This study found that reported maltreatment was related to delinquency, and sexualized behaviors partially mediated the relationship between child maltreatment and juvenile delinquency. Specifically, children with more maltreatment reports before age 8 had increased sexualized behaviors at age 8, which in turn predicted greater delinquent behaviors at age 12. These results suggest that in addition to maltreatment experiences, early sexualized behaviors (i.e., at age 8) may also be markers for subsequent delinquent behaviors (i.e., at age 12). Researchers and clinicians should work to further clarify the connections among child maltreatment, sexualized behaviors, and delinquency. C1 [Merrick, Melissa T.] Ctr Dis Control & Prevent, Div Violence Prevent, Natl Ctr Injury Prevent & Control, Atlanta, GA 30329 USA. [Litrownik, Alan J.] San Diego State Univ, Dept Psychol, San Diego, CA 92182 USA. [Margolis, Benyamin] Maternal & Child Hlth Bur, Div Home Visiting & Early Childhood Syst, Hlth Resources & Serv Adm, Rockville, MD USA. [Wiley, Tisha R. A.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Everson, Mark D.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Dubowitz, Howard] Univ Maryland, Dept Pediat, College Pk, MD 20742 USA. [English, Diana] Univ Washington, Sch Social Work, Seattle, WA 98195 USA. RP Merrick, MT (reprint author), Ctr Dis Control & Prevent, Div Violence Prevent, Natl Ctr Injury Prevent & Control, Atlanta, GA 30329 USA. EM kcq7@cdc.gov NR 64 TC 1 Z9 1 U1 3 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1062-1024 EI 1573-2843 J9 J CHILD FAM STUD JI J. Child Fam. Stud. PD AUG PY 2015 VL 24 IS 8 BP 2217 EP 2228 DI 10.1007/s10826-014-0024-3 PG 12 WC Family Studies; Psychology, Developmental; Psychiatry SC Family Studies; Psychology; Psychiatry GA CN1AU UT WOS:000358148300004 ER PT J AU Ouaguia, L Morales, O Wychowski, C Carpentier, A Aoudjehane, L Dubuisson, J Calmus, Y de Launoit, Y Conti, F Delhem, N AF Ouaguia, L. Morales, O. Wychowski, C. Carpentier, A. Aoudjehane, L. Dubuisson, J. Calmus, Y. de Launoit, Y. Conti, F. Delhem, N. TI Hepatitis C virus contributes to aggravation of the immunosuppressive environment by increasing the suppressive activity of natural regulatory T cells SO JOURNAL OF CLINICAL VIROLOGY LA English DT Meeting Abstract CT Viral Hepatitis Summit CY APR 10-12, 2015 CL Shanghai, PEOPLES R CHINA C1 [Ouaguia, L.; Morales, O.; de Launoit, Y.; Delhem, N.] CNRS, Inst Biol Lille, UMR 8161, Lille, France. [Wychowski, C.; Dubuisson, J.] CNRS, INSERM, Ctr Infect & Immunite Lille, UMR 8204,U1019, Lille, France. [Carpentier, A.] NIH, Bethesda, MD 20892 USA. [Aoudjehane, L.; Calmus, Y.; Conti, F.] Univ Paris 06, F-75012 Paris, France. [Aoudjehane, L.; Calmus, Y.; Conti, F.] CdR St Antoine, INSERM, UMR S 938, F-75012 Paris, France. [Calmus, Y.; Conti, F.] Hop St Antoine, AP HP, Ctr Transplantat Hepat, Pole Digestif, F-75012 Paris, France. [Calmus, Y.; Conti, F.] Univ Paris 05, Fac Med, F-75014 Paris, France. 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 1386-6532 EI 1873-5967 J9 J CLIN VIROL JI J. Clin. Virol. PD AUG PY 2015 VL 69 MA P0003 BP 224 EP 224 DI 10.1016/j.jcv.2015.06.010 PG 1 WC Virology SC Virology GA CN3IH UT WOS:000358318400049 ER PT J AU Koh, C Canini, L Dahari, H Cooper, S Cory, D Winters, MA Choong, I Cotler, SJ Kleiner, DE Yurdaydin, C Heller, T Glenn, JS AF Koh, C. Canini, L. Dahari, H. Cooper, S. Cory, D. Winters, M. A. Choong, I. Cotler, S. J. Kleiner, D. E. Yurdaydin, C. Heller, T. Glenn, J. S. TI Dose-dependent decrease in hepatitis delta virus (HDV) RNA achieved with the oral prenylation inhibitor lonafarnib in a proof-of-concept, randomised, double-blinded, placebo-controlled study in patients with chronic HDV infection SO JOURNAL OF CLINICAL VIROLOGY LA English DT Meeting Abstract CT Viral Hepatitis Summit CY APR 10-12, 2015 CL Shanghai, PEOPLES R CHINA C1 [Koh, C.; Heller, T.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Canini, L.; Dahari, H.; Cotler, S. J.] Loyola Univ, Med Ctr, Dept Med, Div Hepatol, New Orleans, LA 70118 USA. [Canini, L.] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH8 9YL, Midlothian, Scotland. [Dahari, H.] Los Alamos Natl Lab, Theoret Biol & Biophys, Los Alamos, NM 87545 USA. [Cooper, S.] Calif Pacific Med Ctr, Div Hepatol, San Francisco, CA USA. [Cory, D.; Choong, I.] Eiger Biopharmaceut, New York, NY USA. [Winters, M. A.; Glenn, J. S.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA. [Kleiner, D. E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Yurdaydin, C.] Ankara Univ, Sch Med, Dept Gastroenterol, TR-06100 Ankara, Turkey. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 EI 1873-5967 J9 J CLIN VIROL JI J. Clin. Virol. PD AUG PY 2015 VL 69 MA OP0001 BP 247 EP 247 DI 10.1016/j.jcv.2015.06.071 PG 1 WC Virology SC Virology GA CN3IH UT WOS:000358318400109 ER PT J AU Nilsen, W AF Nilsen, Wendy TI The Use of Technology to Enhance Health SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP Nilsen, W (reprint author), NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. EM nilsenwj@od.nih.gov NR 6 TC 0 Z9 0 U1 1 U2 1 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 2015 VL 30 IS 8 BP 1047 EP 1048 DI 10.1007/s11606-015-3307-5 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CN3WR UT WOS:000358359400003 PM 25851304 ER PT J AU Voynova, E Qi, CF Scott, B Bolland, S AF Voynova, Elisaveta Qi, Chen-Feng Scott, Bethany Bolland, Silvia TI Cutting Edge: Induction of Inflammatory Disease by Adoptive Transfer of an Atypical NK Cell Subset SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; KILLER DENDRITIC CELLS; NATURAL-KILLER; T-CELLS; IN-VIVO; MICE; EXPRESSION; DIFFERENTIATION; AUTOIMMUNITY; GAMMA AB Several mouse models of systemic lupus erythematosus, including Fc gamma RIIB-KO and TLR7tg mice, develop an expansion of an atypical NK cell subset with functional similarity to cells referred as IFN-producing killer DCs or pre-mature NKs in other systems. In this study, we show that atypical NKs purified from spleens of systemic lupus erythematosus-prone mice, and identified as NK1.1(+)CD11c(+)CD122(+)MHC-II+, induce persistent autoimmune disease in an IFN-I- and CD40L-dependent manner when transferred to wild-type mice. A single transfer of 4 X 10(6) NK1.1(+) cells from TLR7tg into wild-type induces a 2-wk-long wave of inflammatory cytokines in the serum; a sustained increase in T cell activation and follicular helper cells for the following months; and a progressive expansion of dendritic cells, monocytes, and granulocytes. Furthermore, IL-15 deficiency, which impedes development of NK cells, ameliorates the autoimmune pathology of TLR7tg mice. These results suggest that cells of the NK lineage can develop into cytokine-producing/APCs that affect the priming and progression of systemic autoimmune disease. C1 [Voynova, Elisaveta; Qi, Chen-Feng; Scott, Bethany; Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Bolland, S (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM SBolland@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 22 TC 1 Z9 1 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2015 VL 195 IS 3 BP 806 EP 809 DI 10.4049/jimmunol.1500540 PG 4 WC Immunology SC Immunology GA CM9ZO UT WOS:000358070400009 PM 26109646 ER PT J AU Iyer, SS Gangadhara, S Victor, B Gomez, R Basu, R Hong, JJ Labranche, C Montefiori, DC Villinger, F Moss, B Amara, RR AF Iyer, Smita S. Gangadhara, Sailaja Victor, Blandine Gomez, Rosy Basu, Rahul Hong, Jung Joo Labranche, Celia Montefiori, David C. Villinger, Francois Moss, Bernard Amara, Rama Rao TI Codelivery of Envelope Protein in Alum with MVA Vaccine Induces CXCR3-Biased CXCR5(+) and CXCR5(-) CD4 T Cell Responses in Rhesus Macaques SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACUTE VIRAL-INFECTION; FOLLICULAR HELPER; B-CELLS; PLASMABLAST RESPONSES; MONOCLONAL-ANTIBODIES; MUCOSAL CHALLENGE; SIV INFECTION; VIRUS; IMMUNIZATION; EXPRESSION AB The goal of an HIV vaccine is to generate robust and durable protective Ab. Vital to this goal is the induction of CD4(+) T follicular helper (T-FH) cells. However, very little is known about the T-FH response to HIV vaccination and its relative contribution to magnitude and quality of vaccine-elicited Ab titers. In this study, we investigated these questions in the context of a DNA/modified vaccinia virus Ankara SIV vaccine with and without gp140 boost in aluminum hydroxide in rhesus macaques. In addition, we determined the frequency of vaccine-induced CD4(+) T cells coexpressing chemokine receptor, CXCR5 (facilitates migration to B cell follicles) in blood and whether these responses were representative of lymph node T-FH responses. We show that booster modified vaccinia virus Ankara immunization induced a distinct and transient accumulation of proliferating CXCR5(+) and CXCR5(-) CD4 T cells in blood at day 7 postimmunization, and the frequency of the former but not the latter correlated with T-FH and B cell responses in germinal centers of the lymph node. Interestingly, gp140 boost induced a skewing toward CXCR3 expression on germinal center T-FH cells, which was strongly associated with longevity, avidity, and neutralization potential of vaccine-elicited Ab response. However, CXCR3(+) cells preferentially expressed the HIV coreceptor CCR5, and vaccine-induced CXCR3(+) CXCR5(+) cells showed a moderate positive association with peak viremia following SIV251 infection. Taken together, our findings demonstrate that vaccine regimens that elicit CXCR3-biased T-FH cell responses favor Ab persistence and avidity but may predispose to higher acute viremia in the event of breakthrough infections. C1 [Iyer, Smita S.; Gangadhara, Sailaja; Victor, Blandine; Gomez, Rosy; Basu, Rahul; Hong, Jung Joo; Villinger, Francois; Amara, Rama Rao] Emory Univ, Emory Vaccine Ctr, Yerkes Natl Primate Res Ctr, Div Microbiol & Immunol, Atlanta, GA 30329 USA. [Labranche, Celia; Montefiori, David C.] Duke Univ, Dept Surg, Durham, NC 27705 USA. [Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Amara, Rama Rao] Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30329 USA. RP Amara, RR (reprint author), Emory Univ, Emory Vaccine Ctr, Yerkes Natl Primate Res Ctr, Div Microbiol & Immunol, Room 3024,954 Gatewood Rd, Atlanta, GA 30329 USA. EM ramara@emory.edu FU National Institutes of Health Grants [PO1 AI088575, P51 OD011132, P30 AI50409, HHSN27201100016C]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. FX This work was supported in part by National Institutes of Health Grants PO1 AI088575 (to R.R.A.), P51 OD011132 (to Yerkes National Primate Research Center), P30 AI50409 (to Emory Center for AIDS Research), and HHSN27201100016C (to D.C.M.). Partial support was also provided by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 34 TC 12 Z9 12 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2015 VL 195 IS 3 BP 994 EP 1005 DI 10.4049/jimmunol.1500083 PG 12 WC Immunology SC Immunology GA CM9ZO UT WOS:000358070400028 PM 26116502 ER PT J AU Thompson, EA Liang, F Lindgren, G Sandgren, KJ Quinn, KM Darrah, PA Koup, RA Seder, RA Kedl, RM Lore, K AF Thompson, Elizabeth A. Liang, Frank Lindgren, Gustaf Sandgren, Kerrie J. Quinn, Kylie M. Darrah, Patricia A. Koup, Richard A. Seder, Robert A. Kedl, Ross M. Lore, Karin TI Human Anti-CD40 Antibody and Poly IC:LC Adjuvant Combination Induces Potent T Cell Responses in the Lung of Nonhuman Primates SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; AGONIST CD40 ANTIBODY; DENDRITIC CELLS; MONOCLONAL-ANTIBODY; IN-VIVO; PHASE-I; IMMUNE MODULATION; CONSERVED REGIONS; PEPTIDE-COCKTAIL; CANCER-PATIENTS AB Nonlive vaccine platforms that induce potent cellular immune responses in mucosal tissue would have broad application for vaccines against infectious diseases and tumors. Induction of cellular immunity could be optimized by targeted activation of multiple innate and costimulatory signaling pathways, such as CD40 or TLRs. In this study, we evaluated immune activation and elicitation of T cell responses in nonhuman primates after immunization with peptide Ags adjuvanted with an agonistic anti-CD40Ab, with or without the TLR3 ligand poly IC:LC. We found that i.v. administration of the anti-CD40Ab induced rapid and transient innate activation characterized by IL-12 production and upregulated costimulatory and lymph node homing molecules on dendritic cells. Using fluorescently labeled Abs for in vivo tracking, we found that the anti-CD40Ab bound to all leukocytes, except T cells, and disseminated to multiple organs. CD4(+) and CD8(+) T cell responses were significantly enhanced when the anti-CD40Ab was coadministered with poly IC: LC compared with either adjuvant given alone and were almost exclusively compartmentalized to the lung. Notably, Ag-specific T cells in the bronchoalveolar lavage were sustained at similar to 5-10%. These data indicate that systemic administration of anti-CD40Ab may be particularly advantageous for vaccines and/or therapies that require T cell immunity in the lung. C1 [Thompson, Elizabeth A.; Liang, Frank; Lindgren, Gustaf; Sandgren, Kerrie J.; Lore, Karin] Karolinska Inst, Dept Med, Clin Immunol & Allergy Unit, S-17176 Stockholm, Sweden. [Thompson, Elizabeth A.; Liang, Frank; Quinn, Kylie M.; Darrah, Patricia A.; Koup, Richard A.; Seder, Robert A.; Lore, Karin] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Kedl, Ross M.] Univ Colorado Denver, Dept Immunol & Microbiol, Aurora, CO 80045 USA. RP Kedl, RM (reprint author), Univ Colorado Denver, Dept Immunol & Microbiol, 12800 E 19th Ave, Aurora, CO 80045 USA. EM ross.kedl@ucdenver.edu; Karin.Lore@ki.se FU Vetenskapsradet [521-2012-3377]; Swedish Governmental Agency for Innovation Systems (Vinnova) [2010-00999]; Small Business Innovation Research Phase 2 Grant [5R44AI080030]; U.S. National Institutes of Health FX This work was supported by the Vetenskapsradet (Grant 521-2012-3377 to K.L.), the Swedish Governmental Agency for Innovation Systems (Vinnova) (Grant 2010-00999 to K.L.), intramural funds as U.S. National Institutes of Health investigators (to R.A.K. and R.A.S.), and Small Business Innovation Research Phase 2 Grant 5R44AI080030 to ImmuRx, Inc. NR 49 TC 6 Z9 6 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2015 VL 195 IS 3 BP 1015 EP 1024 DI 10.4049/jimmunol.1500078 PG 10 WC Immunology SC Immunology GA CM9ZO UT WOS:000358070400030 PM 26123354 ER PT J AU Schmuth, M Elentner, A Ortner, D Clausen, B Gonzalez, F Fernandez-Salguero, P Dubrac, S AF Schmuth, M. Elentner, A. Ortner, D. Clausen, B. Gonzalez, F. Fernandez-Salguero, P. Dubrac, S. TI Skin response to a carcinogen involves the xenobiotic receptor pregnane X receptor SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 06-09, 2015 CL Atlanta, GA SP Soc Investigat Dermatol C1 [Schmuth, M.; Elentner, A.; Ortner, D.; Dubrac, S.] Med Univ Innsbruck, A-6020 Innsbruck, Austria. [Gonzalez, F.] NCI, Natl Inst Hlth, Lab Metab, Bethesda, MD 20892 USA. [Fernandez-Salguero, P.] Univ Extremadura, Fac Sci, Badajoz, Spain. [Clausen, B.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Immunol, D-55122 Mainz, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2015 VL 135 IS 8 MA LB754 BP S3 EP S3 PG 1 WC Dermatology SC Dermatology GA CN2SL UT WOS:000358272100048 ER PT J AU Shomorony, A Pfeifer, CR Aronova, MA Zhang, G Cai, T Xu, H Notkins, AL Leapman, RD AF Shomorony, A. Pfeifer, C. R. Aronova, M. A. Zhang, G. Cai, T. Xu, H. Notkins, A. L. Leapman, R. D. TI Combining quantitative 2D and 3D image analysis in the serial block face SEM: application to secretory organelles of pancreatic islet cells SO JOURNAL OF MICROSCOPY LA English DT Article DE alpha cells; beta cells; serial block face SEM; stereology; pancreatic islets; secretory granules ID BETA-CELLS; ELECTRON-MICROSCOPY; DOCKED GRANULES; INSULIN; EXOCYTOSIS; GLUCOSE; BLOOD; RECONSTRUCTION; ARCHITECTURE; RETINA AB A combination of two-dimensional (2D) and three-dimensional (3D) analyses of tissue volume ultrastructure acquired by serial block face scanning electron microscopy can greatly shorten the time required to obtain quantitative information from big data sets that contain many billions of voxels. Thus, to analyse the number of organelles of a specific type, or the total volume enclosed by a population of organelles within a cell, it is possible to estimate the number density or volume fraction of that organelle using a stereological approach to analyse randomly selected 2D block face views through the cells, and to combine such estimates with precise measurement of 3D cell volumes by delineating the plasma membrane in successive block face images. The validity of such an approach can be easily tested since the entire 3D tissue volume is available in the serial block face scanning electron microscopy data set. We have applied this hybrid 3D/2D technique to determine the number of secretory granules in the endocrine and cells of mouse pancreatic islets of Langerhans, and have been able to estimate the total insulin content of a beta cell. C1 [Shomorony, A.; Pfeifer, C. R.; Aronova, M. A.; Zhang, G.; Leapman, R. D.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Cai, T.; Xu, H.; Notkins, A. L.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Leapman, RD (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bldg 13,Room 3N17,13 South Dr, Bethesda, MD 20892 USA. EM leapmanr@mail.nih FU National Institute of Biomedical Imaging and Bioengineering; National Institute of Dental and Craniofacial Research, NIH FX This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, and the National Institute of Dental and Craniofacial Research, NIH. NR 41 TC 4 Z9 4 U1 3 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-2720 EI 1365-2818 J9 J MICROSC-OXFORD JI J. Microsc.. PD AUG PY 2015 VL 259 IS 2 BP 155 EP 164 DI 10.1111/jmi.12276 PG 10 WC Microscopy SC Microscopy GA CN3CF UT WOS:000358300600010 PM 26139222 ER PT J AU Wieczorek, L Krebs, SJ Kalyanaraman, V Whitney, S Tovanabutra, S Moscoso, CG Sanders-Buell, E Williams, C Slike, B Molnar, S Dussupt, V Alam, SM Chenine, AL Tong, T Hill, EL Liao, HX Hoelscher, M Maboko, L Zolla-Pazner, S Haynes, BF Pensiero, M McCutchan, F Malek-Salehi, S Cheng, RH Robb, ML VanCott, T Michael, NL Marovich, MA Alving, CR Matyas, GR Rao, M Polonis, VR AF Wieczorek, Lindsay Krebs, Shelly J. Kalyanaraman, Vaniambadi Whitney, Stephen Tovanabutra, Sodsai Moscoso, Carlos G. Sanders-Buell, Eric Williams, Constance Slike, Bonnie Molnar, Sebastian Dussupt, Vincent Alam, S. Munir Chenine, Agnes-Laurence Tong, Tina Hill, Edgar L. Liao, Hua-Xin Hoelscher, Michael Maboko, Leonard Zolla-Pazner, Susan Haynes, Barton F. Pensiero, Michael McCutchan, Francine Malek-Salehi, Shawyon Cheng, R. Holland Robb, Merlin L. VanCott, Thomas Michael, Nelson L. Marovich, Mary A. Alving, Carl R. Matyas, Gary R. Rao, Mangala Polonis, Victoria R. TI Comparable Antigenicity and Immunogenicity of Oligomeric Forms of a Novel, Acute HIV-1 Subtype C gp145 Envelope for Use in Preclinical and Clinical Vaccine Research SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BROADLY NEUTRALIZING ANTIBODIES; RECOMBINANT GLYCOPROTEIN-120 VACCINE; MONOCLONAL-ANTIBODIES; NONNEUTRALIZING ANTIBODIES; IMMUNE-RESPONSES; EFFICACY TRIAL; CONFORMATIONAL EPITOPE; DEPENDENT EPITOPE; GENETIC SUBTYPES AB Eliciting broadly reactive functional antibodies remains a challenge in human immunodeficiency virus type 1 (HIV-1) vaccine development that is complicated by variations in envelope (Env) subtype and structure. The majority of new global HIV-1 infections are subtype C, and novel antigenic properties have been described for subtype C Env proteins. Thus, an HIV-1 subtype C Env protein (CO6980v0c22) from an infected person in the acute phase (Fiebig stage I/II) was developed as a research reagent and candidate immunogen. The gp145 envelope is a novel immunogen with a fully intact membrane-proximal external region (MPER), extended by a polylysine tail. Soluble gp145 was enriched for trimers that yielded the expected "fan blade" motifs when visualized by cryoelectron microscopy. CO6980v0c22 gp145 reacts with the 4E10, PG9, PG16, and VRC01 HIV-1 neutralizing monoclonal antibodies (MAbs), as well as the V1/V2-specific PGT121, 697, 2158, and 2297 MAbs. Different gp145 oligomers were tested for immunogenicity in rabbits, and purified dimers, trimers, and larger multimers elicited similar levels of cross-subtype binding and neutralizing antibodies to tier 1 and some tier 2 viruses. Immunized rabbit sera did not neutralize the highly resistant CO6980v0c22 pseudovirus but did inhibit the homologous infectious molecular clone in a peripheral blood mononuclear cell (PBMC) assay. This Env is currently in good manufacturing practice (GMP) production to be made available for use as a clinical research tool and further evaluation as a candidate vaccine. IMPORTANCE At present, the product pipeline for HIV vaccines is insufficient and is limited by inadequate capacity to produce large quantities of vaccine to standards required for human clinical trials. Such products are required to evaluate critical questions of vaccine formulation, route, dosing, and schedule, as well as to establish vaccine efficacy. The gp145 Env protein presented in this study forms physical trimers, binds to many of the well-characterized broad neutralizing MAbs that target conserved Env epitopes, and induce cross-subtype neutralizing antibodies as measured in both cell line and primary cell assays. This subtype C Env gp145 protein is currently undergoing good manufacturing practice production for use as a reagent for preclinical studies and for human clinical research. This product will serve as a reagent for comparative studies and may represent a next-generation candidate HIV immunogen. C1 [Wieczorek, Lindsay; Krebs, Shelly J.; Tovanabutra, Sodsai; Sanders-Buell, Eric; Slike, Bonnie; Molnar, Sebastian; Dussupt, Vincent; Chenine, Agnes-Laurence; McCutchan, Francine; Robb, Merlin L.; Michael, Nelson L.; Marovich, Mary A.; Alving, Carl R.; Matyas, Gary R.; Rao, Mangala; Polonis, Victoria R.] Mil HIV Res Program, Bethesda, MD 20817 USA. [Wieczorek, Lindsay; Krebs, Shelly J.; Tovanabutra, Sodsai; Sanders-Buell, Eric; Slike, Bonnie; Molnar, Sebastian; Dussupt, Vincent; Chenine, Agnes-Laurence; McCutchan, Francine; Robb, Merlin L.] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Kalyanaraman, Vaniambadi; Whitney, Stephen; VanCott, Thomas] Adv Biosci Labs Inc, Rockville, MD USA. [Wieczorek, Lindsay; Moscoso, Carlos G.; Malek-Salehi, Shawyon; Cheng, R. Holland] Univ Calif Davis, Davis, CA 95616 USA. [Williams, Constance; Zolla-Pazner, Susan] NYU, Sch Med, New York, NY USA. [Williams, Constance; Zolla-Pazner, Susan] Vet Affairs Med Ctr, New York, NY USA. [Alam, S. Munir; Liao, Hua-Xin; Haynes, Barton F.] Duke Univ, Durham, NC USA. [Tong, Tina; Hill, Edgar L.] Henry M Jackson Fdn Adv Mil Med, HJF DAIDS, Bethesda, MD USA. [Pensiero, Michael; Marovich, Mary A.] NIH, Div Aids, Bethesda, MD 20892 USA. [Hoelscher, Michael] Klinikum Univ Munich, Dept Infect Dis & Trop Med, Munich, Germany. [Hoelscher, Michael] German Ctr Infect Res DZIF, Munich, Germany. [Maboko, Leonard] Mbeya Med Res Ctr, Natl Inst Med Res, Mbeya, Tanzania. [Michael, Nelson L.; Alving, Carl R.; Matyas, Gary R.; Rao, Mangala; Polonis, Victoria R.] Walter Reed Army Inst Res, Silver Spring, MD USA. RP Polonis, VR (reprint author), Mil HIV Res Program, Bethesda, MD 20817 USA. EM vpolonis@hivresearch.org RI Hoelscher, Michael/D-3436-2012 FU Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-11-2-0174]; U.S. Department of Defense (DOD) (U.S. Army Medical Research and Materiel Command) [W81XWH-11-2-0174]; Division of AIDS, National Institute for Allergy and Infectious Diseases, NIH; National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services [HHSN272200800014C]; NIH [HL59725]; Fisher BioService, Inc. [FBS-0022C-06]; Department of Veterans Affairs FX This work was supported by a cooperative agreement (W81XWH-11-2-0174) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DOD) (U.S. Army Medical Research and Materiel Command), working together with the Division of AIDS, National Institute for Allergy and Infectious Diseases, NIH. This project has also been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services, under contract HHSN272200800014C. Additional support was provided by NIH grant HL59725, a contract (FBS-0022C-06) with Fisher BioService, Inc., and funds from the Department of Veterans Affairs. The views expressed here are our private opinions and are not to be considered official or to reflect the views of the U.S. Army, the U.S. Department of Defense, or the U.S. Government. The use of trade names is for identification only and does not imply endorsement by the U.S. Government. NR 97 TC 8 Z9 8 U1 0 U2 10 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 2015 VL 89 IS 15 BP 7478 EP 7493 DI 10.1128/JVI.00412-15 PG 16 WC Virology SC Virology GA CN2UP UT WOS:000358277800005 PM 25972551 ER PT J AU Shytaj, IL Nickel, G Arts, E Farrell, N Biffoni, M Pal, R Chung, HK LaBranche, C Montefiori, D Vargas-Inchaustegui, D Robert-Guroff, M Lewis, MG Sacha, JB Palamara, AT Savarino, A AF Shytaj, Iart Luca Nickel, Gabrielle Arts, Eric Farrell, Nicholas Biffoni, Mauro Pal, Ranajit Chung, Hye Kyung LaBranche, Celia Montefiori, David Vargas-Inchaustegui, Diego Robert-Guroff, Marjorie Lewis, Mark G. Sacha, Jonah B. Palamara, Anna Teresa Savarino, Andrea TI Two-Year Follow-Up of Macaques Developing Intermittent Control of the Human Immunodeficiency Virus Homolog Simian Immunodeficiency Virus SIVmac251 in the Chronic Phase of Infection SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; AFRICAN-GREEN MONKEYS; VIRAL LOAD; IMMUNE ACTIVATION; BUTHIONINE SULFOXIMINE; ESCAPE MUTATIONS; HIV PERSISTENCE; CELL RESPONSES; AIDS; INHIBITION AB Off-therapy control of viremia by HIV-infected individuals has been associated with two likely players: a restricted viral reservoir and an efficient cell-mediated immune response. We previously showed that a combination of highly suppressive antiretroviral therapy and two experimental drugs, i.e., auranofin and buthionine sulfoximine, was able to reduce the viral reservoir, elicit efficient cell-mediated antiviral responses, and induce intermittent posttherapy viral load control in chronically SIVmac251-infected macaques. We here show that the macaques that had received this drug combination and then stopped antiretroviral therapy were also able to maintain low numbers of activated CD4(+) T cells at viral rebound. Moreover, these macaques consistently displayed low-level simian immunodeficiency virus (SIV) diversity, which was in line with the strong and broadly reactive cell-mediated immune responses against conserved Gag antigens. Extended follow-up showed that the two macaques that had received the complete drug combination remained healthy and did not develop AIDS in 2 years of follow-up after therapy suspension. This disease-free survival is longer than twice the average time of progression to AIDS in SIVmac251-infected rhesus macaques. These results suggest that limited numbers of activated T cells at viral rebound and subsequent development of broadly reactive cell-mediated responses may be interrelated in reducing the viral reservoir. IMPORTANCE The HIV reservoir in CD4(+) T cells represents one main obstacle to HIV eradication. Recent studies, however, show that a drastic reduction of this reservoir is insufficient for inducing a functional cure of AIDS. In the present work, we thoroughly studied and subjected to long-term follow-up two macaques showing intermittent control of the virus following suspension of antiretroviral therapy plus an experimental antireservoir treatment, i.e., the gold salt auranofin and the investigational chemotherapeutic agent buthionione sulfoximine (BSO). We found that these drugs were able to decrease the number of activated CD4(+) T cells, which are preferential targets for HIV infection. Then, efficient immune responses against the virus were developed in the macaques, which remained healthy during 2 years of follow-up. This result may furnish another building block for future attempts to cure HIV/AIDS. C1 [Shytaj, Iart Luca; Biffoni, Mauro; Savarino, Andrea] Ist Super Sanita, I-00161 Rome, Italy. [Nickel, Gabrielle; Arts, Eric] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Farrell, Nicholas] Virginia Commonwealth Univ, Richmond, VA USA. [Pal, Ranajit; Chung, Hye Kyung] ABL, Rockville, MD USA. [LaBranche, Celia; Montefiori, David] Duke Univ, Durham, NC USA. [Vargas-Inchaustegui, Diego; Robert-Guroff, Marjorie] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Lewis, Mark G.] Bioqual Inc, Rockville, MD USA. [Sacha, Jonah B.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Vaccine & Gene Therapy Inst, Portland, OR USA. [Sacha, Jonah B.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Pathobiol & Immunol, Portland, OR USA. [Palamara, Anna Teresa] Univ Roma La Sapienza, Dept Publ Hlth & Infect Dis, Inst Pasteur, Fdn Cenci Bolognetti Ist, I-00185 Rome, Italy. [Palamara, Anna Teresa] IRCCS San Raffaele Pisana, Rome, Italy. RP Savarino, A (reprint author), Ist Super Sanita, Viale Regina Elena 299, I-00161 Rome, Italy. EM andrea.savarino@iss.it RI Biffoni, Mauro/J-8318-2016; OI Biffoni, Mauro/0000-0002-1304-9060; Shytaj, Iart Luca/0000-0002-9980-1275 FU ISS intramural grants; ISS travel grants; NIAID-NIH [HHSN27201100016C]; NSF [1058726]; Intramural Research Program of the NIH, National Cancer Institute FX The work was supported by ISS intramural grants (recipient, A.S.), ISS travel grants (recipients, I.L.S. and A.S.), NIAID-NIH contract HHSN27201100016C (recipient, D.M.), NSF grant 1058726 (recipient, N.F.), and, in part, the Intramural Research Program of the NIH, National Cancer Institute (recipient, M.R.-G.). NR 51 TC 5 Z9 5 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2015 VL 89 IS 15 BP 7521 EP 7535 DI 10.1128/JVI.00396-15 PG 15 WC Virology SC Virology GA CN2UP UT WOS:000358277800008 PM 25972547 ER PT J AU Lauck, M Alkhovsky, SV Bao, YM Bailey, AL Shevtsova, ZV Shchetinin, AM Vishnevskaya, TV Lackemeyer, MG Postnikova, E Mazur, S Wada, JR Radoshitzky, SR Friedrich, TC Lapin, BA Deriabin, PG Jahrling, PB Goldberg, TL O'Connor, DH Kuhn, JH AF Lauck, Michael Alkhovsky, Sergey V. Bao, Yiming Bailey, Adam L. Shevtsova, Zinaida V. Shchetinin, Alexey M. Vishnevskaya, Tatyana V. Lackemeyer, Matthew G. Postnikova, Elena Mazur, Steven Wada, Jiro Radoshitzky, Sheli R. Friedrich, Thomas C. Lapin, Boris A. Deriabin, Petr G. Jahrling, Peter B. Goldberg, Tony L. O'Connor, David H. Kuhn, Jens H. TI Historical Outbreaks of Simian Hemorrhagic Fever in Captive Macaques Were Caused by Distinct Arteriviruses SO JOURNAL OF VIROLOGY LA English DT Article ID NONHUMAN-PRIMATES; VIRUS ISOLATE; ALIGNMENT; MONKEYS; STRAINS; DISEASE; TOOL; SHF AB Simian hemorrhagic fever (SHF) is lethal for macaques. Based on clinical presentation and serological diagnosis, all reported SHF outbreaks were thought to be caused by different strains of the same virus, simian hemorrhagic fever virus (SHFV; Arteriviridae). Here we show that the SHF outbreaks in Sukhumi in 1964 and in Alamogordo in 1989 were caused not by SHFV but by two novel divergent arteriviruses. Our results indicate that multiple divergent simian arteriviruses can cause SHF. C1 [Lauck, Michael; Bailey, Adam L.; Friedrich, Thomas C.; Goldberg, Tony L.; O'Connor, David H.] Univ Wisconsin, Madison, WI USA. [Alkhovsky, Sergey V.; Shchetinin, Alexey M.; Vishnevskaya, Tatyana V.; Deriabin, Petr G.] Minist Hlth Russian Federat, NF Gamaleya Fed Res Ctr Epidemiol & Microbiol, DI Ivanovsky Inst Virol, Moscow, Russia. [Bao, Yiming] NIH, Informat Engn Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Shevtsova, Zinaida V.] Abkhazian Acad Sci, Sci Res Inst Expt Pathol & Therapy, Sukhumi, Rep of Georgia. [Lackemeyer, Matthew G.; Postnikova, Elena; Mazur, Steven; Wada, Jiro; Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. [Radoshitzky, Sheli R.] US Army Med Res Inst Infect Dis, Frederick, MD USA. [Lapin, Boris A.] Russian Acad Med Sci, Sci Res Inst Med Primatol, Soci, Russia. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. EM kuhnjens@mail.nih.gov OI Postnikova, Elena/0000-0002-0275-2148; Shchetinin, Alexey/0000-0003-1842-3899; Vishnevskaya, Tatyana/0000-0002-6963-8681; Friedrich, Thomas/0000-0001-9831-6895; Lauck, Michael/0000-0003-2813-3705 FU Battelle Memorial Institute; U.S. National Institute of Allergy and Infectious Diseases [HHSN272200700016I]; NIH, NIH-National Science Foundation Ecology of Infectious Disease program [TW009237, R01 AI077376]; Office of Research Infrastructure Programs grant [P51OD011106]; Intramural Research Program of the NIH, National Library of Medicine FX The content of this publication does not necessarily reflect the views or policies of the U.S. Department of the Army, the U.S. Department of Defense, the U.S. Department of Health and Human Services, or the institutions and companies with which we are affiliated. This work was funded in part through the Battelle Memorial Institute's prime contract with the U.S. National Institute of Allergy and Infectious Diseases under contract HHSN272200700016I. The subcontractors to Battelle Memorial Institute who performed this work are E.P. and J.H.K, employees of Tunnell Government Services, Inc.; M.G.L., an employee of Lovelace Respiratory Research Institute; and S.M., an employee of MRIGlobal. This work was also funded in part by NIH grant TW009237 as part of the joint NIH-National Science Foundation Ecology of Infectious Disease program, grant R01 AI077376, and by Office of Research Infrastructure Programs grant P51OD011106. This research was also supported in part by the Intramural Research Program of the NIH, National Library of Medicine (Y.B.). NR 45 TC 7 Z9 7 U1 0 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 2015 VL 89 IS 15 BP 8082 EP 8087 DI 10.1128/JVI.01046-15 PG 6 WC Virology SC Virology GA CN2UP UT WOS:000358277800052 PM 25972539 ER PT J AU Lamers, SL Newman, RM Laeyendecker, O Tobian, AAR Colgrove, RC Ray, SC Koelle, DM Cohen, J Knipe, DM Quinn, TC AF Lamers, Susanna L. Newman, Ruchi M. Laeyendecker, Oliver Tobian, Aaron A. R. Colgrove, Robert C. Ray, Stuart C. Koelle, David M. Cohen, Jeffrey Knipe, David M. Quinn, Thomas C. TI Global Diversity within and between Human Herpesvirus 1 and 2 Glycoproteins SO JOURNAL OF VIROLOGY LA English DT Article ID SIMPLEX-VIRUS TYPE-2; DETECTING POSITIVE SELECTION; AMINO-ACID SITES; NUCLEOTIDE SUBSTITUTIONS; EVOLUTIONARY TIMESCALE; IMMUNOSORBENT ASSAYS; MOLECULAR PHYLOGENY; GENITAL HERPES; RECOMBINATION; PERFORMANCE AB Human herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are large-genome DNA viruses that establish a persistent infection in sensory neurons and commonly manifest with recurring oral or genital erosions that transmit virus. HSV encodes 12 predicted glycoproteins that serve various functions, including cellular attachment, entry, and egress. Glycoprotein G is currently the target of an antibody test to differentiate HSV-1 from HSV-2; however, this test has shown reduced capacity to differentiate HSV strains in East Africa. Until the recent availability of 26 full-length HSV-1 and 36 full-length HSV-2 sequences, minimal comparative information was available for these viruses. In this study, we use a variety of sequence analysis methods to compare all available sequence data for HSV-1 and HSV-2 glycoproteins, using viruses isolated in Europe, Asia, North America, the Republic of South Africa, and East Africa. We found numerous differences in diversity, nonsynonymous/synonymous substitution rates, and recombination rates between HSV-1 glycoproteins and their HSV-2 counterparts. Phylogenetic analysis revealed that while most global HSV-2 glycoprotein G sequences did not form clusters within or between continents, one clade (supported at 60.5%) contained 37% of the African sequences analyzed. Accordingly, sequences from this African subset contained unique amino acid signatures, not only in glycoprotein G, but also in glycoproteins I and E, which may account for the failure of sensitive antibody tests to distinguish HSV-1 from HSV-2 in some African individuals. Consensus sequences generated in the study can be used to improve diagnostic assays that differentiate HSV-1 from HSV-2 in global populations. IMPORTANCE Human herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are large DNA viruses associated with recurring oral or genital erosions that transmit virus. Up to 12 HSV-1 and HSV-2 glycoproteins are involved in HSV cell entry or are required for viral spread in animals, albeit some are dispensable for replication in vitro. The recent availability of comparable numbers of full-length HSV-1 and HSV-2 sequences enabled comparative analysis of gene diversity of glycoproteins within and between HSV types. Overall, we found less glycoprotein sequence diversity within HSV-2 than within the HSV-1 strains studied, while at the same time, several HSV-2 glycoproteins were evolving under less selective pressure. Because HSV glycoproteins are the focus of antibody tests to detect and differentiate between infections with the two strains and are constituents of vaccines in clinical-stage development, these findings will aid in refining the targets for diagnostic tests and vaccines. C1 [Lamers, Susanna L.] Bioinfoexperts LLC, Thibodaux, LA 70301 USA. [Newman, Ruchi M.] Broad Inst, Boston, MA USA. [Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Tobian, Aaron A. R.; Cohen, Jeffrey] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Colgrove, Robert C.; Knipe, David M.] Harvard Univ, Dept Microbiol & Immunobiol, Sch Med, Boston, MA USA. [Colgrove, Robert C.; Quinn, Thomas C.] Mt Auburn Hosp, Dept Med, Cambridge, MA USA. [Ray, Stuart C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Koelle, David M.] Univ Washington, Dept Med, Lab Med & Global Hlth, Seattle, WA 98195 USA. [Koelle, David M.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. RP Lamers, SL (reprint author), Bioinfoexperts LLC, Thibodaux, LA 70301 USA. EM susanna@bioinfox.com RI Ray, Stuart/B-7527-2008; Koelle, David/Q-6529-2016; OI Ray, Stuart/0000-0002-1051-7260; Koelle, David/0000-0003-1255-9023; Laeyendecker, Oliver/0000-0002-6429-4760 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900018C]; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases; [AI057552]; [AI094019]; [AI030731] FX This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272200900018C to the Broad Institute's Genomic Sequencing Center for Infectious Diseases; grant AI057552 to D.M. Knipe; and grants AI094019 and AI030731 to D.M. Koelle. This work was also supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases. NR 61 TC 8 Z9 8 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2015 VL 89 IS 16 BP 8206 EP 8218 DI 10.1128/JVI.01302-15 PG 13 WC Virology SC Virology GA CN2UT UT WOS:000358278200011 PM 26018161 ER PT J AU Newman, RM Lamers, SL Weiner, B Ray, SC Colgrove, RC Diaz, F Jing, LC Wang, K Saif, S Young, S Henn, M Laeyendecker, O Tobian, AAR Cohen, JI Koelle, DM Quinn, TC Knipe, DM AF Newman, Ruchi M. Lamers, Susanna L. Weiner, Brian Ray, Stuart C. Colgrove, Robert C. Diaz, Fernando Jing, Lichen Wang, Kening Saif, Sakina Young, Sarah Henn, Matthew Laeyendecker, Oliver Tobian, Aaron A. R. Cohen, Jeffrey I. Koelle, David M. Quinn, Thomas C. Knipe, David M. TI Genome Sequencing and Analysis of Geographically Diverse Clinical Isolates of Herpes Simplex Virus 2 SO JOURNAL OF VIROLOGY LA English DT Article ID EVOLUTIONARY TIMESCALE; MOLECULAR PHYLOGENY; MAXIMUM-LIKELIHOOD; SOUTH-AFRICA; TYPE-1; RECOMBINATION; DNA; INFECTION; CELLS; IDENTIFICATION AB Herpes simplex virus 2 (HSV-2), the principal causative agent of recurrent genital herpes, is a highly prevalent viral infection worldwide. Limited information is available on the amount of genomic DNA variation between HSV-2 strains because only two genomes have been determined, the HG52 laboratory strain and the newly sequenced SD90e low-passage-number clinical isolate strain, each from a different geographical area. In this study, we report the nearly complete genome sequences of 34 HSV-2 low-passage-number and laboratory strains, 14 of which were collected in Uganda, 1 in South Africa, 11 in the United States, and 8 in Japan. Our analyses of these genomes demonstrated remarkable sequence conservation, regardless of geographic origin, with the maximum nucleotide divergence between strains being 0.4% across the genome. In contrast, prior studies indicated that HSV-1 genomes exhibit more sequence diversity, as well as geographical clustering. Additionally, unlike HSV-1, little viral recombination between HSV-2 strains could be substantiated. These results are interpreted in light of HSV-2 evolution, epidemiology, and pathogenesis. Finally, the newly generated sequences more closely resemble the low-passage-number SD90e than HG52, supporting the use of the former as the new reference genome of HSV-2. IMPORTANCE Herpes simplex virus 2 (HSV-2) is a causative agent of genital and neonatal herpes. Therefore, knowledge of its DNA genome and genetic variability is central to preventing and treating genital herpes. However, only two full-length HSV-2 genomes have been reported. In this study, we sequenced 34 additional HSV-2 low-passage-number and laboratory viral genomes and initiated analysis of the genetic diversity of HSV-2 strains from around the world. The analysis of these genomes will facilitate research aimed at vaccine development, diagnosis, and the evaluation of clinical manifestations and transmission of HSV-2. This information will also contribute to our understanding of HSV evolution. C1 [Newman, Ruchi M.; Weiner, Brian; Saif, Sakina; Young, Sarah; Henn, Matthew] Broad Inst Harvard, Cambridge, MA 02142 USA. [Newman, Ruchi M.; Weiner, Brian; Saif, Sakina; Young, Sarah; Henn, Matthew] MIT, Cambridge, MA 02139 USA. [Lamers, Susanna L.] Bioinfoexperts LLC, Thibodaux, LA USA. [Ray, Stuart C.; Tobian, Aaron A. R.; Quinn, Thomas C.] Johns Hopkins Univ, Dept Pathol & Med, Baltimore, MD USA. [Colgrove, Robert C.; Diaz, Fernando; Knipe, David M.] Harvard Univ, Dept Microbiol & Immunobiol, Sch Med, Boston, MA USA. [Colgrove, Robert C.] Mt Auburn Hosp, Dept Med, Cambridge, MA USA. [Jing, Lichen; Koelle, David M.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Immunoregulat Lab, NIH, Baltimore, MD USA. [Wang, Kening; Cohen, Jeffrey I.] NIAID, Infect Dis Lab, NIH, Baltimore, MD USA. [Koelle, David M.] Univ Washington, Dept Lab Med & Global Hlth, Seattle, WA 98195 USA. [Koelle, David M.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. RP Newman, RM (reprint author), Broad Inst Harvard, Cambridge, MA 02142 USA. EM rnewman4@mgh.harvard.edu RI Ray, Stuart/B-7527-2008; Koelle, David/Q-6529-2016; OI Ray, Stuart/0000-0002-1051-7260; Koelle, David/0000-0003-1255-9023; Laeyendecker, Oliver/0000-0002-6429-4760 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900018C]; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases; [AI057552]; [AI030731] FX This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272200900018C to the Broad Institute's Genomic Sequencing Center for Infectious Diseases; grant AI057552 to D.M. Knipe; and grant AI030731 to D.M. Koelle. This work was also supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases. NR 36 TC 15 Z9 15 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2015 VL 89 IS 16 BP 8219 EP 8232 DI 10.1128/JVI.01303-15 PG 14 WC Virology SC Virology GA CN2UT UT WOS:000358278200012 PM 26018166 ER PT J AU Saunders, KO Wang, LS Joyce, MG Yang, ZY Balazs, AB Cheng, C Ko, SY Kong, WP Rudicell, RS Georgiev, IS Duan, LJ Foulds, KE Donaldson, M Xu, L Schmidt, SD Todd, JP Baltimore, D Roederer, M Haase, AT Kwong, PD Rao, SS Mascola, JR Nabel, GJ AF Saunders, Kevin O. Wang, Lingshu Joyce, M. Gordon Yang, Zhi-Yong Balazs, Alejandro B. Cheng, Cheng Ko, Sung-Youl Kong, Wing-Pui Rudicell, Rebecca S. Georgiev, Ivelin S. Duan, Lijie Foulds, Kathryn E. Donaldson, Mitzi Xu, Ling Schmidt, Stephen D. Todd, John-Paul Baltimore, David Roederer, Mario Haase, Ashley T. Kwong, Peter D. Rao, Srinivas S. Mascola, John R. Nabel, Gary J. TI Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody Gene Transfer Protects Nonhuman Primates from Mucosal Simian-Human Immunodeficiency Virus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; HEMOPHILIA-B; IN-VITRO; VECTORED IMMUNOPROPHYLAXIS; PASSIVE-IMMUNIZATION; IMPROVES PROTECTION; THERAPEUTIC LEVELS; CELL RESPONSES; SHIV CHALLENGE; HIV-1 VACCINE AB Broadly neutralizing antibodies (bnAbs) can prevent lentiviral infection in nonhuman primates and may slow the spread of human immunodeficiency virus type 1 (HIV-1). Although protection by passive transfer of human bnAbs has been demonstrated in monkeys, durable expression is essential for its broader use in humans. Gene-based expression of bnAbs provides a potential solution to this problem, although immune responses to the viral vector or to the antibody may limit its durability and efficacy. Here, we delivered an adeno-associated viral vector encoding a simianized form of a CD4bs bnAb, VRC07, and evaluated its immunogenicity and protective efficacy. The expressed antibody circulated in macaques for 16 weeks at levels up to 66 mu g/ml, although immune suppression with cyclosporine (CsA) was needed to sustain expression. Gene-delivered simian VRC07 protected against simian-human immunodeficiency virus (SHIV) infection in monkeys 5.5 weeks after treatment. Gene transfer of an anti-HIV antibody can therefore protect against infection by viruses that cause AIDS in primates when the host immune responses are controlled. IMPORTANCE Sustained interventions that can prevent HIV-1 infection are needed to halt the spread of the HIV-1 pandemic. The protective capacity of anti-HIV antibody gene therapy has been established in mouse models of HIV-1 infection but has not been established for primates. We show here a proof-of-concept that gene transfer of anti-HIV antibody genes can protect against infection by viruses that cause AIDS in primates when host immune responses are controlled. C1 [Saunders, Kevin O.; Wang, Lingshu; Joyce, M. Gordon; Yang, Zhi-Yong; Cheng, Cheng; Ko, Sung-Youl; Kong, Wing-Pui; Rudicell, Rebecca S.; Georgiev, Ivelin S.; Foulds, Kathryn E.; Donaldson, Mitzi; Xu, Ling; Schmidt, Stephen D.; Todd, John-Paul; Roederer, Mario; Kwong, Peter D.; Rao, Srinivas S.; Mascola, John R.; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Balazs, Alejandro B.] MIT & Harvard, MGH, Ragon Inst, Cambridge, MA USA. [Duan, Lijie; Haase, Ashley T.] Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. [Baltimore, David] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM John.Mascola@nih.gov; Gary.Nabel@sanofi.com RI Schmidt, Stephen/B-5398-2012 FU Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH; NIH Nonhuman Primate Reagent Resource (NIAID) [HHSN 2722000900037C] FX The macaque control IgG used in these studies was provided by the NIH Nonhuman Primate Reagent Resource (R24 RR016001 and NIAID contract HHSN 2722000900037C). This work was supported by the intramural research program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH. NR 56 TC 15 Z9 15 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2015 VL 89 IS 16 BP 8334 EP 8345 DI 10.1128/JVI.00908-15 PG 12 WC Virology SC Virology GA CN2UT UT WOS:000358278200021 PM 26041300 ER PT J AU Garcia-Arriaza, J Perdiguero, B Heeney, J Seaman, M Montefiori, DC Labranche, C Yates, NL Shen, XY Tomaras, GD Ferrari, G Foulds, KE McDermott, A Kao, SF Roederer, M Hawkins, N Self, S Yao, JS Farrell, P Phogat, S Tartaglia, J Barnett, SW Burke, B Cristillo, A Weiss, D Lee, C Kibler, K Jacobs, B Asbach, B Wagner, R Ding, S Pantaleo, G Esteban, M AF Garcia-Arriaza, Juan Perdiguero, Beatriz Heeney, Jonathan Seaman, Michael Montefiori, David C. Labranche, Celia Yates, Nicole L. Shen, Xiaoying Tomaras, Georgia D. Ferrari, Guido Foulds, Kathryn E. McDermott, Adrian Kao, Shing-Fen Roederer, Mario Hawkins, Natalie Self, Steve Yao, Jiansheng Farrell, Patrick Phogat, Sanjay Tartaglia, Jim Barnett, Susan W. Burke, Brian Cristillo, Anthony Weiss, Deborah Lee, Carter Kibler, Karen Jacobs, Bert Asbach, Benedikt Wagner, Ralf Ding, Song Pantaleo, Giuseppe Esteban, Mariano TI Head-to-Head Comparison of Poxvirus NYVAC and ALVAC Vectors Expressing Identical HIV-1 Clade C Immunogens in Prime-Boost Combination with Env Protein in Nonhuman Primates SO JOURNAL OF VIROLOGY LA English DT Article ID VACCINE EFFICACY TRIAL; B-CELL RESPONSES; PHASE-I TRIAL; VIRAL LOAD; DNA PRIME; VIRUS; MVA; CANDIDATES; NEUTRALIZATION; IMMUNIZATION AB We compared the HIV-1-specific cellular and humoral immune responses elicited in rhesus macaques immunized with two poxvirus vectors (NYVAC and ALVAC) expressing the same HIV-1 antigens from clade C, Env gp140 as a trimeric cell-released protein and a Gag-Pol-Nef polyprotein as Gag-induced virus-like particles (VLPs) (referred to as NYVAC-C and ALVAC-C). The immunization protocol consisted of two doses of the corresponding poxvirus vector plus two doses of a combination of the poxvirus vector and a purified HIV-1 gp120 protein from clade C. This immunogenicity profile was also compared to that elicited by vaccine regimens consisting of two doses of the ALVAC vector expressing HIV-1 antigens from clades B/E (ALVAC-vCP1521) plus two doses of a combination of ALVAC-vCP1521 and HIV-1 gp120 protein from clades B/E (similar to the RV144 trial regimen) or clade C. The results showed that immunization of macaques with NYVAC-C stimulated at different times more potent HIV-1-specific CD4(+) T-cell responses and induced a trend toward higher-magnitude HIV-1-specific CD8(+) T-cell immune responses than did ALVAC-C. Furthermore, NYVAC-C induced a trend toward higher levels of binding IgG antibodies against clade CHIV-1 gp140, gp120, or murine leukemia virus (MuLV) gp70-scaffolded V1/V2 and toward best cross-clade-binding IgG responses against HIV-1 gp140 from clades A, B, and group M consensus, than did ALVAC-C. Of the linear binding IgG responses, most were directed against the V3 loop in all immunization groups. Additionally, NYVAC-C and ALVAC-C also induced similar levels of HIV-1-neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC) responses. Interestingly, binding IgA antibody levels against HIV-1 gp120 or MuLV gp 70-scaffolded V1/V2 were absent or very low in all immunization groups. Overall, these results provide a comprehensive survey of the immunogenicity of NYVACversus ALVAC expressing HIV-1 antigens in nonhuman primates and indicate that NYVAC may represent an alternative candidate to ALVAC in the development of a future HIV-1 vaccine. IMPORTANCE The finding of a safe and effective HIV/AIDS vaccine immunogen is one of the main research priorities. Here, we generated two poxvirus-based HIV vaccine candidates (NYVAC and ALVAC vectors) expressing the same clade C HIV-1 antigens in separate vectors, and we analyzed in nonhuman primates their immunogenicity profiles. The results showed that immunization with NYVAC-C induced a trend toward higher HIV-1-specific cellular and humoral immune responses than did ALVAC-C, indicating that this new NYVAC vector could be a novel optimized HIV/AIDS vaccine candidate for human clinical trials. C1 [Garcia-Arriaza, Juan; Perdiguero, Beatriz; Esteban, Mariano] CSIC, Ctr Nacl Biotecnol, Dept Mol & Cellular Biol, Madrid, Spain. [Heeney, Jonathan] Univ Cambridge, Dept Vet Med, Cambridge, England. [Seaman, Michael] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Viral Pathogenesis, Boston, MA 02215 USA. [Montefiori, David C.; Labranche, Celia; Yates, Nicole L.; Shen, Xiaoying; Tomaras, Georgia D.; Ferrari, Guido] Duke Univ, Durham, NC USA. [Foulds, Kathryn E.; McDermott, Adrian; Kao, Shing-Fen; Roederer, Mario] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Hawkins, Natalie; Self, Steve] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. [Yao, Jiansheng; Farrell, Patrick; Phogat, Sanjay; Tartaglia, Jim] Sanofi Pasteur, Swiftwater, PA USA. [Barnett, Susan W.; Burke, Brian] Novartis Vaccines & Diagnost Inc, Cambridge, MA USA. [Cristillo, Anthony; Weiss, Deborah] Adv BioSci Labs Inc, Kensington, MD USA. [Lee, Carter] Global Solut Infect Dis, San Francisco, CA USA. [Kibler, Karen; Jacobs, Bert] Arizona State Univ, Biodesign Inst, Tempe, AZ USA. [Asbach, Benedikt; Wagner, Ralf] Univ Regensburg, D-93053 Regensburg, Germany. [Ding, Song] EuroVacc Fdn, Lausanne, Switzerland. [Pantaleo, Giuseppe] Univ Lausanne, Univ Vaudois, Ctr Hosp, Div Immunol & Allergy,Dept Med, Lausanne, Switzerland. RP Esteban, M (reprint author), CSIC, Ctr Nacl Biotecnol, Dept Mol & Cellular Biol, Madrid, Spain. EM mesteban@cnb.csic.es RI Tomaras, Georgia/J-5041-2016; Pantaleo, Giuseppe/K-6163-2016; OI Heeney, Jonathan/0000-0003-2702-1621 FU PTVDC/CAVD Program; Bill and Melinda Gates Foundation (BMGF); BMGF CAVIMC [1032144]; NIH/NIAID Duke Center for AIDS Research (CFAR) [5P30 AI064518]; DAIDS, NIAID, NIH [HHSN266200500007C] FX This investigation was supported by the PTVDC/CAVD Program with support from the Bill and Melinda Gates Foundation (BMGF). Humoral immune monitoring data were supported by the BMGF CAVIMC 1032144 grant and the NIH/NIAID Duke Center for AIDS Research (CFAR; 5P30 AI064518). Novartis Vaccines received support for this work under contract number HHSN266200500007C from DAIDS, NIAID, NIH. NR 56 TC 10 Z9 10 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 2015 VL 89 IS 16 BP 8525 EP 8539 DI 10.1128/JVI.01265-15 PG 15 WC Virology SC Virology GA CN2UT UT WOS:000358278200036 PM 26041302 ER PT J AU VanBlargan, LA Davis, KA Dowd, KA Akey, DL Smith, JL Pierson, TC AF VanBlargan, Laura A. Davis, Kaitlin A. Dowd, Kimberly A. Akey, David L. Smith, Janet L. Pierson, Theodore C. TI Context-Dependent Cleavage of the Capsid Protein by the West Nile Virus Protease Modulates the Efficiency of Virus Assembly SO JOURNAL OF VIROLOGY LA English DT Article ID YELLOW-FEVER VIRUS; ANTIBODY-MEDIATED NEUTRALIZATION; NS2B/NS3 SERINE-PROTEASE; DENGUE-VIRUS; SUBSTRATE-SPECIFICITY; IN-VITRO; NS3 PROTEASE; NS2B-3 PROTEINASE; INHIBITORS; INFECTION AB The molecular mechanisms that define the specificity of flavivirus RNA encapsulation are poorly understood. Virions composed of the structural proteins of one flavivirus and the genomic RNA of a heterologous strain can be assembled and have been developed as live attenuated vaccine candidates for several flaviviruses. In this study, we discovered that not all combinations of flavivirus components are possible. While a West Nile virus (WNV) subgenomic RNA could readily be packaged by structural proteins of the DENV2 strain 16681, production of infectious virions with DENV2 strain New Guinea C (NGC) structural proteins was not possible, despite the very high amino acid identity between these viruses. Mutagenesis studies identified a single residue (position 101) of the DENV capsid (C) protein as the determinant for heterologous virus production. C101 is located at the P1' position of the NS2B/3 protease cleavage site at the carboxy terminus of the C protein. WNV NS2B/3 cleavage of the DENV structural polyprotein was possible when a threonine (Thr101 in strain 16681) but not a serine (Ser101 in strain NGC) occupied the P1' position, a finding not predicted by in vitro protease specificity studies. Critically, both serine and threonine were tolerated at the P1' position of WNV capsid. More extensive mutagenesis revealed the importance of flanking residues within the polyprotein in defining the cleavage specificity of the WNV protease. A more detailed understanding of the context dependence of viral protease specificity may aid the development of new protease inhibitors and provide insight into associated patterns of drug resistance. IMPORTANCE West Nile virus (WNV) and dengue virus (DENV) are mosquito-borne flaviviruses that cause considerable morbidity and mortality in humans. No specific antiflavivirus therapeutics are available for treatment of infection. Proteolytic processing of the flavivirus polyprotein is an essential step in the replication cycle and is an attractive target for antiviral development. The design of protease inhibitors has been informed by insights into the molecular details of the interactions of proteases and their substrates. In this article, studies of the processing of WNV and DENV capsid proteins by the WNV protease identified an unexpected contribution of the sequence surrounding critical residues within the cleavage site on protease specificity. This demonstration of context-dependent protease cleavage has implications for the design of chimeric flaviviruses, new therapeutics, and the interpretation of flavivirus protease substrate specificity studies. C1 [VanBlargan, Laura A.; Davis, Kaitlin A.; Dowd, Kimberly A.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [VanBlargan, Laura A.] Univ Maryland, Biol Sci Grad Program, College Pk, MD 20742 USA. [Davis, Kaitlin A.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Akey, David L.; Smith, Janet L.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Smith, Janet L.] Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA. RP Pierson, TC (reprint author), NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; NIH [P01 AI-055672, 2T32AI051967-06A1] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH, to T.C.P. and NIH grant P01 AI-055672 to J.L.S. L.A.V. was additionally supported by supported by NIH Institutional Training grant 2T32AI051967-06A1 awarded to the University of Maryland. NR 71 TC 0 Z9 0 U1 3 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2015 VL 89 IS 16 BP 8632 EP 8642 DI 10.1128/JVI.01253-15 PG 11 WC Virology SC Virology GA CN2UT UT WOS:000358278200045 PM 26063422 ER PT J AU Shen, XY Duffy, R Howington, R Cope, A Sadagopal, S Park, H Pal, R Kwa, S Ding, S Yang, OO Fouda, GG Le Grand, R Bolton, D Esteban, M Phogat, S Roederer, M Amara, RR Picker, LJ Seder, RA McElrath, MJ Barnett, S Permar, SR Shattock, R DeVico, AL Felber, BK Pavlakis, GN Pantaleo, G Korber, BT Montefiori, DC Tomaras, GD AF Shen, Xiaoying Duffy, Ryan Howington, Robert Cope, Alethea Sadagopal, Shanmugalakshmi Park, Haesun Pal, Ranajit Kwa, Suefen Ding, Song Yang, Otto O. Fouda, Genevieve G. Le Grand, Roger Bolton, Diane Esteban, Mariano Phogat, Sanjay Roederer, Mario Amara, Rama R. Picker, Louis J. Seder, Robert A. McElrath, M. Juliana Barnett, Susan Permar, Sallie R. Shattock, Robin DeVico, Anthony L. Felber, Barbara K. Pavlakis, George N. Pantaleo, Giuseppe Korber, Bette T. Montefiori, David C. Tomaras, Georgia D. TI Vaccine-Induced Linear Epitope-Specific Antibodies to Simian Immunodeficiency Virus SIVmac239 Envelope Are Distinct from Those Induced to the Human Immunodeficiency Virus Type 1 Envelope in Nonhuman Primates SO JOURNAL OF VIROLOGY LA English DT Article ID B-CELL RESPONSES; PATHOGENIC SHIVS; RHESUS MACAQUES; INFECTION; MONKEYS; TRIAL; ACQUISITION; PROTECTION; DIVERSITY; BINDING AB To evaluate antibody specificities induced by simian immunodeficiency virus (SIV) versus human immunodeficiency virus type 1 (HIV-1) envelope antigens in nonhuman primate (NHP), we profiled binding antibody responses to linear epitopes in NHP studies with HIV-1 or SIV immunogens. We found that, overall, HIV-1 Env IgG responses were dominated by V3, with the notable exception of the responses to the vaccine strain A244 Env that were dominated by V2, whereas the anti-SIV mac239 Env responses were dominated by V2 regardless of the vaccine regimen. C1 [Shen, Xiaoying; Duffy, Ryan; Howington, Robert; Fouda, Genevieve G.; Permar, Sallie R.; Tomaras, Georgia D.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC 27705 USA. [Shen, Xiaoying; Duffy, Ryan; Howington, Robert; Montefiori, David C.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Permar, Sallie R.; Tomaras, Georgia D.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. [Permar, Sallie R.; Tomaras, Georgia D.] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. [Tomaras, Georgia D.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Cope, Alethea; Shattock, Robin] Univ London Imperial Coll Sci Technol & Med, Infect Dis Sect, Mucosal Infect & Immun Grp, London, England. [Sadagopal, Shanmugalakshmi; Kwa, Suefen; Amara, Rama R.] Emory Univ, Yerkes Natl Primate Res Ctr, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Park, Haesun; Picker, Louis J.] Oregon Hlth & Sci Univ, VGTI, Portland, OR 97201 USA. [Pal, Ranajit] Adv Bioscience Labs Inc, Rockville, MD USA. [Ding, Song; Pantaleo, Giuseppe] CHU Vaudois, Serv Immunol & Allergy, Lab AIDS Immunopathogenesis, Lausanne, Switzerland. [Yang, Otto O.] Univ Calif Los Angeles, Geffen Sch Med, Dept Med, Los Angeles, CA USA. [Yang, Otto O.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA. [Yang, Otto O.] AIDS Healthcare Fdn, Los Angeles, CA USA. [Le Grand, Roger] Univ Paris 11, CEA, Fontenay aux Roses, iMETI,DSV,IMDIT Ctr,Inserm,Div Immuno Virol,U1184, Orsay, France. [Bolton, Diane; Roederer, Mario; Seder, Robert A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Esteban, Mariano] CSIC, Ctr Nacl Biotecnol, Dept Mol & Cellular Biol, Madrid, Spain. [Phogat, Sanjay] Sanofi Pasteur, Swiftwater, PA USA. [McElrath, M. Juliana] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Barnett, Susan] Novartis Vaccines & Diagnost Inc, Cambridge, MA USA. [DeVico, Anthony L.] Inst Human Virol, Baltimore, MD USA. [Felber, Barbara K.] NCI, Ctr Canc Res, Human Retrovirus Pathogenesis Sect, Frederick, MD USA. [Pavlakis, George N.] NCI, Ctr Canc Res, Human Retrovirus Sect, Frederick, MD USA. [Korber, Bette T.] Los Alamos Natl Lab, Theoret Biol & Biophys, Los Alamos, NM USA. RP Shen, XY (reprint author), Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC 27705 USA. EM sxshen@duke.edu; gdt@duke.edu RI Tomaras, Georgia/J-5041-2016; Pantaleo, Giuseppe/K-6163-2016; OI Korber, Bette/0000-0002-2026-5757 FU Bill & Melinda Gates Foundation Comprehensive Antibody Vaccine Immune Monitoring Consortium (CAVIMC) [38619, 1032144]; NIH NIAID grants [HHSN27201100016, HHSN266200600005C]; CHAVI/HVTN Early Stage Investigator Award [5U19AI067854, R01AI106380, R21 AI87382]; Europrise European grant [LSHP-CT-2006-037611]; HVTN LC (HIV Vaccine Trials Network grant) [UM1AI068618]; Duke Division of Laboratory Animal Research; Duke Center for AIDS Research (CFAR) Immunology Core and Biostatistics and Computational Biology Cores (NIH) [5P30 AI064518] FX This work is supported by the Bill & Melinda Gates Foundation Comprehensive Antibody Vaccine Immune Monitoring Consortium (CAVIMC) (38619 and 1032144) and NIH NIAID grants HHSN27201100016 and HHSN266200600005C, a CHAVI/HVTN Early Stage Investigator Award (5U19AI067854) (to X.S.), and grants R01AI106380 and R21 AI87382, as well a Europrise European grant (LSHP-CT-2006-037611), and by the HVTN LC (an HIV Vaccine Trials Network grant [UM1AI068618]) and the Duke Division of Laboratory Animal Research.; We thank Tong Xu for quality control (QC) of the peptide microarray data; Hongmei Gao, Kelli Greene, and Celia Labranche for program management; Marcella Sarzotti-Kelsoe, Dan Ozaki, and the Central Quality Assurance Unit; A. Valentin, M. Rosati, V. Kulkarni R. Jalah, V. Patel, and C. Alicea for participating in the AUP417 study; and J. P. Todd (VRC) and Bioqual, Inc., for assistance with the VRC145 macaque study. We thank Global Solutions for Infectious Diseases for provision of AIDSVAX immunogen for study P167. We acknowledge support from the Duke Center for AIDS Research (CFAR) Immunology Core and Biostatistics and Computational Biology Cores (an NIH-funded program [5P30 AI064518]), and we thank Cliburn Chan and Nathan Vandergrift for statistical consultation. NR 41 TC 7 Z9 7 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2015 VL 89 IS 16 BP 8643 EP 8650 DI 10.1128/JVI.03635-14 PG 8 WC Virology SC Virology GA CN2UT UT WOS:000358278200046 PM 26018159 ER PT J AU Clark, DV Kibuuka, H Millard, M Wakabi, S Lukwago, L Taylor, A Eller, MA Eller, LA Michael, NL Honko, AN Olinger, GG Schoepp, RJ Hepburn, MJ Hensley, LE Robb, ML AF Clark, Danielle V. Kibuuka, Hannah Millard, Monica Wakabi, Salim Lukwago, Luswa Taylor, Alison Eller, Michael A. Eller, Leigh Anne Michael, Nelson L. Honko, Anna N. Olinger, Gene G., Jr. Schoepp, Randal J. Hepburn, Matthew J. Hensley, Lisa E. Robb, Merlin L. TI Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study SO LANCET INFECTIOUS DISEASES LA English DT Article ID HEMORRHAGIC-FEVER; LASSA FEVER; CHIKUNGUNYA; INFECTION; EPIDEMIC; KIKWIT; CONGO; SURVIVORS AB Background The limited data available for long-term Ebola virus disease health outcomes suggest that sequelae persist for longer than 1 year after infection. The magnitude of the present outbreak in west Africa necessitates a more complete understanding of the health effects and future medical needs of these patients. Methods We invited adult survivors of the 2007 Bundibugyo Ebola virus outbreak in Uganda and their contacts to take part in an observational study roughly 29 months after the outbreak. We collected information about health status, functional limitations, and demographics. We collected blood samples for clinical chemistry, haematology, and filovirus antibodies using ELISA. Analyses were restricted to probable and confirmed survivors and their seronegative contacts. Findings We recruited 70 survivors of the 2007 Bundibugyo Ebola virus and 223 contacts. We did analyses for 49 probable and confirmed survivors and 157 seronegative contacts. Survivors of the Bundibugyo Ebola virus were at significantly increased risk of ocular deficits (retro-orbital pain [RR 4.3, 95% CI 1.9-9.6; p<0.0001], blurred vision [1.9, 1.1-3.2; p=0.018]), hearing loss (2.3, 1.2-4.5; p=0.010), difficulty swallowing (2.1, 1.1-3.9; p=0.017), difficulty sleeping (1.9, 1.3-2.8; p=0.001), arthralgias (2.0, 1.1-3.6; p=0.020), and various constitutional symptoms controlling for age and sex. Chronic health problems (prevalence ratio [PR] 2.1, 95% CI 1.2-3.6; p=0.008) and limitations due to memory loss or confusion (PR 5.8, 1.5-22.4; p=0.010) were also reported more frequently by survivors of Bundibugyo Ebola virus. Interpretation Long-term sequelae persist for more than 2 years after Ebola virus disease. Definition of health consequences related to Ebola virus disease could improve patient care for survivors and contribute to understanding of disease pathogenesis. C1 [Clark, Danielle V.; Michael, Nelson L.] Walter Reed Army Inst Res, Silver Spring, MD USA. [Clark, Danielle V.] Naval Med Res Ctr, Biol Def Res Directorate, Ft Detrick, MD 21702 USA. [Kibuuka, Hannah; Millard, Monica; Wakabi, Salim; Taylor, Alison] Makerere Univ, Walter Reed Project, Kampala, Uganda. [Lukwago, Luswa] Minist Hlth, Kampala, Uganda. [Eller, Michael A.; Eller, Leigh Anne; Michael, Nelson L.; Robb, Merlin L.] US Mil, HIV Res Program, Bethesda, MD USA. [Honko, Anna N.; Olinger, Gene G., Jr.; Hensley, Lisa E.] US Army, Med Res Inst Infect Dis, Div Virol, Ft Detrick, MD 21702 USA. [Schoepp, Randal J.] US Army, Med Res Inst Infect Dis, Diagnost Syst Div, Ft Detrick, MD 21702 USA. [Hepburn, Matthew J.] US Army, Med Res Inst Infect Dis, Div Med, Ft Detrick, MD 21702 USA. [Honko, Anna N.; Olinger, Gene G., Jr.; Hensley, Lisa E.] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD USA. RP Clark, DV (reprint author), Naval Med Res Ctr, Biol Def Res Directorate, Ft Detrick, MD 21702 USA. EM dclark@aceso-sepsis.org OI Honko, Anna/0000-0001-9165-148X FU Chemical Biological Technologies Directorate, Defense Threat Reduction Agency FX Chemical Biological Technologies Directorate, Defense Threat Reduction Agency. NR 25 TC 44 Z9 44 U1 2 U2 14 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD AUG PY 2015 VL 15 IS 8 BP 905 EP 912 DI 10.1016/S1473-3099(15)70152-0 PG 8 WC Infectious Diseases SC Infectious Diseases GA CN1LW UT WOS:000358182500029 PM 25910637 ER PT J AU Wu, UI Holland, SM AF Wu, Un-In Holland, Steven M. TI Host susceptibility to non-tuberculous mycobacterial infections SO LANCET INFECTIOUS DISEASES LA English DT Review ID INTERFERON-GAMMA-RECEPTOR; PRIMARY CILIARY DYSKINESIA; B ESSENTIAL MODULATOR; ANTITUMOR NECROSIS FACTOR; INHERITED INTERLEUKIN-12 DEFICIENCY; RECESSIVE IFN-GAMMA-R1 DEFICIENCY; CHRONIC MUCOCUTANEOUS CANDIDIASIS; STEM-CELL TRANSPLANTATION; BACILLE CALMETTE-GUERIN; HUMAN STAT1 DEFICIENCY AB Non-tuberculous mycobacteria cause a broad range of clinical disorders, from cutaneous infections, such as cervical or intrathoracic lymphadenitis in children, to disseminated infections at all ages. Recognition of the underlying immune defect is crucial for rational treatment, preventive care, family screening, and, in some cases, transplantation. So far, at least seven autosomal mutations (in IL12B, IL12RB1, ISG15, IFNGR1, IFNGR2, STAT1, and IRF8) and two X-linked mutations (in IKBKG and CYBB), mostly presenting in childhood, have been reported to confer susceptibility to disseminated non-tuberculous mycobacterial infection. GATA2 deficiency and anti-interferon gamma autoantibodies also give rise to disseminated infection, typically in late childhood or adulthood. Furthermore, isolated pulmonary non-tuberculous mycobacterial infection has been increasing in prevalence in people without recognised immune dysfunction. In this Review, we discuss how to detect and differentiate host susceptibility factors underlying localised and systemic non-tuberculous mycobacterial infections. C1 [Wu, Un-In; Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Wu, Un-In] Natl Taiwan Univ Hosp, Dept Internal Med, Div Infect Dis, Taipei 100, Taiwan. RP Holland, SM (reprint author), Lab Clin Infect Dis, CRC B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov OI WU, UN-IN/0000-0001-8182-6071 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health. NR 163 TC 12 Z9 13 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD AUG PY 2015 VL 15 IS 8 BP 968 EP 980 DI 10.1016/S1473-3099(15)00089-4 PG 13 WC Infectious Diseases SC Infectious Diseases GA CN1LW UT WOS:000358182500036 PM 26049967 ER PT J AU Li, WD Saud, SM Young, MR Colburn, NH Hua, BJ AF Li, Weidong Saud, Shakir M. Young, Matthew R. Colburn, Nancy H. Hua, Baojin TI Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE Cryptotanshinone; Colorectal cancer treatment; Signal transducer and activator of transcription 3; Proliferation; Apoptosis ID CELL-PROLIFERATION; COLON-CANCER; CYCLIN D1; SIGNAL TRANSDUCERS; TANSHINONE IIA; POOR-PROGNOSIS; EXPRESSION; APOPTOSIS; CARCINOMA; THERAPY AB Cryptotanshinone (CPT) is a natural compound extracted from herbal medicine that has been previously shown to possess antitumor properties in various types of human cancer cells. In the present study, we examined the potential role of CPT in the treatment of colorectal cancer. Using SW480, HCT116, and LOVO colorectal cancer cell lines, the effects of CPT on cell viability, apoptosis, and tumorigenicity were evaluated. The results showed that CPT significantly inhibited the growth and viability of SW480, HCT116, and LOVO cell lines by inducing apoptosis and prevented anchorage dependent growth on agar. In addition, CPT inhibited the activation of Signal transducer and activator of transcription 3 (Stat3) pathways in colorectal cancer cells. Stat3 is a transcription factor that mediates the expression of various genes associated with many cellular processes, such as inflammation and cell growth, and has been shown to promote several cancer types, including colorectal cancer. These findings indicate that CPT may be a potential candidate for the treatment and prevention of colorectal cancer in part by inhibiting the activation of Stat3. C1 [Li, Weidong; Hua, Baojin] China Acad Chinese Med Sci, Guanganmen Hosp, Dept Oncol, Beijing 100053, Peoples R China. [Saud, Shakir M.] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Rockville, MD 20850 USA. [Li, Weidong; Saud, Shakir M.; Young, Matthew R.; Colburn, Nancy H.] Ctr Canc Res, Basic Res Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Hua, BJ (reprint author), China Acad Chinese Med Sci, Guanganmen Hosp, Dept Oncol, Beijing 100053, Peoples R China. EM dr.huabaojin@hotmail.com FU National Cancer Institute; National Institutes of Health [ZIA BC 011159]; National Natural Science Foundation of China [81273718, 81102587]; China Postdoctoral Science Foundation [2012T50199] FX The authors thank Dr. Jeffrey D. White and Dr. Libin Jia from Office of Cancer Complementary and Alternative Medicine, National Cancer Institute, National Institutes of Health for support of this study. We thank Dr. Yinling Hu from Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health for support of this study. This work was supported by National Cancer Institute, National Institutes of Health intramural funding (ZIA BC 011159), National Natural Science Foundation of China (No. 81273718 and No. 81102587), and China Postdoctoral Science Foundation (No. 2012T50199). NR 57 TC 7 Z9 8 U1 1 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 EI 1573-4919 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD AUG PY 2015 VL 406 IS 1-2 BP 63 EP 73 DI 10.1007/s11010-015-2424-0 PG 11 WC Cell Biology SC Cell Biology GA CN1WR UT WOS:000358211800007 PM 25912550 ER PT J AU Zhou, XK Ye, Y Sun, YY Li, XF Wang, WX Privratsky, B Tan, SR Zhou, ZG Huang, CH Wei, YQ Birnbaumer, L Singh, BB Wu, M AF Zhou, Xikun Ye, Yan Sun, Yuyang Li, Xuefeng Wang, Wenxue Privratsky, Breanna Tan, Shirui Zhou, Zongguang Huang, Canhua Wei, Yu-Quan Birnbaumer, Lutz Singh, Brij B. Wu, Min TI Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase C alpha Signaling SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PSEUDOMONAS-AERUGINOSA INFECTION; NF-KAPPA-B; STORE-OPERATED CHANNELS; EPITHELIAL-CELLS; TRPC CHANNELS; KLEBSIELLA-PNEUMONIAE; ENDOTHELIAL-CELLS; ALVEOLAR MACROPHAGES; CYTOKINE PRODUCTION; CA2+ INFLUX AB Transient receptor potential channel 1 (TRPC1) is a nonselective cation channel that is required for Ca2+ homeostasis necessary for cellular functions. However, whether TRPC1 is involved in infectious disease remains unknown. Here, we report a novel function for TRPC1 in host defense against Gram-negative bacteria. TRPC1(-/-) mice exhibited decreased survival, severe lung injury, and systemic bacterial dissemination upon infection. Furthermore, silencing of TRPC1 showed decreased Ca2+ entry, reduced proinflammatory cytokines, and lowered bacterial clearance. Importantly, TRPC1 functioned as an endogenous Ca2+ entry channel critical for proinflammatory cytokine production in both alveolar macrophages and epithelial cells. We further identified that bacterium-mediated activation of TRPC1 was dependent on Toll-like receptor 4 (TLR4), which induced endoplasmic reticulum (ER) store depletion. After activation of phospholipase C gamma (PLC-gamma), TRPC1 mediated Ca2+ entry and triggered protein kinase C alpha (PKC alpha) activity to facilitate nuclear translocation of NF-kappa B/Jun N-terminal protein kinase (JNK) and augment the proinflammatory response, leading to tissue damage and eventually mortality. These findings reveal that TRPC1 is required for host defense against bacterial infections through the TLR4-TRPC1-PKC alpha signaling circuit. C1 [Zhou, Xikun; Li, Xuefeng; Huang, Canhua; Wei, Yu-Quan] Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, State Key Lab Biotherapy, Chengdu 610064, Peoples R China. [Zhou, Xikun; Ye, Yan; Sun, Yuyang; Li, Xuefeng; Wang, Wenxue; Privratsky, Breanna; Tan, Shirui; Singh, Brij B.; Wu, Min] Univ N Dakota, Dept Basic Sci, Grand Forks, ND 58201 USA. [Zhou, Zongguang] Sichuan Univ, West China Hosp, Dept Gastrointestinal Surg, Chengdu 610064, Peoples R China. [Birnbaumer, Lutz] NIEHS, Neurosci Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Singh, BB (reprint author), Univ N Dakota, Dept Basic Sci, Grand Forks, ND 58201 USA. EM brij.singh@med.und.edu; min.wu@med.und.edu FU FAMRI [103007]; National Natural Science Foundation of China [81202324]; China Postdoctoral Science Foundation [2014T70873]; NIH [Z01-ES101864]; [NIH P20 RR017699]; [NIH R01 AI109317-01A1]; [AI101973-01]; [AI097532-01A1]; [R01 DE017102] FX This project was supported by FAMRI (no. 103007) and grants NIH P20 RR017699, NIH R01 AI109317-01A1, and AI101973-01 to M.W., grants AI097532-01A1 and R01 DE017102 to B.B.S., National Natural Science Foundation of China (no. 81202324) and China Postdoctoral Science Foundation (no. 2014T70873) grants to X.Z., and an Intramural Research Program of the NIH (project Z01-ES101864) grant to L.B. NR 45 TC 3 Z9 3 U1 0 U2 7 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 2015 VL 35 IS 16 BP 2729 EP 2739 DI 10.1128/MCB.00256-15 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CN2VC UT WOS:000358279100002 PM 26031335 ER PT J AU DiPilato, LM Ahmad, F Harms, M Seale, P Manganiello, V Birnbaum, MJ AF DiPilato, Lisa M. Ahmad, Faiyaz Harms, Matthew Seale, Patrick Manganiello, Vincent Birnbaum, Morris J. TI The Role of PDE3B Phosphorylation in the Inhibition of Lipolysis by Insulin SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; DEPENDENT PROTEIN-KINASE; HORMONE-SENSITIVE LIPASE; BROWN ADIPOSE-TISSUE; RAT ADIPOCYTES; 3T3-L1 ADIPOCYTES; CAMP-PHOSPHODIESTERASE; LIPID-METABOLISM; PERILIPIN-A; FAT-CELLS AB Inhibition of adipocyte lipolysis by insulin is important for whole-body energy homeostasis; its disruption has been implicated as contributing to the development of insulin resistance and type 2 diabetes mellitus. The main target of the antilipolytic action of insulin is believed to be phosphodiesterase 3B (PDE3B), whose phosphorylation by Akt leads to accelerated degradation of the prolipolytic second messenger cyclic AMP (cAMP). To test this hypothesis genetically, brown adipocytes lacking PDE3B were examined for their regulation of lipolysis. In Pde3b knockout (KO) adipocytes, insulin was unable to suppress beta-adrenergic receptor-stimulated glycerol release. Reexpressing wild-type PDE3B in KO adipocytes fully rescued the action of insulin against lipolysis. Surprisingly, a mutant form of PDE3B that ablates the major Akt phosphorylation site, murine S273, also restored the ability of insulin to suppress lipolysis. Taken together, these data suggest that phosphorylation of PDE3B by Akt is not required for insulin to suppress adipocyte lipolysis. C1 [DiPilato, Lisa M.; Birnbaum, Morris J.] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Harms, Matthew; Seale, Patrick] Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. [Ahmad, Faiyaz; Manganiello, Vincent] NIH, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. RP Birnbaum, MJ (reprint author), Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. EM birnbaum@mail.med.upenn.edu FU NIH [R01DK093959, F32DK884443]; NHLBI Intramural Research Program FX This work was supported by NIH grants R01DK093959 to M.J.B. and F32DK884443 to L.M.D. Vincent Manganiello and Faiyaz Ahmad are supported by the NHLBI Intramural Research Program. NR 61 TC 7 Z9 7 U1 0 U2 6 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 2015 VL 35 IS 16 BP 2752 EP 2760 DI 10.1128/MCB.00422-15 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CN2VC UT WOS:000358279100004 PM 26031333 ER PT J AU Trotter, KW King, HA Archer, TK AF Trotter, Kevin W. King, Heather A. Archer, Trevor K. TI Glucocorticoid Receptor Transcriptional Activation via the BRG1-Dependent Recruitment of TOP2 beta and Ku70/86 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CHROMATIN REMODELING COMPLEXES; MAMMALIAN SWI/SNF COMPLEXES; DEPENDENT PROTEIN-KINASE; STRAND BREAK REPAIR; ANDROGEN RECEPTOR; IN-VIVO; ESTROGEN-RECEPTOR; NUCLEAR RECEPTORS; TOPOISOMERASE-II; CANCER CELLS AB BRG1, the central ATPase of the human SWI/SNF complex, is critical for biological functions, including nuclear receptor (NR)-regulated transcription. Analysis of BRG1 mutants demonstrated that functional motifs outside the ATPase domain are important for transcriptional activity. In the course of experiments examining protein interactions mediated through these domains, Ku70 (XRCC6) was found to associate with a BRG1 fragment encompassing the conserved helicase-SANT-associated (HSA) and BRK domains of BRG1. Subsequent transcriptional activation assays and chromatin immunoprecipitation studies showed that Ku70/86 and components of the topoisomerase II beta (TOP2 beta)/poly(ADP ribose) polymerase 1 (PARP1) complex are necessary for NR-mediated SWI/SNF-dependent transcriptional activation from endogenous promoters. In addition to establishing Ku-BRG1 binding and TOP2 beta/PARP1 recruitment by nuclear receptor transactivation, we demonstrate that the transient appearance of glucocorticoid receptor (GR)/BRG1-dependent, TOP2 beta-mediated double-strand DNA breaks is required for efficient GR-stimulated transcription. Taken together, these results suggest that a direct interaction between Ku70/86 and BRG1 brings together SWI/SNF remodeling capabilities and TOP2 beta activity to enhance the transcriptional response to hormone stimulation. C1 [Trotter, Kevin W.; King, Heather A.; Archer, Trevor K.] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov NR 77 TC 5 Z9 6 U1 0 U2 3 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 2015 VL 35 IS 16 BP 2799 EP 2817 DI 10.1128/MCB.00230-15 PG 19 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CN2VC UT WOS:000358279100008 PM 26055322 ER PT J AU Chu, CH Chen, SH Wang, QS Langenbach, R Li, H Zeldin, D Chen, SL Wang, SJ Gao, H Lu, RB Hong, JS AF Chu, Chun-Hsien Chen, Shih-Heng Wang, Qingshan Langenbach, Robert Li, Hong Zeldin, Darryl Chen, Shiou-Lan Wang, Shijun Gao, Huiming Lu, Ru-Band Hong, Jau-Shyong TI PGE(2) Inhibits IL-10 Production via EP2-Mediated beta-Arrestin Signaling in Neuroinflammatory Condition SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Microglia; IL-10; PGE2; COX-2; EP2; beta-arrestin ID TUMOR-NECROSIS-FACTOR; PROSTAGLANDIN E-2; GENE-EXPRESSION; NEURODEGENERATIVE DISEASES; NADPH-OXIDASE; EP2 RECEPTOR; FACTOR-ALPHA; MOUSE SKIN; IN-VITRO; LIPOPOLYSACCHARIDE AB Regulatory mechanisms of the expression of interleukin-10 (IL-10) in brain inflammatory conditions remain elusive. To address this issue, we used multiple primary brain cell cultures to study the expression of IL-10 in lipopolysaccharide (LPS)-elicited inflammatory conditions. In neuron-glia cultures, LPS triggered well-orchestrated expression of various immune factors in the following order: tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE(2)), and lastly IL-10, and these inflammatory mediators were mainly produced from microglia. While exogenous application of individual earlier-released pro-inflammatory factors (e.g., TNF-alpha, IL-1 beta, or PGE(2)) failed to induce IL-10 expression, removal of LPS from the cultures showed the requirement of continuing presence of LPS for IL-10 expression. Interestingly, genetic disruption of tnf-alpha, its receptors tnf-r1/r2, and cox-2 and pharmacological inhibition of COX-2 activity enhanced LPS-induced IL-10 production in microglia, which suggests negative regulation of IL-10 induction by the earlier-released TNF-alpha and PGE(2). Further studies showed that negative regulation of IL-10 production by TNF-alpha is mediated by PGE(2). Mechanistic studies indicated that PGE(2)-elicited suppression of IL-10 induction was eliminated by genetic disruption of the PGE(2) receptor EP2 and was mimicked by the specific agonist for the EP2, butaprost, but not agonists for the other three EP receptors. Inhibition of cAMP-dependent signal transduction failed to affect PGE(2)-mediated inhibition of IL-10 production, suggesting that a G protein-independent pathway was involved. Indeed, deficiency in beta-arrestin-1 or beta-arrestin-2 abolished PGE(2)-elicited suppression of IL-10 production. In conclusion, we have demonstrated that COX-2-derived PGE(2) inhibits IL-10 expression in brain microglia through a novel EP2- and beta-arrestin-dependent signaling pathway. C1 [Chu, Chun-Hsien; Chen, Shih-Heng; Wang, Qingshan; Wang, Shijun; Gao, Huiming; Hong, Jau-Shyong] Natl Inst Environm Hlth Sci, Neuropharmacol Sect, Natl Inst Health, Res Triangle Pk, NC 27709 USA. [Langenbach, Robert] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, Natl Inst Health, Res Triangle Pk, NC 27709 USA. [Zeldin, Darryl] Natl Inst Environm Hlth Sci, Lab Resp Biol, Natl Inst Health, Res Triangle Pk, NC 27709 USA. [Chen, Shiou-Lan] Kaohsiung Med Univ, Dept Neurol, Sch Med, Kaohsiung 80780, Taiwan. [Wang, Shijun] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA. [Gao, Huiming] Nanjing Univ, Model Anim Res Ctr, Nanjing 210061, Jiangsu, Peoples R China. [Gao, Huiming] Nanjing Univ, MOE Key Lab Model Anim Dis Study, Nanjing 210061, Jiangsu, Peoples R China. [Lu, Ru-Band] Natl Cheng Kung Univ Hosp, Inst Behav Med, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ Hosp, Dept Psychiat, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Inst Allied Hlth Sci, Coll Med, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Addict Res Ctr, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Dept Psychiat, Coll Med & Hosp, Tainan 70428, Taiwan. RP Gao, H (reprint author), Nanjing Univ, Model Anim Res Ctr, 12 Xuefu Rd, Nanjing 210061, Jiangsu, Peoples R China. EM gaohm@nju.edu.cn; rblu@mail.ncku.edu.tw FU NIH/NIEHS [ES090082, ES025043]; National Natural Science Foundation of China; Jiangsu Province of China FX This work was supported in part by the Intramural Research Program of the NIH/NIEHS (ES090082; ES025043), the National Natural Science Foundation of China, and the award to high-level innovative and entrepreneurial talents of Jiangsu Province of China. We thank Anthony Lockhart for the assistance with animal colony management and maintenance of the timed pregnant mice. NR 49 TC 3 Z9 3 U1 1 U2 9 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD AUG PY 2015 VL 52 IS 1 BP 587 EP 600 DI 10.1007/s12035-014-8889-0 PG 14 WC Neurosciences SC Neurosciences & Neurology GA CN3QO UT WOS:000358341600052 PM 25218510 ER PT J AU Chung, T Christopher-Stine, L Paik, JJ Corse, A Mammen, AL AF Chung, Tae Christopher-Stine, Lisa Paik, Julie J. Corse, Andrea Mammen, Andrew L. TI The composition of cellular infiltrates in anti-HMG-CoA reductase-associated myopathy SO MUSCLE & NERVE LA English DT Article DE anti-HMGCR myopathy; autoimmune myopathy; immune-mediated necrotizing myopathy; muscle histology; myositis ID INFLAMMATORY MYOPATHIES; NECROTIZING MYOPATHY; DISEASE-ACTIVITY; MUSCLE INJURY; DERMATOMYOSITIS; POLYMYOSITIS; SUBSETS; COMPLEX; CELLS; AUTOANTIBODIES AB Introduction: To characterize cellular infiltrates in muscle biopsies from patients with anti-3-hydroxy-3-methyl-gulatryl-CoA reductase (HMGCR)-associated myopathy. Methods: Biopsies from 18 anti-HMGCR myopathy and 7 control dermatomyositis patients were analyzed. Results: CD4+ and CD8+ T-cells were scattered within the endomysium in 50% of anti-HMGCR biopsies. All anti-HMGCR biopsies included increased endomysial and/or perivascular CD163+ M2 macrophages; CD11c+ M1 macrophages were present in 18.8%. CD123+ plasmacytoid dendritic (PD) cells were observed within the endomysium and perivascular spaces in 62.5% of anti-HMGCR biopsies. Membrane attack complex was deposited on endothelial cells in 50% and on the sarcolemma of nonnecrotic muscle fibers in 85.7% of anti-HMGCR cases. Major histocompatibility complex class I antigen was up-regulated in 87.5% of the anti-HMGCR cases. Conclusions: In addition to necrosis, scattered CD4+, CD8+, and PD cells are characteristic of anti-HMGCR myopathy. Predominant M2 polarization suggests infiltrating macrophages are more likely to be involved with tissue repair than destruction. Muscle Nerve, 2015. Muscle Nerve52: 189-195, 2015 C1 [Chung, Tae] Johns Hopkins Univ, Sch Med, Dept Phys Med & Rehabil, Baltimore, MD USA. [Christopher-Stine, Lisa; Paik, Julie J.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Corse, Andrea] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Mammen, Andrew L.] NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Express, NIH, Bethesda, MD 20892 USA. RP Mammen, AL (reprint author), NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Express, NIH, 50 South Dr,Room 1146,Bldg 50,MSC 8024, Bethesda, MD 20892 USA. EM andrew.mammen@nih.gov FU Huayi and Siuling Zhang Discovery Fund; Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX This work was supported by the Huayi and Siuling Zhang Discovery Fund. This work was supported [in part] by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. ALM and LC-S have patented the anti-HMGCR antibody test. NR 24 TC 18 Z9 18 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X EI 1097-4598 J9 MUSCLE NERVE JI Muscle Nerve PD AUG PY 2015 VL 52 IS 2 BP 189 EP 195 DI 10.1002/mus.24642 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CN4DI UT WOS:000358379500005 PM 25737145 ER PT J AU Arrowsmith, CH Audia, JE Austin, C Baell, J Bennett, J Blagg, J Bountra, C Brennan, PE Brown, PJ Bunnage, ME Buser-Doepner, C Campbell, RM Carter, AJ Cohen, P Copeland, RA Cravatt, B Dahlin, JL Dhanak, D Edwards, AM Frye, SV Gray, N Grimshaw, CE Hepworth, D Howe, T Huber, KVM Jin, J Knapp, S Kotz, JD Kruger, RG Lowe, D Mader, MM Marsden, B Mueller-Fahrnow, A Muller, S O'Hagan, RC Overington, JP Owen, DR Rosenberg, SH Roth, B Ross, R Schapira, M Schreiber, SL Shoichet, B Sundstrom, M Superti-Furga, G Taunton, J Toledo-Sherman, L Walpole, C Walters, MA Willson, TM Workman, P Young, RN Zuercher, WJ AF Arrowsmith, Cheryl H. Audia, James E. Austin, Christopher Baell, Jonathan Bennett, Jonathan Blagg, Julian Bountra, Chas Brennan, Paul E. Brown, Peter J. Bunnage, Mark E. Buser-Doepner, Carolyn Campbell, Robert M. Carter, Adrian J. Cohen, Philip Copeland, Robert A. Cravatt, Ben Dahlin, Jayme L. Dhanak, Dashyant Edwards, Aled M. Frye, Stephen V. Gray, Nathanael Grimshaw, Charles E. Hepworth, David Howe, Trevor Huber, Kilian V. M. Jin, Jian Knapp, Stefan Kotz, Joanne D. Kruger, Ryan G. Lowe, Derek Mader, Mary M. Marsden, Brian Mueller-Fahrnow, Anke Mueller, Susanne O'Hagan, Ronan C. Overington, John P. Owen, Dafydd R. Rosenberg, Saul H. Roth, Brian Ross, Ruth Schapira, Matthieu Schreiber, Stuart L. Shoichet, Brian Sundstrom, Michael Superti-Furga, Giulio Taunton, Jack Toledo-Sherman, Leticia Walpole, Chris Walters, Michael A. Willson, Timothy M. Workman, Paul Young, Robert N. Zuercher, William J. TI The promise and peril of chemical probes SO NATURE CHEMICAL BIOLOGY LA English DT Article ID SMALL-MOLECULE INHIBITORS; PROTEIN-KINASE; TARGET ENGAGEMENT; POTENT INHIBITOR; DRUG DISCOVERY; CELLS; IDENTIFICATION; RECEPTORS; CHEMISTRY; HYDROLASE AB Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice. C1 [Arrowsmith, Cheryl H.; Brown, Peter J.; Edwards, Aled M.; Schapira, Matthieu] Struct Genom Consortium, Toronto, ON, Canada. [Arrowsmith, Cheryl H.] Univ Toronto, Dept Med Biophys, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Audia, James E.] Constellat Pharmaceut, Cambridge, MA USA. [Austin, Christopher] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Baell, Jonathan] Monash Univ, Fac Pharm & Pharmaceut Sci, Melbourne, Vic 3004, Australia. [Bennett, Jonathan] Merck Res Labs, Discovery Chem, Boston, MA USA. [Blagg, Julian; Workman, Paul] Inst Canc Res, Canc Res UK Canc Therapeut Unit, London SW3 6JB, England. [Bountra, Chas; Brennan, Paul E.; Knapp, Stefan; Marsden, Brian; Mueller, Susanne] Univ Oxford, Struct Genom Consortium, Oxford, England. [Brennan, Paul E.; Knapp, Stefan; Mueller, Susanne] Univ Oxford, Target Discovery Inst, Oxford, England. [Bunnage, Mark E.; Hepworth, David; Owen, Dafydd R.] Pfizer, Worldwide Med Chem, Cambridge, MA USA. [Buser-Doepner, Carolyn] GlaxoSmithKline, Collegeville, PA USA. [Campbell, Robert M.; Mader, Mary M.] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. [Carter, Adrian J.] Boehringer Ingelheim GmbH & Co KG, Corp Dept Res Networking, Ingelheim, Germany. [Cohen, Philip] Univ Dundee, Sir James Black Ctr, Dundee, Scotland. [Copeland, Robert A.] Epizyme Inc, Cambridge, MA USA. [Cravatt, Ben] Scripps Res Inst, Dept Physiol Chem, San Diego, CA USA. [Dahlin, Jayme L.] Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN USA. [Dhanak, Dashyant] Janssen Res & Dev, Spring House, PA USA. [Frye, Stephen V.] Univ N Carolina, Eshelman Sch Pharm, Ctr Integrat Chem Biol & Drug Discovery, Div Chem Biol & Med Chem, Chapel Hill, NC USA. [Gray, Nathanael] Harvard Univ, Dept Biol Chem & Mol Pharmacol, Cambridge, MA 02138 USA. [Grimshaw, Charles E.] Takeda Calif Inc, San Diego, CA USA. [Howe, Trevor] Janssen Res & Dev, High Wycombe, Bucks, England. [Huber, Kilian V. M.; Superti-Furga, Giulio] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1010 Vienna, Austria. [Jin, Jian] Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, New York, NY 10029 USA. [Jin, Jian] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Jin, Jian] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Kotz, Joanne D.; Schreiber, Stuart L.] Broad Inst, Ctr Sci Therapeut, Cambridge, MA USA. [Kruger, Ryan G.] GlaxoSmithKline, Canc Epigenet, Collegeville, PA USA. [Lowe, Derek] Vertex Pharmaceut, Boston, MA USA. [Mueller-Fahrnow, Anke] Bayer Pharma AG, Berlin, Germany. [O'Hagan, Ronan C.] Merck Res Labs, Oncol Discovery, Boston, MA USA. [Overington, John P.] European Bioinformat Inst, European Mol Biol Lab, Hinxton, England. [Overington, John P.] Stratified Med, London, England. [Rosenberg, Saul H.] AbbVie, N Chicago, IL USA. [Roth, Brian; Willson, Timothy M.; Zuercher, William J.] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC USA. [Ross, Ruth; Schapira, Matthieu] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada. [Shoichet, Brian] Univ Calif San Francisco, Sch Pharm, San Francisco, CA 94143 USA. [Sundstrom, Michael] Karolinska Inst, Struct Genom Consortium, Solna, Sweden. [Sundstrom, Michael] Karolinska Univ Hosp, Dept Med, Solna, Sweden. [Sundstrom, Michael] Karolinska Inst, Solna, Sweden. [Superti-Furga, Giulio] Med Univ Vienna, Ctr Physiol & Pharmacol, Vienna, Austria. [Taunton, Jack] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Taunton, Jack] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA USA. [Toledo-Sherman, Leticia] CHDI Fdn, CHDI Management, Los Angeles, CA USA. [Walpole, Chris] McGill Univ, Struct Genom Consortium, Montreal, PQ, Canada. [Walters, Michael A.] Univ Minnesota, Minneapolis, MN USA. [Willson, Timothy M.; Zuercher, William J.] Univ N Carolina, Struct Genom Consortium, Chapel Hill, NC USA. [Young, Robert N.] Simon Fraser Univ, Dept Chem, Burnaby, BC V5A 1S6, Canada. RP Arrowsmith, CH (reprint author), Struct Genom Consortium, Toronto, ON, Canada. EM aled.edwards@utoronto.ca RI Huber, Kilian/L-6921-2015; Baell, Jonathan/E-5844-2017; OI Huber, Kilian/0000-0002-1103-5300; Baell, Jonathan/0000-0003-2114-8242; Knapp, Stefan/0000-0001-5995-6494; Muller-Knapp, Susanne/0000-0003-2402-4157; Overington, John/0000-0002-5859-1064 FU Cancer Research UK [11566]; Medical Research Council [MC_UU_12016/11, MR/K000985/1]; NIGMS NIH HHS [R01 GM103893]; Wellcome Trust [100294, 104104, 106169] NR 39 TC 118 Z9 119 U1 21 U2 66 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD AUG PY 2015 VL 11 IS 8 BP 536 EP 541 DI 10.1038/nchembio.1867 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CN2MJ UT WOS:000358255300003 PM 26196764 ER PT J AU Overstreet-Wadiche, L McBain, CJ AF Overstreet-Wadiche, Linda McBain, Chris J. TI Neurogliaform cells in cortical circuits SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID STRATUM LACUNOSUM-MOLECULARE; HIPPOCAMPAL CA1 INTERNEURONS; NEWLY GENERATED NEURONS; CAJAL-RETZIUS CELLS; RAT HIPPOCAMPUS; ADULT HIPPOCAMPUS; CEREBRAL-CORTEX; DENTATE GYRUS; RECEPTOR MODULATION; GAMMA-OSCILLATIONS AB Recent research into local-circuit GABAergic inhibitory interneurons of the mammalian central nervous system has provided unprecedented insight into the mechanics of neuronal circuitry and its dysfunction. Inhibitory interneurons consist of a broad array of anatomically and neurochemically diverse cell types, and this suggests that each occupies an equally diverse functional role. Although neurogliaform cells were observed by Cajal over a century ago, our understanding of the functional role of this class of interneurons is in its infancy. However, it is rapidly becoming clear that this cell type operates under a distinct repertoire of rules to provide novel forms of inhibitory control of numerous afferent pathways. C1 [Overstreet-Wadiche, Linda] Univ Alabama Birmingham, McKnight Brain Inst, Dept Neurobiol, Birmingham, AL 35294 USA. [McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, Bethesda, MD 20892 USA. RP McBain, CJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, Bldg 35,Room 3C903, Bethesda, MD 20892 USA. EM mcbainc@mail.nih.gov OI Wadiche, Linda/0000-0001-7367-5998 FU NINDS NIH HHS [R01 NS064025] NR 93 TC 3 Z9 3 U1 5 U2 23 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 2015 VL 16 IS 8 BP 458 EP 468 DI 10.1038/nrn3969 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CN1MT UT WOS:000358184800007 PM 26189693 ER PT J AU Smith, RF McDonald, CG Bergstrom, HC Ehlinger, DG Brielmaier, JM AF Smith, Robert F. McDonald, Craig G. Bergstrom, Hadley C. Ehlinger, Daniel G. Brielmaier, Jennifer M. TI Adolescent nicotine induces persisting changes in development of neural connectivity SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review ID ANXIETY-LIKE BEHAVIOR; LONG-TERM CHANGES; MEDIAL PREFRONTAL CORTEX; MESSENGER-RNA EXPRESSION; NUCLEUS-ACCUMBENS; DOPAMINE-RECEPTOR; PYRAMIDAL NEURONS; FUNCTIONAL CONNECTIVITY; ADULT RATS; STRUCTURAL PLASTICITY AB Adolescent nicotine induces persisting changes in development of neural connectivity. A large number of brain changes occur during adolescence as the CNS matures. These changes suggest that the adolescent brain may still be susceptible to developmental alterations by substances which impact its growth. Here we review recent studies on adolescent nicotine which show that the adolescent brain is differentially sensitive to nicotine-induced alterations in dendritic elaboration, in several brain areas associated with processing reinforcement and emotion, specifically including nucleus accumbens, medial prefrontal cortex, basolateral amygdala, bed nucleus of the stria terminalis, and dentate gyrus. Both sensitivity to nicotine, and specific areas responding to nicotine, differ between adolescent and adult rats, and dendritic changes in response to adolescent nicotine persist into adulthood. Areas sensitive to, and not sensitive to, structural remodeling induced by adolescent nicotine suggest that the remodeling generally corresponds to the extended amygdala. Evidence suggests that dendritic remodeling is accompanied by persisting changes in synaptic connectivity. Modeling, electrophysiological, neurochemical, and behavioral data are consistent with the implication of our anatomical studies showing that adolescent nicotine induces persisting changes in neural connectivity. Emerging data thus suggest that early adolescence is a period when nicotine consumption, presumably mediated by nicotine-elicited changes in patterns of synaptic activity, can sculpt late brain development, with consequent effects on synaptic interconnection patterns and behavior regulation. Adolescent nicotine may induce a more addiction-prone phenotype, and the structures altered by nicotine also subserve some emotional and cognitive functions, which may also be altered, We suggest that dendritic elaboration and associated changes are mediated by activity-dependent synaptogenesis, acting in part through D1DR receptors, in a network activated by nicotine. The adolescent nicotine effects reviewed here suggest that modification of late CNS development constitutes a hazard of adolescent nicotine use. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Smith, Robert F.; McDonald, Craig G.; Brielmaier, Jennifer M.] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Bergstrom, Hadley C.] NIAAA, Lab Behav & Genom Neurosci, NIH, Rockville, MD 20814 USA. [Ehlinger, Daniel G.] Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. RP Smith, RF (reprint author), George Mason Univ, Dept Psychol, MSN 3F5, Fairfax, VA 22030 USA. EM bsmith@gmu.edu FU Virginia Foundation for Healthy Youth FX Much of the authors' work cited herein was supported by grants from the Virginia Foundation for Healthy Youth (formerly Virginia Tobacco Settlement Foundation) to RFS. NR 122 TC 17 Z9 17 U1 1 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 EI 1873-7528 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD AUG PY 2015 VL 55 BP 432 EP 443 DI 10.1016/j.neubiorev.2015.05.019 PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CN2SA UT WOS:000358271000030 PM 26048001 ER PT J AU Wood, ET Ercan, AE Branzoli, F Webb, A Sati, P Reich, DS Ronen, I AF Wood, Emily T. Ercan, Ayse Ece Branzoli, Francesca Webb, Andrew Sati, Pascal Reich, Daniel S. Ronen, Itamar TI Reproducibility and optimization of in vivo human diffusion-weighted MRS of the corpus callosum at 3T and 7T SO NMR IN BIOMEDICINE LA English DT Article DE diffusion-weighted MRS; inter-subject variability; intra-subject variability; power calculations; white matter ID MAGNETIC-RESONANCE-SPECTROSCOPY; HUMAN BRAIN; TENSOR SPECTROSCOPY; MULTIPLE-SCLEROSIS; CEREBRAL-ISCHEMIA; NMR-SPECTROSCOPY; METABOLITES; COEFFICIENTS; SOFTWARE; SYSTEM AB Diffusion-weighted MRS (DWS) of brain metabolites enables the study of cell-specific alterations in tissue microstructure by probing the diffusion of intracellular metabolites. In particular, the diffusion properties of neuronal N-acetylaspartate (NAA), typically co-measured with N-acetylaspartyl glutamate (NAAG) (NAA+NAAG=tNAA), have been shown to be sensitive to intraneuronal/axonal damage in pathologies such as stroke and multiple sclerosis. Lacking, so far, are empirical assessments of the reproducibility of DWS measures across time and subjects, as well as a systematic investigation of the optimal acquisition parameters for DWS experiments, both of which are sorely needed for clinical applications of the method. In this study, we acquired comprehensive single-volume DWS datasets of the human corpus callosum at 3T and 7T. We investigated the inter- and intra-subject variability of empirical and modeled diffusion properties of tNAA [D-avg(tNAA) and D-model(tNAA), respectively]. Subsequently, we used a jackknife-like resampling approach to explore the variance of these properties in partial data subsets reflecting different total scan durations. The coefficients of variation (C-V) and repeatability coefficients (C-R) for D-avg(tNAA) and D-model(tNAA) were calculated for both 3T and 7T, with overall lower variability in the 7T results. Although this work is limited to the estimation of the diffusion properties in the corpus callosum, we show that a careful choice of diffusion-weighting conditions at both field strengths allows the accurate measurement of tNAA diffusion properties in clinically relevant experimental time. Based on the resampling results, we suggest optimized acquisition schemes of 13-min duration at 3T and 10-min duration at 7T, whilst retaining low variability (C-V approximate to 8%) for the tNAA diffusion measures. Power calculations for the estimation of D-model(tNAA) and D-avg(tNAA) based on the suggested schemes show that less than 21 subjects per group are sufficient for the detection of a 10% effect between two groups in case-control studies. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Wood, Emily T.; Sati, Pascal; Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, NIH, Bethesda, MD 20892 USA. [Wood, Emily T.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Ercan, Ayse Ece; Webb, Andrew; Ronen, Itamar] Leiden Univ, Dept Radiol, CJ Gorter Ctr High Field MRI, Med Ctr, NL-2333 ZA Leiden, Netherlands. [Branzoli, Francesca] Ctr NeuroImaging Res CENIR, Inst Cerveau & Moelle Epiniere ICM, Paris, France. [Branzoli, Francesca] Univ Paris 06, INSERM, Sorbonne Univ, UMR S 1127,CNRS,UMR 7225, Paris, France. RP Ronen, I (reprint author), Leiden Univ, Dept Radiol, CJ Gorter Ctr High Field MRI, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands. EM i.ronen@lumc.nl RI Ronen, Itamar/E-8518-2016; webb, andrew/G-9642-2016; Reich, Daniel/E-5701-2010; OI Ronen, Itamar/0000-0002-6872-4895; Reich, Daniel/0000-0002-2628-4334; Wood, Emily/0000-0003-0395-4849; Ercan, Ece/0000-0002-8187-2075 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health (NIH) Clinical Center Radiology and Imaging Sciences MRI technologists; Medical Scientist Training Program (MSTP); NINDS Competitive Intramural Graduate Fellowship; NINDS Neuroimmunology Clinic FX We would like to thank the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS), and the NINDS Neuroimmunology Clinic and the National Institutes of Health (NIH) Clinical Center Radiology and Imaging Sciences MRI technologists for their support and expertise. Emily Wood was supported by a Medical Scientist Training Program (MSTP) grant and by an NINDS Competitive Intramural Graduate Fellowship. NR 47 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD AUG PY 2015 VL 28 IS 8 BP 976 EP 987 DI 10.1002/nbm.3340 PG 12 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA CN1JD UT WOS:000358174600006 PM 26084563 ER PT J AU Chew, EY Klein, ML Clemons, TE Agron, E Abecasis, GR AF Chew, Emily Y. Klein, Michael L. Clemons, Traci E. Agron, Elvira Abecasis, Goncalo R. TI Re: Chew et al.: No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38 (Ophthalmology 2014;121:2173-80) Reply SO OPHTHALMOLOGY LA English DT Letter ID MACULAR DEGENERATION; EYE DISEASE; ANTIOXIDANTS; ZINC C1 [Chew, Emily Y.; Agron, Elvira] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Klein, Michael L.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 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 Intramural NIH HHS; NEI NIH HHS [HHS-NOI-EY-0-2127] NR 5 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2015 VL 122 IS 8 BP E46 EP E47 PG 3 WC Ophthalmology SC Ophthalmology GA CN3JV UT WOS:000358322900002 PM 26210599 ER PT J AU Zalewski, CK Chien, WW King, KA Muskett, JA Baron, RE Butman, JA Griffith, AJ Brewer, CC AF Zalewski, Chris K. Chien, Wade W. King, Kelly A. Muskett, Julie A. Baron, Rachel E. Butman, John A. Griffith, Andrew J. Brewer, Carmen C. TI Vestibular Dysfunction in Patients with Enlarged Vestibular Aqueduct SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE enlarged vestibular aqueduct; EVA; hearing loss; dizziness; vestibular dysfunction; LVAS; vertigo; VEMP; VNG; RVT ID HEARING-LOSS; PENDRED-SYNDROME; SLC26A4 GENE; INNER-EAR; MUTATIONS; BONE; POPULATION; GENOTYPE AB Objective Enlarged vestibular aqueduct (EVA) is the most common inner ear malformation. While a strong correlative relationship between EVA and hearing loss is well established, its association with vestibular dysfunction is less well understood. In this study, we examine the effects of EVA on the vestibular system in patients with EVA. Study Design Prospective, cross-sectional study of a cohort ascertained between 1999 and 2013. Setting National Institutes of Health Clinical Center, a federal biomedical research facility. Subjects and Methods In total, 106 patients with unilateral or bilateral EVA, defined as a midpoint diameter greater than 1.5 mm, were referred or self-referred to participate in a study of the clinical and molecular aspects of EVA. Clinical history was ascertained with respect to the presence or absence of various vestibular signs and symptoms and history of head trauma. Videonystagmography (VNG), cervical vestibular evoked myogenic potential (cVEMP), and rotational vestibular testing (RVT) were performed to assess the vestibular function. Results Of the patients with EVA, 45% had vestibular signs and symptoms, and 44% of tested patients had abnormal VNG test results. An increased number of vestibular signs and symptoms was correlated with the presence of bilateral EVA (P = .008) and a history of head injury (P < .001). Abnormal VNG results also correlated with a history of head injury (P = .018). Conclusion Vestibular dysfunction is common in patients with EVA. However, not all patients with vestibular signs and symptoms have abnormal vestibular test results. Clinicians should be aware of the high prevalence of vestibular dysfunction in patients with EVA. C1 [Zalewski, Chris K.; Chien, Wade W.; King, Kelly A.; Muskett, Julie A.; Baron, Rachel E.; Griffith, Andrew J.; Brewer, Carmen C.] Natl Inst Deafness & Other Commun Disorders NIDCD, NIH, Bethesda, MD USA. [Chien, Wade W.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. [Butman, John A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Griffith, AJ (reprint author), NIDCD, NIH, Porter Neurosci Res Ctr, 35A Convent Dr,Room GF103, Bethesda, MD 20892 USA. EM griffita@nidcd.nih.gov FU National Institute on Deafness and Other Communication Disorders (NIDCD) under an intramural research program; NIDCD FX Funding source: This was study was funded by the National Institute on Deafness and Other Communication Disorders (NIDCD) under an intramural research program. The NIDCD provided funding for patient recruitment, examination, and testing. NR 32 TC 7 Z9 7 U1 3 U2 15 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD AUG PY 2015 VL 153 IS 2 BP 257 EP 262 DI 10.1177/0194599815585098 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA CN4FW UT WOS:000358387000017 PM 25968061 ER PT J AU Himes, SK Wu, JW Jacobson, DL Tassiopoulos, K Hazra, R Kacanek, D Van Dyke, RB Rich, KC Siberry, GK Huestis, MA AF Himes, Sarah K. Wu, Julia W. Jacobson, Denise L. Tassiopoulos, Katherine Hazra, Rohan Kacanek, Deborah Van Dyke, Russell B. Rich, Kenneth C. Siberry, George K. Huestis, Marilyn A. CA PHACS TI Meconium Tenofovir Concentrations and Growth and Bone Outcomes in Prenatally Tenofovir Exposed HIV-Uninfected Children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE meconium; tenofovir; antiretroviral; birth; growth; bone; DXA; HIV-exposed uninfected children ID HIV-1-INFECTED PREGNANT-WOMEN; HUMAN-IMMUNODEFICIENCY-VIRUS; DISOPROXIL FUMARATE; INFECTED MOTHERS; RHESUS MACAQUES; MINERAL DENSITY; ANTIVIRAL DRUGS; MACACA-MULATTA; SAFETY; PHARMACOKINETICS AB Background: Maternal tenofovir disoproxil fumarate (TDF) treatment among HIV-infected pregnant women results in fetal tenofovir (TFV) exposure. Fetal TFV toxicity was demonstrated in animals, but most clinical investigations have not observed toxicity in humans. Methods: We evaluated HIV-exposed, uninfected infants in the Surveillance Monitoring for Antiretroviral Therapy Toxicities cohort of the Pediatric HIV/AIDS Cohort Study whose mothers were prescribed TDF for 8 third trimester weeks. Infant dual-energy X-ray absorptiometry scans were obtained at 0-4 weeks to measure whole body bone mineral content. Meconium TFV concentrations were quantified by liquid chromatography-tandem mass spectrometry. Results: Fifty-eight TFV-exposed infants had meconium TFV quantified. Detectable concentrations were 11-48,100ng/g; 3 infants had undetectable concentrations. Maternal TDF prescription duration ranged from 8 to 41 gestational weeks; infant gestational ages were 36-41 weeks. Meconium TFV concentrations were not correlated with TFV exposure duration or timing and did not vary by concomitant prescription of protease inhibitors. Increased meconium TFV concentrations were associated with greater gestational ages ( = 0.29, P = 0.03) and lower maternal plasma HIV RNA before delivery ( = -0.29, P = 0.04). Meconium TFV concentrations were not associated with infant weight, length (n = 58) or bone mineral content (n = 49). Conclusions: For the first time, we explored associations between meconium TFV concentrations and infant growth and bone measurements; we did not observe a meconium concentration-dependent relationship for these infant outcomes. These findings support other clinical research failing to show dose-response relationships for growth and bone outcomes among intrauterine TFV-exposed infants. High meconium TFV concentrations correlated with low maternal viral load, suggesting maternal TDF adherence significantly contributes to meconium TFV concentrations. C1 [Himes, Sarah K.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wu, Julia W.; Tassiopoulos, Katherine] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Jacobson, Denise L.; Kacanek, Deborah] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Hazra, Rohan; Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD USA. [Van Dyke, Russell B.] Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. [Rich, Kenneth C.] Univ Illinois, Dept Pediat, Chicago, IL USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, IRP, NIH, 251 Bayview Blvd,Suite 200,Rm 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism through Harvard University School of Public Health [HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3]; Tulane University School of Medicine [HD052104, 3U01HD052104-06S1] FX The Pediatric HIV/AIDS Cohort Study (PHACS) was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with cofunding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3; principal investigator: George Seage; project director: Julie Alperen) and the Tulane University School of Medicine (HD052104, 3U01HD052104-06S1; principal investigator: Russell Van Dyke; co-principal investigator: Kenneth Rich; project director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Julie Davidson). The authors have no other funding or conflicts of interest to disclose. The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or U.S. Department of Health and Human Services. NR 51 TC 6 Z9 6 U1 0 U2 2 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 2015 VL 34 IS 8 BP 851 EP 857 DI 10.1097/INF.0000000000000747 PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA CN4PE UT WOS:000358411500012 PM 25961889 ER PT J AU Nghiem-Rao, TH Tunc, I Mavis, AM Cao, YM Polzin, EM Firary, MF Wang, XJ Simpson, PM Patel, SB AF Nghiem-Rao, T. Hang Tunc, Ilker Mavis, Alisha M. Cao, Yumei Polzin, Elizabeth M. Firary, Mary F. Wang, Xujing Simpson, Pippa M. Patel, Shailendra B. TI Kinetics of phytosterol metabolism in neonates receiving parenteral nutrition SO PEDIATRIC RESEARCH LA English DT Article ID INTRAVENOUS LIPID EMULSIONS; LIVER-DISEASE; FISH-OIL; INTESTINAL FAILURE; PLANT STEROLS; CHOLESTASIS; CHOLESTEROL; INFANTS; SITOSTEROLEMIA; PLASMA AB BACKGROUND: Phytosterols in soybean oil (SO) lipids likely contribute to parenteral nutrition-associated liver disease (PNALD) in infants. No characterization of phytosterol metabolism has been done in infants receiving SO lipids. METHODS: In a prospective cohort study, 45 neonates (36 SO lipid vs. 9 control) underwent serial blood sample measurements of sitosterol, campesterol, and stigmasterol. Mathematical modeling was used to determine pharmacokinetic parameters of phytosterol metabolism and phytosterol exposure. RESULTS: Compared to controls, SO lipid-exposed infants had significantly higher levels of sitosterol and campesterol (P < 0.01). During SO lipid infusion, sitosterol and campesterol reached half of steady-state plasma levels within 1.5 and 0.8 d, respectively. Steady-state level was highest for sitosterol (1.68 mg/dl), followed by campesterol (0.98 mg/dl), and lowest for stigmasterol (0.01 mg/dl). Infants born < 28 wk gestational age had higher sitosterol steady-state levels (P = 0.03) and higher area under the curve for sitosterol (P = 0.03) during the first 5 d of SO lipid (AUC(5)) than infants born >= 28 wk gestational age. CONCLUSION: Phytosterols in SO lipid accumulate rapidly in neonates. Very preterm infants receiving SO lipid have higher sitosterol exposure, and may have poorly developed mechanisms of eliminating phytosterols that may contribute to their vulnerability to PNALD. C1 [Nghiem-Rao, T. Hang; Mavis, Alisha M.; Cao, Yumei; Simpson, Pippa M.] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Tunc, Ilker; Wang, Xujing] NHLBI, Bioinformat & Syst Biol, NIH, Bethesda, MD 20892 USA. [Polzin, Elizabeth M.] Childrens Hosp Wisconsin, Dept Clin Nutr, Milwaukee, WI 53201 USA. [Firary, Mary F.] Childrens Hosp Wisconsin, Dept Pharm, Milwaukee, WI 53201 USA. [Patel, Shailendra B.] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Patel, Shailendra B.] Zablocki Vet Affairs Med Ctr, Milwaukee, WI USA. RP Nghiem-Rao, TH (reprint author), Med Coll Wisconsin, Dept Pediat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM hnghiem@mcw.edu OI Patel, Shailendra/0000-0003-0046-5513 FU Gerber Foundation (Fremont, MI); National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health (Bethesda, MD) [8UL1TR000055]; Clinical and Translational Science Institute of Southeast Wisconsin (Bethesda, MD) [UL1RR031973]; Wisconsin Corporation for Biomedical Research (Milwaukee, WI); Biomedical Laboratory Research and Development Program, Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (Washington, DC) FX A portion of this work was supported by The Gerber Foundation (Fremont, MI) to T.H.N.-R., the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (Bethesda, MD) through grant number 8UL1TR000055 to T.H.N.-R., the Clinical and Translational Science Institute of Southeast Wisconsin (Bethesda, MD) through grant number UL1RR031973 to P.M.S., the Wisconsin Corporation for Biomedical Research (Milwaukee, WI) to S.B.P., and the Biomedical Laboratory Research and Development Program, Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (Washington, DC) to S.B.P. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the various funding agencies. NR 40 TC 2 Z9 2 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0031-3998 EI 1530-0447 J9 PEDIATR RES JI Pediatr. Res. PD AUG PY 2015 VL 78 IS 2 BP 181 EP 189 DI 10.1038/pr.2015.78 PG 9 WC Pediatrics SC Pediatrics GA CN5IH UT WOS:000358462500010 PM 25897540 ER PT J AU Yzer, M Weisman, S Mejia, N Hennrikus, D Choi, K DeSimone, S AF Yzer, Marco Weisman, Susan Mejia, Nicole Hennrikus, Deborah Choi, Kelvin DeSimone, Susan TI Informing Tobacco Cessation Benefit Use Interventions for Unionized Blue-Collar Workers: A Mixed-Methods Reasoned Action Approach SO PREVENTION SCIENCE LA English DT Article DE Tobacco use cessation; Health benefit use; Reasoned action theory; Blue-collar workers; Mixed methods; Intervention design ID SMOKING-CESSATION; UNITED-STATES; PLANNED BEHAVIOR; DESIGN; ADULTS; LEVEL AB Blue-collar workers typically have high rates of tobacco use but low rates of using tobacco cessation resources available through their health benefits. Interventions to motivate blue-collar tobacco users to use effective cessation support are needed. Reasoned action theory is useful in this regard as it can identify the beliefs that shape tobacco cessation benefit use intentions. However, conventional reasoned action research cannot speak to how those beliefs can best be translated into intervention messages. In the present work, we expand the reasoned action approach by adding additional qualitative inquiry to better understand blue-collar smokers' beliefs about cessation benefit use. Across three samples of unionized blue-collar tobacco users, we identified (1) the 35 attitudinal, normative, and control beliefs that represented tobacco users' belief structure about cessation benefit use; (2) instrumental attitude as most important in explaining cessation intention; (3) attitudinal beliefs about treatment options' efficacy, health effects, and monetary implications of using benefits as candidates for message design; (4) multiple interpretations of cessation beliefs (e.g., short and long-term health effects); and (5) clear implications of these interpretations for creative message design. Taken together, the findings demonstrate how a mixed-method reasoned action approach can inform interventions that promote the use of tobacco cessation health benefits. C1 [Yzer, Marco] Univ Minnesota, Sch Journalism & Mass Commun, Minneapolis, MN 55455 USA. [Weisman, Susan; Mejia, Nicole] William Mitchell Coll Law, Publ Hlth Law Ctr, St Paul, MN USA. [Hennrikus, Deborah] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN 55455 USA. [Choi, Kelvin] Natl Inst Minor Hlth & Hlth Dispar, NIH, Div Intramural Res, Bethesda, MD USA. [DeSimone, Susan] DeSimone Inc, Edina, MN USA. RP Yzer, M (reprint author), Univ Minnesota, Sch Journalism & Mass Commun, 110 Murphy Hall,206 Church St SE, Minneapolis, MN 55455 USA. EM mcyzer@umn.edu FU ClearWay Minnesota [RC-2012-0007]; Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health FX Preparation of this article was supported by research grant RC-2012-0007 from ClearWay Minnesota. Dr. Choi's effort on the manuscript was supported by the Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health. The opinions and comments expressed in this manuscript are the authors' own and do not represent those of ClearWay Minnesota or the National Institutes of Health and the US Government. NR 25 TC 0 Z9 0 U1 2 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 EI 1573-6695 J9 PREV SCI JI Prev. Sci. PD AUG PY 2015 VL 16 IS 6 BP 811 EP 821 DI 10.1007/s11121-015-0566-7 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CN1HN UT WOS:000358169500005 PM 25975798 ER PT J AU Berger, VW AF Berger, Vance W. TI Conflicts of Interest, Selective Inertia, and Research Malpractice in Randomized Clinical Trials: An Unholy Trinity SO SCIENCE AND ENGINEERING ETHICS LA English DT Article DE Conflict of interest; Incentives; Selective inertia; Technology transfer ID RUN-IN SELECTION; JADAD SCORE; QUALITY; BIAS; OSTEOARTHRITIS; DESIGNS; KNEE AB Recently a great deal of attention has been paid to conflicts of interest in medical research, and the Institute of Medicine has called for more research into this important area. One research question that has not received sufficient attention concerns the mechanisms of action by which conflicts of interest can result in biased and/or flawed research. What discretion do conflicted researchers have to sway the results one way or the other? We address this issue from the perspective of selective inertia, or an unnatural selection of research methods based on which are most likely to establish the preferred conclusions, rather than on which are most valid. In many cases it is abundantly clear that a method that is not being used in practice is superior to the one that is being used in practice, at least from the perspective of validity, and that it is only inertia, as opposed to any serious suggestion that the incumbent method is superior (or even comparable), that keeps the inferior procedure in use, to the exclusion of the superior one. By focusing on these flawed research methods we can go beyond statements of potential harm from real conflicts of interest, and can more directly assess actual (not potential) harm. C1 [Berger, Vance W.] NCI, Rockville, MD 20850 USA. [Berger, Vance W.] Univ Maryland Baltimore Cty, Biometry Res Grp, NCI, Rockville, MD 20850 USA. RP Berger, VW (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM vance917@gmail.com FU Intramural NIH HHS [Z99 CA999999] NR 40 TC 3 Z9 3 U1 2 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1353-3452 EI 1471-5546 J9 SCI ENG ETHICS JI Sci. Eng. Ethics PD AUG PY 2015 VL 21 IS 4 BP 857 EP 874 DI 10.1007/s11948-014-9576-2 PG 18 WC Ethics; Engineering, Multidisciplinary; History & Philosophy Of Science; Multidisciplinary Sciences; Philosophy SC Social Sciences - Other Topics; Engineering; History & Philosophy of Science; Science & Technology - Other Topics; Philosophy GA CN1II UT WOS:000358171900008 PM 25150846 ER PT J AU Winkler, C Race, B Phillips, K Peterson, K AF Winkler, Clayton W. Race, Brent Phillips, Katie Peterson, Karin E. TI Capillaries in the olfactory bulb but not the cortex are highly susceptible to virus-induced vascular leak and promote viral neuroinvasion SO ACTA NEUROPATHOLOGICA LA English DT Article DE Bunyavirus; Neuroinvasion; Olfactory bulb; Brain capillary endothelial cells; Olfactory sensory neurons; Blood brain barrier ID BLOOD-BRAIN-BARRIER; LA-CROSSE VIRUS; CENTRAL-NERVOUS-SYSTEM; ENDOTHELIAL-CELLS; ENCEPHALITIS-VIRUS; UNITED-STATES; IN-VITRO; INFECTION; ENTRY; MICE AB Viral neuroinvasion is a critical step in the pathogenesis of viral encephalitis. Multiple mechanisms of neuroinvasion have been identified, but their relative contribution to central nervous system (CNS) infection remains unclear for many viruses. In this study, we examined neuroinvasion of the mosquito-borne bunyavirus La Crosse (LACV), the leading cause of pediatric viral encephalitis in the USA. We found that the olfactory bulb (OB) and tract were the initial areas of CNS virus infection in mice. Removal of the OB reduced the incidence of LACV-induced disease demonstrating the importance of this area to neuroinvasion. However, we determined that infection of the OB was not due to axonal transport of virus from olfactory sensory neurons as ablation of these cells did not affect viral pathogenesis. Instead, we found that OB capillaries were compromised allowing leakage of virus-sized particles into the brain. Analysis of OB capillaries demonstrated specific alterations in cytoskeletal and Rho GTPase protein expression not observed in capillaries from other brain areas such as the cortex where leakage did not occur. Collectively, these findings indicate that LACV neuroinvasion occurs through hematogenous spread in specific brain regions where capillaries are prone to virus-induced activation such as the OB. Capillaries in these areas may be "hot spots" that are more susceptible to neuroinvasion not only for LACV, but other neurovirulent viruses as well. C1 [Winkler, Clayton W.; Race, Brent; Phillips, Katie; Peterson, Karin E.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Peterson, K (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM petersonka@niaid.nih.gov RI Peterson, Karin/D-1492-2016 OI Peterson, Karin/0000-0003-4177-7249 FU Division of Intramural Research (DIR), as part of the Nation Institute of Allergy and Infectious Disease (NIAID) within the National Institutes of Health (NIH) FX This study was performed at Rocky Mountain Laboratories (RML) and funded by the Division of Intramural Research (DIR), as part of the Nation Institute of Allergy and Infectious Disease (NIAID) within the National Institutes of Health (NIH). We thank Suzette A. Priola, Byron Caughey, Lara M. Myers, Sonja M. Best, Roger A. Moore, Burhan A. Khan, Tyson A. Woods and Paul F. Policastro for critical reading of the manuscript. Also, we thank Dan Long, Vinod Nair, Nancy Kurtz and Aaron B. Carmody for technical assistance with experiments. Figure preparation and image presentation assistance were provided by Anita Mora and Ryan Kissinger. NR 50 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD AUG PY 2015 VL 130 IS 2 BP 233 EP 245 DI 10.1007/s00401-015-1433-0 PG 13 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA CM9JS UT WOS:000358025300006 PM 25956408 ER PT J AU Longo, VD Antebi, A Bartke, A Barzilai, N Brown-Borg, HM Caruso, C Curiel, TJ de Cabo, R Franceschi, C Gems, D Ingram, DK Johnson, TE Kennedy, BK Kenyon, C Klein, S Kopchick, JJ Lepperdinger, G Madeo, F Mirisola, MG Mitchell, JR Passarino, G Rudolph, KL Sedivy, JM Shadel, GS Sinclair, DA Spindler, SR Suh, Y Vijg, J Vinciguerra, M Fontana, L AF Longo, Valter D. Antebi, Adam Bartke, Andrzej Barzilai, Nir Brown-Borg, Holly M. Caruso, Calogero Curiel, Tyler J. de Cabo, Rafael Franceschi, Claudio Gems, David Ingram, Donald K. Johnson, Thomas E. Kennedy, Brian K. Kenyon, Cynthia Klein, Samuel Kopchick, John J. Lepperdinger, Guenter Madeo, Frank Mirisola, Mario G. Mitchell, James R. Passarino, Giuseppe Rudolph, Karl L. Sedivy, John M. Shadel, Gerald S. Sinclair, David A. Spindler, Stephen R. Suh, Yousin Vijg, Jan Vinciguerra, Manlio Fontana, Luigi TI Interventions to Slow Aging in Humans: Are We Ready? SO AGING CELL LA English DT Review DE aging; anti-aging; centenarians; longevity regulation; dietary restriction; lifespan studies; longevity gene ID LIFE-SPAN EXTENSION; STEM-CELL FUNCTION; GENETICALLY HETEROGENEOUS MICE; HORMONE RECEPTOR ANTAGONISTS; DIETARY-PROTEIN RESTRICTION; TELOMERE-DYSFUNCTIONAL MICE; NORDIHYDROGUAIARETIC ACID; CALORIC RESTRICTION; C-ELEGANS; METABOLIC SYNDROME AB The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in Erice, Italy, on October 8-13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF-I axis; (iii) drugs that inhibit the mTOR-S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro-longevity effects and ability of these interventions to prevent or delay multiple age-related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting. C1 [Longo, Valter D.] Univ So Calif, Davis Sch Gerontol, Los Angeles, CA 90089 USA. [Longo, Valter D.] Univ So Calif, Dept Biol Sci, Longev Inst, Los Angeles, CA 90089 USA. [Longo, Valter D.] FIRC Inst Mol Oncol, IFOM, I-20139 Milan, Italy. [Antebi, Adam] Max Planck Inst Biol Ageing, D-50931 Cologne, Germany. [Bartke, Andrzej] So Illinois Univ, Sch Med, Dept Internal Med, Springfield, IL 62794 USA. [Barzilai, Nir] Albert Einstein Coll Med, Inst Aging Res, Bronx, NY 10461 USA. [Brown-Borg, Holly M.] Univ N Dakota, Sch Med & Hlth Sci, Dept Basic Sci, Grand Forks, ND 58203 USA. [Caruso, Calogero] Univ Palermo, Dept Pathobiol & Med & Forens Biotechnol, Immunosenescence Unit, Palermo, Italy. [Curiel, Tyler J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX USA. [de Cabo, Rafael] NIA, Expt Gerontol Sect, TGB, NIH, Baltimore, MD 21224 USA. [Franceschi, Claudio] DIMES Dept Specialty Diagnost & Expt Med, I-40126 Bologna, Italy. [Gems, David] UCL, Inst Hlth Ageing, Dept Genet Evolut & Environm, London WC1E 6BT, England. [Ingram, Donald K.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutrit Neuroscience & Aging Lab, Baton Rouge, LA 70809 USA. [Johnson, Thomas E.] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. [Kennedy, Brian K.] Buck Inst Res Aging, Novato, CA USA. [Kenyon, Cynthia] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA. [Klein, Samuel] Washington Univ, Sch Med, Ctr Human Nutr, St Louis, MO 63110 USA. [Kopchick, John J.] Ohio Univ, Heritage Coll Osteopath Med, Edison Biotechnol Inst, Dept Biomed Sci, Athens, OH 45701 USA. [Lepperdinger, Guenter] Univ Innsbruck, Inst Alternsforsch, A-6020 Innsbruck, Austria. [Madeo, Frank] Graz Univ, NAWI Graz, Inst Mol Biosci, A-8010 Graz, Austria. [Madeo, Frank] BioTechMed Graz, A-8010 Graz, Austria. [Mirisola, Mario G.] Univ Palermo, Dipartimento Biopatol & Biotecnol Med, I-90133 Palermo, Italy. [Mitchell, James R.] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Passarino, Giuseppe] Univ Calabria, Dept Biol Ecol & Earth Sci, I-87036 Arcavacata Di Rende, Italy. [Rudolph, Karl L.] Fritz Lipmann Inst, Leibniz Inst Age Res, D-07745 Jena, Germany. [Sedivy, John M.] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Labs Mol Med, Providence, RI 02903 USA. [Shadel, Gerald S.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Shadel, Gerald S.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Sinclair, David A.] UNSW Australia, Sch Med Sci, Dept Pharmacol, Lab Ageing Res, Sydney, NSW, Australia. [Sinclair, David A.] Harvard Univ, Sch Med, Dept Genet, Australia Glenn Labs Biol Mech Aging, Boston, MA, Australia. [Spindler, Stephen R.] Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA. [Suh, Yousin] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA. [Suh, Yousin] Albert Einstein Coll Med, Diabet Res & Training Ctr, Dept Med, Bronx, NY 10467 USA. [Suh, Yousin] Albert Einstein Coll Med, Diabet Res & Training Ctr, Inst Aging Res, Bronx, NY 10467 USA. [Vijg, Jan] Albert Einstein Med Ctr, Dept Genet, Bronx, NY USA. [Vinciguerra, Manlio] UCL, Royal Free Hosp, Inst Liver & Digest Hlth, Div Med, London, England. [Fontana, Luigi] Washington Univ, Sch Med, Dept Med, St Louis, MO USA. [Fontana, Luigi] Univ Brescia, Dept Clin & Expt Sci, Brescia, Italy. [Fontana, Luigi] CEINGE Biotecnol Avanzate, Naples, Italy. RP Longo, VD (reprint author), Longev Inst, 3715 Mcclintock Ave, Los Angeles, CA 90089 USA. EM vlongo@usc.edu; lfontana@dom.wustl.edu RI de Cabo, Rafael/J-5230-2016; Bartke, Andzej/D-6640-2017; OI de Cabo, Rafael/0000-0002-3354-2442; Bartke, Andzej/0000-0002-2569-557X; Gems, David/0000-0002-6653-4676; , rafael/0000-0003-2830-5693; Rudolph, Karl Lenhard/0000-0002-4839-2862 FU NIA [R13AG046104] FX The workshop was funded in part by NIA grant R13AG046104. NR 180 TC 65 Z9 66 U1 29 U2 111 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD AUG PY 2015 VL 14 IS 4 BP 497 EP 510 DI 10.1111/acel.12338 PG 14 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA CM8IC UT WOS:000357941900001 PM 25902704 ER PT J AU Robinson, PC Costello, ME Leo, P Bradbury, LA Hollis, K Cortes, A Lee, S Joo, KB Shim, SC Weisman, M Ward, M Zhou, XD Garchon, HJ Chiocchia, G Nossent, J Lie, BA Forre, O Tuomilehto, J Laiho, K Jiang, L Liu, Y Wu, X Elewaut, D Burgos-Vargas, R Gensler, LS Stebbings, S Haroon, N Mulero, J Fernandez-Sueiro, JL Gonzalez-Gay, MA Lopez-Larrea, C Bowness, P Gafney, K Gaston, JSH Gladman, DD Rahman, P Maksymowych, WP Xu, HJ van der Horst-Bruinsma, IE Chou, CT Valle-Onate, R Romero-Sanchez, MC Hansen, IM Pimentel-Santos, FM Inman, RD Martin, J Breban, M Evans, D Reveille, JD Kim, TH Wordsworth, BP Brown, MA AF Robinson, Philip C. Costello, Mary-Ellen Leo, Paul Bradbury, Linda A. Hollis, Kelly Cortes, Adrian Lee, Seunghun Joo, Kyung Bin Shim, Seung-Cheol Weisman, Michael Ward, Michael Zhou, Xiaodong Garchon, Henri-Jean Chiocchia, Gilles Nossent, Johannes Lie, Benedicte A. Forre, Oystein Tuomilehto, Jaakko Laiho, Kari Jiang, Lei Liu, Yu Wu, Xin Elewaut, Dirk Burgos-Vargas, Ruben Gensler, Lianne S. Stebbings, Simon Haroon, Nigil Mulero, Juan Luis Fernandez-Sueiro, Jose Gonzalez-Gay, Miguel A. Lopez-Larrea, Carlos Bowness, Paul Gafney, Karl Gaston, John S. Hill Gladman, Dafna D. Rahman, Proton Maksymowych, Walter P. Xu, Huji van der Horst-Bruinsma, Irene E. Chou, Chung-Tei Valle-Onate, Raphael Consuelo Romero-Sanchez, Maria Hansen, Inger Myrnes Pimentel-Santos, Fernando M. Inman, Robert D. Martin, Javier Breban, Maxime Evans, David Reveille, John D. Kim, Tae-Hwan Wordsworth, B. Paul Brown, Matthew A. TI ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Letter ID DISEASE SUSCEPTIBILITY; LOCI; IDENTIFICATION C1 [Robinson, Philip C.] Univ Queensland, Queensland Brain Inst, Ctr Neurogenet & Stat Genom, Brisbane, Qld 4102, Australia. [Costello, Mary-Ellen; Leo, Paul; Bradbury, Linda A.; Hollis, Kelly; Cortes, Adrian; Evans, David; Brown, Matthew A.] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4102, Australia. [Lee, Seunghun; Joo, Kyung Bin; Kim, Tae-Hwan] Hanyang Univ, Dept Rheumatol, Hosp Rheumat Dis, Seoul 133791, South Korea. [Shim, Seung-Cheol] Eulji Univ Hosp, Div Rheumatol, Dept Med, Taejon, South Korea. [Weisman, Michael] Cedars Sinai Med Ctr, Dept Med Rheumatol, Los Angeles, CA 90048 USA. [Ward, Michael] NIAMSD, NIH, Bethesda, MD 20892 USA. [Zhou, Xiaodong; Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Dept Rheumatol & Clin Immunogenet, Houston, TX 77030 USA. [Garchon, Henri-Jean; Chiocchia, Gilles; Breban, Maxime] Versailles St Quentin Univ, INSERM, U1173, UFR Simone Veil,Lab Excellence INFLAMEX, Versailles, France. [Garchon, Henri-Jean] Ambroise Pare Hosp, AP HP, Div Genet, Paris, France. [Nossent, Johannes] Univ Western Australia, Sch Med, Perth, WA 6009, Australia. [Nossent, Johannes] Sir Charles Gairdner Hosp, Dept Rheumatol, Perth, WA 6000, Australia. [Lie, Benedicte A.] Univ Oslo, Dept Med Genet, Oslo, Norway. [Lie, Benedicte A.] Oslo Univ Hosp, Oslo, Norway. [Lie, Benedicte A.] Oslo Univ Hosp, Dept Immunol, Oslo, Norway. [Forre, Oystein] Univ Hosp Oslo, Dept Rheumatol, Oslo, Norway. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Tuomilehto, Jaakko] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia. [Laiho, Kari] Paijat Hame Cent Hosp, Dept Med, Lahti, Finland. [Jiang, Lei; Liu, Yu; Wu, Xin; Xu, Huji] Second Mil Med Univ, Shanghai Changzheng Hosp, Dept Rheumatol & Immunol, Shanghai, Peoples R China. [Elewaut, Dirk] Ghent Univ Hosp, Dept Rheumatol, Ghent, Belgium. [Elewaut, Dirk] VIB Inflammat Res Ctr, Ghent, Belgium. [Burgos-Vargas, Ruben] Univ Nacl Autonoma Mexico, Fac Med, Dept Rheumatol, Hosp Gen Mexico, Mexico City 04510, DF, Mexico. [Gensler, Lianne S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Stebbings, Simon] Univ Otago, Dept Med, Dunedin Sch Med, Dunedin, New Zealand. [Haroon, Nigil; Inman, Robert D.] Toronto Western Hosp, Div Rheumatol, Toronto, ON M5T 2S8, Canada. [Mulero, Juan] Hosp Puerta Hierro, Dept Rheumatol, Madrid, Spain. [Luis Fernandez-Sueiro, Jose] Inst Invest Biomed A Coruna INIBIC, Complejo Hosp La Coruna, Dept Rheumatol, La Coruna, Spain. [Gonzalez-Gay, Miguel A.] Hosp Marques Valcecilla, Inst Formac & Invest Marques Valcecillas IFIMAV, Dept Rheumatol, Santander, Spain. [Lopez-Larrea, Carlos] Asturias Cent Univ Hosp, Dept Immunol, Oviedo, Spain. [Lopez-Larrea, Carlos] Fdn Renal Inigo Alvarez de Toledo, Madrid, Spain. [Bowness, Paul; Wordsworth, B. Paul] Natl Inst Hlth Res, Oxford Musculoskeletal Biomed Res Unit, Nuffield Orthopaed Ctr, Oxford, England. [Gafney, Karl] Dept Rheumatol, Norwich, Norfolk, England. [Gafney, Karl] Norwich Univ Hosp, Norwich, Norfolk, England. [Gaston, John S. Hill] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England. [Gladman, Dafna D.] Univ Toronto, Div Rheumatol, Toronto, ON, Canada. [Gladman, Dafna D.] Toronto Western Res Inst, Toronto, ON, Canada. [Gladman, Dafna D.] Univ Hlth Network, Psoriat Arthrit Program, Toronto, ON, Canada. [Rahman, Proton] Mem Univ Newfoundland, St John, NF, Canada. [Maksymowych, Walter P.] Univ Alberta, Dept Med, Edmonton, AB, Canada. [van der Horst-Bruinsma, Irene E.] Vrije Univ Amsterdam Med Ctr, Dept Rheumatol, Amsterdam, Netherlands. [Chou, Chung-Tei] Taipei Vet Gen Hosp, Dept Med, Div Allergy Immunol Rheumatol, Taipei, Taiwan. [Chou, Chung-Tei] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. [Valle-Onate, Raphael; Consuelo Romero-Sanchez, Maria] Univ Militar Nueva Granada, SpA Grp Hosp Militar, Bogota, Colombia. [Hansen, Inger Myrnes] Helgelandssykehuset, Mo I Rana, Norway. [Pimentel-Santos, Fernando M.] Univ Nova Lisboa, Fac Ciencias Med, Chron Dis Res Ctr CEDOC, P-1200 Lisbon, Portugal. [Martin, Javier] Consejo Super Invest Cientif, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain. [Breban, Maxime] Ambroise Pare Hosp, AP HP, Div Rheumatol, Paris, France. [Evans, David] Univ Bristol, MRC, Integrat Epidemiol Unit, Bristol BS8 1TH, Avon, England. [Evans, David] Univ Bristol, Sch Social & Community Med, Bristol BS8 1TH, Avon, England. RP Brown, MA (reprint author), Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4102, Australia. EM matt.brown@uq.edu.au RI Robinson, Philip/B-8319-2011; Martin, Javier/B-8141-2008; chiocchia, gilles/F-6287-2013; Elewaut, Dirk/K-6831-2014; Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013; Franco-Hurtado, Fernando/E-5599-2017; OI Robinson, Philip/0000-0002-3156-3418; chiocchia, gilles/0000-0001-9973-0940; Franco-Hurtado, Fernando/0000-0001-5775-0150; bowness, paul/0000-0003-4597-0484 FU Arthritis Research UK [18797, 19356, 19536]; Medical Research Council [MC_UU_12013/4]; NIAMS NIH HHS [P01 AR052915, P01-AR052915] NR 10 TC 8 Z9 8 U1 1 U2 15 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 2015 VL 74 IS 8 BP 1627 EP U209 DI 10.1136/annrheumdis-2015-207416 PG 3 WC Rheumatology SC Rheumatology GA CM4VQ UT WOS:000357683600034 PM 25917849 ER PT J AU Shiramizu, B Goldman, S Smith, L Agsalda-Garcia, M Galardy, P Perkins, SL Frazer, JK Sanger, W Anderson, JR Gross, TG Weinstein, H Harrison, L Barth, MJ Mussolin, L Cairo, MS AF Shiramizu, Bruce Goldman, Stanton Smith, Lynette Agsalda-Garcia, Melissa Galardy, Paul Perkins, Sherrie L. Frazer, J. Kimble Sanger, Warren Anderson, James R. Gross, Thomas G. Weinstein, Howard Harrison, Lauren Barth, Matthew J. Mussolin, Lara Cairo, Mitchell S. TI Impact of persistent minimal residual disease post-consolidation therapy in children and adolescents with advanced Burkitt leukaemia: a Children's Oncology Group Pilot Study Report SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE children; central nervous system; leukaemia ID ACUTE-LYMPHOBLASTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; RISK; CHEMOTHERAPY; CHILDHOOD; RITUXIMAB; STAGE AB Patient-specific primers from 10 children/adolescents with Burkitt leukaemia (BL) +/- central nervous system disease who were treated with French-British-American/Lymphome Malins de Burkitt 96 C1 plus rituximab were developed from diagnostic blood/bone marrow. Minimal residual disease (MRD) was assessed by real-time polymerase chain reaction at the end of induction (EOI) and consolidation (EOC). Seventy per cent (7/10) and 71% (5/7) were MRD-positive at EOI and EOC, respectively, with no disease recurrences. MRD after induction and consolidation did not predict relapse and subsequent therapy appeared to eliminate MRD. Thus, assessing MRD at a later time point is warranted in future trials to determine its clinical significance. C1 [Shiramizu, Bruce; Agsalda-Garcia, Melissa] Univ Hawaii, Div Pediat Hematol Oncol, Honolulu, HI 96822 USA. [Goldman, Stanton] Med City Childrens Hosp, Div Pediat Hematol Oncol, Dallas, TX USA. [Smith, Lynette; Anderson, James R.] Univ Nebraska, Coll Publ Hlth, Dept Biostat, Omaha, NE 68182 USA. [Galardy, Paul] Mayo Clin, Div Pediat Hematol Oncol, Rochester, MN USA. [Perkins, Sherrie L.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Frazer, J. Kimble] Univ Oklahoma, Hlth Sci Ctr, Sect Pediat Hematol Oncol, Oklahoma City, OK USA. [Sanger, Warren] Univ Nebraska Med Ctr, Dept Cytogenet, Omaha, NE USA. [Gross, Thomas G.] NCI, Ctr Global Hlth, NIH, DHHS, Rockville, MD USA. [Weinstein, Howard] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Pediat Hematol Oncol, Boston, MA USA. [Harrison, Lauren; Cairo, Mitchell S.] New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA. [Barth, Matthew J.] Roswell Pk Canc Inst, Dept Pediat, Buffalo, NY 14263 USA. [Mussolin, Lara] Univ Padua, Fdn Citta Speranza, Ist Ric Pediat, Padua, Italy. [Cairo, Mitchell S.] New York Med Coll, Dept Med, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. RP Shiramizu, B (reprint author), Univ Hawaii Manoa, John A Burns Sch Med, Dept Pediat, Pediat Hematol Oncol, 651 Ilalo St, Honolulu, HI 96813 USA. EM bshirami@hawaii.edu OI Frazer, John Kimble/0000-0003-2936-2817 FU Division of Cancer Treatment, National Cancer Institute; National Institutes of Health; Department of Health and Human Services (COG) [CA98543-09, CA98413-09]; Pediatric Cancer Research Foundation [U54MD007584]; Thrasher Research Fund; St. Baldrick's Foundation FX The authors would like to acknowledge Angelo Rosolen, MD, PhD, a leader in childhood and adolescent NHL MRD studies who passed away during the past year. The study was supported by Division of Cancer Treatment, National Cancer Institute, and National Institutes of Health, Department of Health and Human Services (COG) (CA98543-09 and CA98413-09), Pediatric Cancer Research Foundation (M.S.C), U54MD007584 (B.S.), Thrasher Research Fund (B.S.), St. Baldrick's Foundation (B.S.) NR 11 TC 2 Z9 2 U1 0 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 2015 VL 170 IS 3 BP 367 EP 371 DI 10.1111/bjh.13443 PG 5 WC Hematology SC Hematology GA CM9DS UT WOS:000358007400007 PM 25858645 ER PT J AU Medina-Echeverz, J Eggert, T Han, M Greten, T AF Medina-Echeverz, Jose Eggert, Tobias Han, Miaojun Greten, Tim F. TI Hepatic myeloid-derived suppressor cells in cancer SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Review DE Liver; MDSC; Immune suppression; HCC ID TUMOR-BEARING MICE; HEPATOCELLULAR-CARCINOMA PATIENTS; REGULATORY T-CELLS; COLORECTAL-CANCER; KINASE INHIBITOR; LIVER METASTASIS; STELLATE CELLS; MICROENVIRONMENT; ACCUMULATION; INFLAMMATION AB Myeloid-derived suppressor cells are key components of tumor-induced immune suppression. They are composed of a heterogeneous population of immature myeloid cells that abrogates innate and adaptive immune responses. Myeloid-derived suppressor cells accumulate not only in peripheral blood, secondary lymphoid organs and tumors, but also in the liver in preclinical tumor models and in hepatocellular carcinoma patients. The liver, continuously exposed to food and microbial antigens from the intestine, avoids autoimmune damage through the use of specialized mechanisms of immune tolerance. In the context of cancer, myeloid-derived suppressor cells profit the intrinsic tolerogenic properties of the liver to accumulate and exert various immune-suppressive and tumor-promoting mechanisms which go from inducing immune cell dysfunction to supporting the generation of liver metastases. In this review, we seek to describe the phenotype, function, accumulation and therapeutic targeting of hepatic myeloid-derived suppressor cells both in preclinical settings and in the context of human hepatocellular carcinoma. C1 [Medina-Echeverz, Jose; Eggert, Tobias; Han, Miaojun; Greten, Tim F.] Ctr Canc Res, NIH, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Bethesda, MD 20892 USA. RP Greten, T (reprint author), Ctr Canc Res, NIH, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, NIH NCI CCR Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. EM gretentf@mail.nih.gov FU National Cancer Institute, NIH FX We especially thank Joselyn Natasha Allen for artwork design and the NIH Fellows Editorial Board for editorial assistance. This work was supported by the Intramural Research Program of the National Cancer Institute, NIH. NR 62 TC 3 Z9 3 U1 2 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD AUG PY 2015 VL 64 IS 8 BP 931 EP 940 DI 10.1007/s00262-015-1736-y PG 10 WC Oncology; Immunology SC Oncology; Immunology GA CN0ER UT WOS:000358087400001 PM 26133122 ER PT J AU Baker, SG Kramer, BS AF Baker, Stuart G. Kramer, Barnett S. TI Evaluating surrogate endpoints, prognostic markers, and predictive markers: Some simple themes SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT 7th Annual Conference on Statistical Issues in Clinical Trials - The Use of Biomarkers and Surrogate Endpoints in Clinical Trials CY APR, 2014 CL Univ Penn, Philadelphia, PA HO Univ Penn DE Decision analysis; predictive marker; principal stratification; prognostic marker; randomized trial; relative utility curve; subgroup; treatment selection marker ID ADVANCED COLORECTAL-CANCER; RELATIVE UTILITY CURVES; CLINICAL-TRIAL DESIGN; RANDOMIZED-TRIALS; PATIENT TREATMENT; PREVENTION TRIAL; RISK PREDICTION; BREAST-CANCER; TREATMENT-SELECTION; TREATMENT DECISIONS AB Background: A surrogate endpoint is an endpoint observed earlier than the true endpoint (a health outcome) that is used to draw conclusions about the effect of treatment on the unobserved true endpoint. A prognostic marker is a marker for predicting the risk of an event given a control treatment; it informs treatment decisions when there is information on anticipated benefits and harms of a new treatment applied to persons at high risk. A predictive marker is a marker for predicting the effect of treatment on outcome in a subgroup of patients or study participants; it provides more rigorous information for treatment selection than a prognostic marker when it is based on estimated treatment effects in a randomized trial. Methods: We organized our discussion around a different theme for each topic. Results: Fundamentally an extrapolation refers to the non-statistical considerations and assumptions needed when using surrogate endpoints to evaluate a new treatment. Decision analysis to the rescue refers to use the use of decision analysis to evaluate an additional prognostic marker because it is not possible to choose between purely statistical measures of marker performance. The appeal of simplicity refers to a straightforward and efficient use of a single randomized trial to evaluate overall treatment effect and treatment effect within subgroups using predictive markers. Conclusion: The simple themes provide a general guideline for evaluation of surrogate endpoints, prognostic markers, and predictive markers. C1 [Baker, Stuart G.; Kramer, Barnett S.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Canc Prevent Div, 9609 Med Ctr Dr,5E638 MSC 9789, Bethesda, MD 20892 USA. EM sb16i@nih.gov FU National Institutes of Health FX This research was supported by the National Institutes of Health. NR 74 TC 4 Z9 4 U1 2 U2 5 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 2015 VL 12 IS 4 BP 299 EP 308 DI 10.1177/1740774514557725 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CN0DA UT WOS:000358081800002 PM 25385934 ER PT J AU Daniels, M Frangakis, C Charu, V Ghosh, D Mietlowski, WL Kumm, E Joffe, M Taylor, J Wang, SB Baker, S Weisberg, H Hu, C Ellenberg, S AF Daniels, Michael Frangakis, Constantine Charu, Vivek Ghosh, Debashis Mietlowski, William L. Kumm, Elizabeth Joffe, Marshall Taylor, Jeremy Wang, Songbai Baker, Stuart Weisberg, Herb Hu, Chen Ellenberg, Susan TI University of Pennsylvania 7th annual conference on statistical issues in clinical trials: Current issues regarding the use of biomarkers and surrogate endpoints in clinical trials (morning panel discussion) SO CLINICAL TRIALS LA English DT Editorial Material C1 [Daniels, Michael] Univ Texas Austin, Austin, TX 78712 USA. [Frangakis, Constantine; Charu, Vivek] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Ghosh, Debashis] Univ Colorado, Boulder, CO 80309 USA. [Kumm, Elizabeth] I3Statprobe, Aalborg, Denmark. [Joffe, Marshall; Ellenberg, Susan] Univ Penn, Philadelphia, PA 19104 USA. [Taylor, Jeremy] Univ Michigan, Ann Arbor, MI 48109 USA. [Wang, Songbai] Janssen Diagnost, Raritan, NJ USA. [Baker, Stuart] NCI, Bethesda, MD 20892 USA. [Hu, Chen] Amer Coll Radiol, Reston, VA USA. RP Daniels, M (reprint author), Univ Texas Austin, Austin, TX 78712 USA. FU NCATS NIH HHS [UL1 TR001079]; NIAID NIH HHS [R01 AI102710]; NIGMS NIH HHS [T32 GM007309] NR 20 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2015 VL 12 IS 4 BP 323 EP 332 DI 10.1177/1740774515590090 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CN0DA UT WOS:000358081800005 PM 26062596 ER PT J AU Hung, HMJ Inoue, L Pickering, E Zee, J Kattan, M Shaw, P Weisberg, H Huang, Y Baker, S Mietlowski, WL Wang, SB Ellenberg, S Taylor, J AF Hung, H. M. James Inoue, Lurdes Pickering, Eve Zee, Jarcy Kattan, Michael Shaw, Pamela Weisberg, Herbert Huang, Ying Baker, Stuart Mietlowski, William L. Wang, Songbai Ellenberg, Susan Taylor, Jeremy TI University of Pennsylvania 7th annual conference on statistical issues in clinical trials: Current issues regarding the use of biomarkers and surrogate endpoints in clinical trials (afternoon panel discussion session) SO CLINICAL TRIALS LA English DT Editorial Material C1 [Hung, H. M. James] US FDA, Rockville, MD 20857 USA. [Inoue, Lurdes] Univ Washington, Seattle, WA 98195 USA. [Pickering, Eve] Pfizer Inc, New York, NY USA. [Zee, Jarcy; Shaw, Pamela; Ellenberg, Susan] Univ Penn, Philadelphia, PA 19104 USA. [Kattan, Michael] Cleveland Clin, Cleveland, OH USA. [Huang, Ying] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Baker, Stuart] NCI, Bethesda, MD 20892 USA. [Taylor, Jeremy] Univ Michigan, Ann Arbor, MI 48109 USA. RP Hung, HMJ (reprint author), US FDA, Rockville, MD 20857 USA. NR 12 TC 0 Z9 0 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 2015 VL 12 IS 4 BP 365 EP 373 DI 10.1177/1740774515590089 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CN0DA UT WOS:000358081800010 PM 26178573 ER PT J AU Dawson, L Garner, S Anude, C Ndebele, P Karuna, S Holt, R Broder, G Handibode, J Hammer, SM Sobieszczyk, ME AF Dawson, Liza Garner, Sam Anude, Chuka Ndebele, Paul Karuna, Shelly Holt, Renee Broder, Gail Handibode, Jessica Hammer, Scott M. Sobieszczyk, Magdalena E. CA NIAID HIV Vaccine Trials Network TI Testing the waters: Ethical considerations for including PrEP in a phase IIb HIV vaccine efficacy trial SO CLINICAL TRIALS LA English DT Article DE HIV vaccine trials; ethics; standard of prevention; HIV prevention; clinical trial design ID HUMAN-IMMUNODEFICIENCY-VIRUS; POSTEXPOSURE PROPHYLAXIS; COST-EFFECTIVENESS; SOUTH-AFRICA; DOUBLE-BLIND; PREVENTION; INFECTION; EXPERIENCES; EXPOSURE; WOMEN AB Background: The field of HIV prevention research has recently experienced some mixed results in efficacy trials of pre-exposure prophylaxis, vaginal microbicides, and HIV vaccines. While there have been positive trial results in some studies, in the near term, no single method will be sufficient to quell the epidemic. Improved HIV prevention methods, choices among methods, and coverage for all at-risk populations will be needed. The emergence of partially effective prevention methods that are not uniformly available raises complex ethical and scientific questions regarding the design of ongoing prevention trials. Methods: We present here an ethical analysis regarding inclusion of pre-exposure prophylaxis in an ongoing phase IIb vaccine efficacy trial, HVTN 505. This is the first large vaccine efficacy trial to address the issue of pre-exposure prophylaxis, and the decisions made by the protocol team were informed by extensive stakeholder consultations. The key ethical concerns are analyzed here, and the process of stakeholder engagement and decision-making described. Discussion: This discussion and analysis will be useful as current and future research teams grapple with ethical and scientific study design questions emerging with the rapidly expanding evidence base for HIV prevention. C1 [Dawson, Liza] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Garner, Sam] Henry M Jackson Fdn, Bethesda, MD USA. [Anude, Chuka] AstraZeneca, Gaithersburg, MD USA. [Ndebele, Paul] Med Res Council Zimbabwe, Harare, Zimbabwe. [Karuna, Shelly; Broder, Gail] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Holt, Renee] PATH, Seattle, WA USA. [Handibode, Jessica] AVAC Global Advocacy HIV Prevent, New York, NY USA. [Hammer, Scott M.; Sobieszczyk, Magdalena E.] Columbia Univ, Dept Med, New York, NY USA. RP Dawson, L (reprint author), NIAID, Div Aids, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dawsonl@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases of the NIH [UM1AI68614, UM1AI068618, UM1AI68635, UM1AI069496, UM1AI69452, UM1AI069412, UM1AI0 69470, UM1AI069481, UM1AI069439, UM1AI069534, UM1 AI069511, UM1AI069554, UM1AI069418, UM1Al069532, UM1AI069424, UM1AI069501, UM1AI036219, HHSN272200800014C]; Columbia University's Clinical and Translational Science Award from the National Center for Advancing Translational Sciences, NIH [UL1TR000040]; NIH Intramural Research Program, Emory Center for AIDS Research [P30AI50409]; Harvard Center for AIDS Research [P30AI06354]; Baylor-University of Texas Houston Center for AIDS Research [UM1AI036211]; Colorado Clinical Translational Science Institute [TR00 0154]; National Center for Advancing Translational Science, NIH [UL1TR000451] FX No specific funding was provided for the preparation of this article. The HVTN 505 clinical trial was supported by grants from the National Institute of Allergy and Infectious Diseases of the NIH (UM1AI68614, UM1AI068618, UM1AI68635, UM1AI069496, UM1AI69452, UM1AI069412, UM1AI0 69470, UM1AI069481, UM1AI069439, UM1AI069534, UM1 AI069511, UM1AI069554, UM1AI069418, UM1Al069532, UM1AI069424, UM1AI069501, and UM1AI036219 and contract HHSN272200800014C), Columbia University's Clinical and Translational Science Award from the National Center for Advancing Translational Sciences, NIH (UL1TR000040), the NIH Intramural Research Program, Emory Center for AIDS Research (P30AI50409), the Harvard Center for AIDS Research (P30AI06354), the Baylor-University of Texas Houston Center for AIDS Research (UM1AI036211), the Colorado Clinical Translational Science Institute (TR00 0154), and the National Center for Advancing Translational Science, NIH (UL1TR000451). NR 33 TC 2 Z9 2 U1 2 U2 9 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 2015 VL 12 IS 4 BP 394 EP 402 DI 10.1177/1740774515579165 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CN0DA UT WOS:000358081800013 PM 25851992 ER PT J AU Kim, SYH Wilson, R De Vries, R Kim, HM Holloway, RG Kieburtz, K AF Kim, Scott Y. H. Wilson, Renee De Vries, Raymond Kim, H. Myra Holloway, Robert G. Kieburtz, Karl TI "It is not guaranteed that you will benefit": True but misleading? SO CLINICAL TRIALS LA English DT Article DE Informed consent; benefit statements; early-phase trials; research ethics ID PHASE-1 ONCOLOGY TRIALS; INFORMED-CONSENT; CLINICAL-TRIALS AB Background: Participants of early-phase intervention trials for serious conditions provide high estimates of likelihood of benefit, even when informed consent forms do not promise such benefits. However, some technically correct, negatively stated benefits statementssuch as it is not guaranteed that you will benefitcould play a role in raising expectations of benefit because in ordinary English usage such statements denote a likely but not a certain-to-occur event. Methods: An experimental online survey of 584 English-speaking adults recruited online. They were randomized to receive one of two benefit statements (not guaranteed vs some but very small chance), using a hypothetical scenario of an early-phase clinical trial testing an intervention to treat amyotrophic lateral sclerosis. We assessed respondents' willingness to consider participating in the amyotrophic lateral sclerosis trial, their estimates of likelihood of benefit, and their explanations for those estimates. Results: The two arms did not differ in willingness to consider participation in the amyotrophic lateral sclerosis trial. Those receiving not guaranteed benefit statement had higher estimates of benefit than those receiving some but very small chance statement (35.7% (standard deviation 20.2) vs 28.3% (standard deviation 22.0), p<0.0001). A total of 43% of all respondents chose expressions of positive sentiment (hope and need to stay positive) as explanations of their estimates; these respondents' estimates of benefit were higher than others but similar between the two arms. The effect of benefit statements was greatest among those who chose Those are just the facts as the explanation for their estimate (31.0% (standard deviation 22.4%) in not guaranteed arm vs 18.9% (standard deviation 21.0%) in comparison arm, p=0.008). Conclusion: The use of not guaranteed language in benefit statements, when compared to small but very small chance language, appeared to increase the perception of likelihood of benefit of entering an early-phase trial, especially among those who view their estimates of benefits as facts. Such no guarantee benefit statements may be misleading and should not be used in informed consent forms. C1 [Kim, Scott Y. H.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Kim, Scott Y. H.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Wilson, Renee] Univ Rochester, Ctr Human Expt Therapeut, Rochester, NY USA. [De Vries, Raymond] Univ Michigan, Ctr Bioeth & Social Sci Med, Ann Arbor, MI 48109 USA. [De Vries, Raymond] Univ Michigan, Dept Med Educ, Ann Arbor, MI 48109 USA. [Holloway, Robert G.] Univ Rochester, Dept Neurol, Rochester, NY USA. [Kieburtz, Karl] Univ Rochester, Clin & Translat Sci Inst, Dept Environm Med, Rochester, NY USA. [Kieburtz, Karl] Univ Rochester, Clin & Translat Sci Inst, Dept Publ Hlth Sci, Rochester, NY USA. RP Kim, SYH (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. EM scott.kim@nih.gov FU National Institute for Neurological Disorders and Stroke [R01-NS062770]; CTSA from the National Center for Research Resources [UL1 RR024160]; National Center for Advancing Translational Sciences of the National Institutes of Health; Intramural Research Program of the NIH, Clinical Center Department of Bioethics 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 of the National Institutes of Health; and in part by the Intramural Research Program of the NIH, Clinical Center Department of Bioethics. NR 14 TC 3 Z9 3 U1 1 U2 4 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 2015 VL 12 IS 4 BP 424 EP 429 DI 10.1177/1740774515585120 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CN0DA UT WOS:000358081800017 PM 25963311 ER PT J AU Vergano-Vera, E Diaz-Guerra, E Rodriguez-Traver, E Mendez-Gomez, HR Solis, O Pignatelli, J Pickel, J Lee, SH Moratalla, R Vicario-Abejon, C AF Vergano-Vera, Eva Diaz-Guerra, Eva Rodriguez-Traver, Eva Mendez-Gomez, Hector R. Solis, Oscar Pignatelli, Jaime Pickel, James Lee, Sang-Hun Moratalla, Rosario Vicario-Abejon, Carlos TI Nurr1 blocks the mitogenic effect of FGF-2 and EGF, inducing olfactory bulb neural stem cells to adopt dopaminergic and dopaminergic-GABAergic neuronal phenotypes SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE transcription factors; neural stem cells; dopaminergic neurons; GABAergic neurons; Fgfr2 ID ORPHAN NUCLEAR RECEPTOR; FIBROBLAST-GROWTH-FACTOR; EMBRYONIC STEM; TYROSINE-HYDROXYLASE; PARKINSONS-DISEASE; IN-VITRO; HIPPOCAMPAL-NEURONS; VENTRAL MIDBRAIN; PRECURSOR CELLS; L-DOPA AB The transcription factor Nurr1 is expressed in the mouse olfactory bulb (OB), although it remains unknown whether it influences the generation of dopaminergic neurons (DA) (DA neurons) in cells isolated from this brain region. We found that expressing Nurr1 in proliferating olfactory bulb stem cells (OBSCs) produces a marked inhibition of cell proliferation and the generation of immature neurons immunoreactive for tyrosine hydroxylase (TH) concomitant with marked upregulations of Th, Dat, Gad, and Fgfr2 transcripts. In long-term cultures, these cells develop neurochemical and synaptic markers of mature-like mesencephalic DA neurons, expressing GIRK2, VMAT2, DAT, calretinin, calbindin, synapsin-I, and SV2. Concurring with the increase in both Th and Gad expression, a subpopulation of induced cells was both TH- and GAD-immunoreactive indicating that they are dopaminergic-GABAergic neurons. Indeed, these cells could mature to express VGAT, suggesting they can uptake and store GABA in vesicles. Remarkably, the dopamine D1 receptor agonist SKF-38393 induced c-Fos in TH+ cells and dopamine release was detected in these cultures under basal and KCl-evoked conditions. By contrast, cotransducing the Neurogenin2 and Nurr1 transcription factors produced a significant decrease in the number of TH-positive neurons. Our results indicate that Nurr1 overexpression in OBSCs induces the formation of two populations of mature dopaminergic neurons with features of the ventral mesencephalon or of the OB, capable of responding to functional dopaminergic stimuli and of releasing dopamine. They also suggest that the accumulation of Fgfr2 by Nurr1 in OBSCs may be involved in the generation of DA neurons. (c) 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 823-841, 2015 C1 [Vergano-Vera, Eva; Diaz-Guerra, Eva; Rodriguez-Traver, Eva; Mendez-Gomez, Hector R.; Solis, Oscar; Pignatelli, Jaime; Moratalla, Rosario; Vicario-Abejon, Carlos] CSIC, Inst Cajal, Madrid, Spain. [Vergano-Vera, Eva; Diaz-Guerra, Eva; Rodriguez-Traver, Eva; Mendez-Gomez, Hector R.; Solis, Oscar; Pignatelli, Jaime; Moratalla, Rosario; Vicario-Abejon, Carlos] CIBERNED, Madrid, Spain. [Pickel, James] NIMH, Transgen Core, NIH, Bethesda, MD 20892 USA. [Lee, Sang-Hun] Hanyang Univ, Coll Med, Dept Biochem & Mol Biol, Seoul 133791, South Korea. RP Vicario-Abejon, C (reprint author), CSIC, Inst Cajal, Madrid, Spain. EM cvicario@cajal.csic.es RI Pignatelli, Jaime/L-3122-2014; Diaz Guerra, Eva/F-8048-2016; Rodriguez-Traver, Eva/F-8636-2016; Vicario-Abejon, Carlos/G-2814-2016; Solis, Oscar/H-9170-2015; OI Pignatelli, Jaime/0000-0002-8431-2241; Diaz Guerra, Eva/0000-0003-4866-5880; Rodriguez-Traver, Eva/0000-0002-7414-7959; Solis, Oscar/0000-0002-8285-5891; Moratalla, Rosario/0000-0002-7623-8010 FU Spanish Ministerio de Economia y Competitividad (MINECO) [BFU2010-1963, SAF2013-47596-R]; Spanish Ministerio de Economia y Competitividad [BFU2010-20664, SAF2013-48532-R]; Ministerio de Sanidad Politica Social e Igualdad (Instituto de Salud Carlos III, ISCIII) [CIBERNED CB06/05/065, CIBERNED CB06/05/0055]; Comunidad de Madrid (CM) [S2011/BMD-2336]; CM; CONACYT (Gobierno de Mexico); MINECO FX Contract grant sponsor: Spanish Ministerio de Economia y Competitividad (MINECO: BFU2010-1963 and SAF2013-47596-R) (to C.V.-A.).; Contract grant sponsor: Spanish Ministerio de Economia y Competitividad (BFU2010-20664 and SAF2013-48532-R) (to R.M.).; Contract grant sponsor: Ministerio de Sanidad Politica Social e Igualdad (Instituto de Salud Carlos III, ISCIII: CIBERNED CB06/05/065) (to C.V.-A.).; Contract grant sponsor: Ministerio de Sanidad Politica Social e Igualdad (Instituto de Salud Carlos III, ISCIII: CIBERNED CB06/05/0055) (to R.M.).; Contract grant sponsor: Comunidad de Madrid (CM: S2011/BMD-2336) (to R.M. and C.V.-A.).; Contract grant sponsor: CM, CONACYT (Gobierno de Mexico), and MINECO (to H.R.M.-G., O.S., and E.R.-T.). NR 77 TC 6 Z9 7 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8451 EI 1932-846X J9 DEV NEUROBIOL JI Dev. Neurobiol. PD AUG PY 2015 VL 75 IS 8 BP 823 EP 841 DI 10.1002/dneu.22251 PG 19 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA CN0TF UT WOS:000358125800003 PM 25447275 ER PT J AU Krauze, AV Myrehaug, SD Chang, MG Holdford, DJ Smith, S Shih, J Tofilon, PJ Fine, HA Camphausen, K AF Krauze, Andra V. Myrehaug, Sten D. Chang, Michael G. Holdford, Diane J. Smith, Sharon Shih, Joanna Tofilon, Philip J. Fine, Howard A. Camphausen, Kevin TI A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID NEWLY-DIAGNOSED GLIOBLASTOMA; ADJUVANT TEMOZOLOMIDE; PLUS TEMOZOLOMIDE; MALIGNANT GLIOMA; RANDOMIZED-TRIAL; MULTIFORME; RADIOTHERAPY; SURVIVAL; CONCOMITANT; ERLOTINIB AB Purpose: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. Conclusions: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study. Published by Elsevier Inc. C1 [Krauze, Andra V.; Smith, Sharon; Shih, Joanna; Tofilon, Philip J.; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Myrehaug, Sten D.] Lakeridge Hlth Durham Reg Canc Ctr, Dept Radiat Oncol, Oshawa, ON, Canada. [Chang, Michael G.; Holdford, Diane J.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Fine, Howard A.] NYU, Langone Med Ctr, New York, NY USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, CRC, 10 Ctr Dr,Bldg 10,Rm B2-3561, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov FU National Institutes of Health/National Cancer Institute FX This work was supported in part by the intramural program of the National Institutes of Health/National Cancer Institute. NR 35 TC 19 Z9 19 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2015 VL 92 IS 5 BP 986 EP 992 DI 10.1016/j.ijrobp.2015.04.038 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CM7TY UT WOS:000357900600017 PM 26194676 ER PT J AU Gane, EJ Lim, YS Gordon, SC Visvanathan, K Sicard, E Fedorak, RN Roberts, S Massetto, B Ye, Z Pflanz, S Garrison, KL Gaggar, A Subramanian, GM McHutchison, JG Kottilil, S Freilich, B Coffin, CS Cheng, W Kim, YJ AF Gane, Edward J. Lim, Young-Suk Gordon, Stuart C. Visvanathan, Kumar Sicard, Eric Fedorak, Richard N. Roberts, Stuart Massetto, Benedetta Ye, Zhishen Pflanz, Stefan Garrison, Kimberly L. Gaggar, Anuj Subramanian, G. Mani McHutchison, John G. Kottilil, Shyamasundaran Freilich, Bradley Coffin, Carla S. Cheng, Wendy Kim, Yoon Jun TI The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection SO JOURNAL OF HEPATOLOGY LA English DT Article DE Hepatitis B virus; HBsAg; Immune response; TLR ID INTERFERON-ALPHA THERAPY; SEX-SPECIFIC ASSOCIATION; T-CELLS; TLR7; IFN; POLYMORPHISMS; CHEMOKINES; ANALOGS; INNATE; LIVER AB Background & Aims: GS-9620 is an oral agonist of toll-like receptor 7, a pattern-recognition receptor whose activation results in innate and adaptive immune stimulation. We evaluated the safety, pharmacokinetics, and pharmacodynamics of GS-9620 in patients with chronic hepatitis B. Methods: In two double-blind, phase 1b trials of identical design, 49 treatment-naive and 51 virologically suppressed patients were randomized 5: 1 to receive GS-9620 (at doses of 0.3 mg, 1 mg, 2 mg, 4 mg) or placebo as a single dose or as two doses seven days apart. Pharmacodynamic assessment included evaluation of peripheral mRNA expression of interferon-stimulated gene 15 (ISG15), serum interferon gamma-induced protein 10 and serum interferon (IFN)-alpha. Results: Overall, 74% of patients were male and 75% were HBeAg negative at baseline. No subject discontinued treatment due to adverse events. Fifty-eight percent experienced >= 1 adverse event, all of which were mild to moderate in severity. The most common adverse event was headache. No clinically significant changes in HBsAg or HBV DNA levels were observed. Overall, a transient dose-dependent induction of peripheral ISG15 gene expression was observed peaking within 48 hours of dosing followed by return to baseline levels within seven days. Higher GS-9620 dose, HBeAg positive status, and low HBsAg level at baseline were independently associated with greater probability of ISG15 response. Most patients (88%) did not show detectable levels of serum IFN-alpha at any time point. Conclusions: Oral GS-9620 was safe, well tolerated, and associated with induction of peripheral ISG15 production in the absence of significant systemic IFN-alpha levels or related symptoms. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Gane, Edward J.] Auckland City Hosp, New Zealand Liver Transplant Unit, Auckland, New Zealand. [Gane, Edward J.] Univ Auckland, Auckland 1, New Zealand. [Lim, Young-Suk] Univ Ulsan, Coll Med, Asan Med Ctr, Seoul, South Korea. [Gordon, Stuart C.] Henry Ford Hlth Syst, Detroit, MI USA. [Visvanathan, Kumar] Univ Melbourne, Parkville, Vic 3052, Australia. [Sicard, Eric] Algorithme Pharma, Montreal, PQ, Canada. [Fedorak, Richard N.] Univ Alberta, Edmonton, AB, Canada. [Roberts, Stuart] Alfred Hlth, Melbourne, Vic, Australia. [Massetto, Benedetta; Ye, Zhishen; Pflanz, Stefan; Garrison, Kimberly L.; Gaggar, Anuj; Subramanian, G. Mani; McHutchison, John G.] Gilead Sci Inc, Foster City, CA 94404 USA. [Kottilil, Shyamasundaran] NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Freilich, Bradley] Kansas City Gastroenterol & Hepatol, Kansas City, MO USA. [Coffin, Carla S.] Univ Calgary, Calgary, AB, Canada. [Cheng, Wendy] Royal Perth Hosp, Perth, WA 6001, Australia. [Kim, Yoon Jun] Seoul Natl Univ, Coll Med, Seoul, South Korea. RP Gane, EJ (reprint author), Auckland City Hosp, New Zealand Liver Transplant Unit, Private Bag 1142, Auckland, New Zealand. EM edgane@adhb.govt.nz OI Fedorak, Richard/0000-0002-7382-0080 FU Gilead Sciences, Inc., Foster City, California, USA FX This study was supported by Gilead Sciences, Inc., Foster City, California, USA. NR 34 TC 33 Z9 37 U1 1 U2 14 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 2015 VL 63 IS 2 BP 320 EP 328 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CM8YX UT WOS:000357991700008 PM 25733157 ER PT J AU Mellinger, JL Pencina, KM Massaro, JM Hoffmann, U Seshadri, S Fox, CS O'Donnell, CJ Speliotes, EK AF Mellinger, Jessica L. Pencina, Karol M. Massaro, Joseph M. Hoffmann, Udo Seshadri, Sudha Fox, Caroline S. O'Donnell, Christopher J. Speliotes, Elizabeth K. TI Hepatic steatosis and cardiovascular disease outcomes: An analysis of the Framingham Heart Study SO JOURNAL OF HEPATOLOGY LA English DT Article DE Fatty liver; Abdominal aortic calcium; Coronary artery calcium; Cardiovascular disease ID NONALCOHOLIC FATTY LIVER; CORONARY-ARTERY CALCIUM; TYPE-2 DIABETIC-PATIENTS; COMPUTED-TOMOGRAPHY; ADIPOSE-TISSUE; INSULIN-RESISTANCE; RISK-FACTORS; EVENTS; PREDICTOR; COHORT AB Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and is associated with development of metabolic disease including atherosclerotic cardiovascular disease (CVD). Our aim is to examine the association of hepatic steatosis with prevalent clinical and subclinical CVD outcomes in a large community-based sample, the Framingham Heart Study. Methods: Hepatic steatosis was measured in 3529 participants using multidetector computed tomography scanning. Multivariable logistic regression was used to determine whether hepatic steatosis is associated with prevalent CVD adjusted for covariates. We also tested whether associations were independent of other metabolic diseases/traits. The primary clinical outcome was composite prevalent clinical CVD defined by prior non-fatal myocardial infarction, stroke, transient ischemic attack, heart failure, or peripheral arterial disease. Subclinical cardiovascular outcomes were coronary artery calcium (CAC) and abdominal artery calcium (AAC). Results: 3014 participants were included (50.5% women). There was a non-significant association of hepatic steatosis with clinical CVD (OR 1.14 [p = 0.07]). Hepatic steatosis was associated with both CAC and AAC (OR 1.20 [p < 0.001] and OR 1.16 [p < 0.001], respectively). Associations persisted for CAC even when controlling for other risk factors/metabolic diseases, but for AAC, the associations became non-significant after adjustment for visceral adipose tissue. The association between hepatic steatosis and AAC was stronger in men than in women (p sex interaction = 0.022). Conclusion: There was a significant association of hepatic steatosis with subclinical CVD outcomes independent of many metabolic diseases/traits with a trend towards association between hepatic steatosis and clinical CVD outcomes. The association with AAC was stronger in men than in women. (C) 2015 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Mellinger, Jessica L.; Speliotes, Elizabeth K.] Univ Michigan, Div Gastroenterol, Dept Internal Med, Ann Arbor, MI 48109 USA. [Pencina, Karol M.] Boston Univ, Stat & Consulting Unit, Boston, MA 02215 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Stat, Boston, MA 02215 USA. [Hoffmann, Udo; O'Donnell, Christopher J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol,Dept Med, Boston, MA 02115 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR PET CT Program,Dept Radiol, Boston, MA 02115 USA. [Seshadri, Sudha] Boston Univ, Dept Neurol, Boston, MA 02215 USA. [Seshadri, Sudha; Fox, Caroline S.; O'Donnell, Christopher J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Fox, Caroline S.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD USA. [Speliotes, Elizabeth K.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. RP Speliotes, EK (reprint author), Univ Michigan Hlth Syst, Div Gastroenterol & Hepatol, Taubman Ctr 3912, 1500 E Med Ctr Dr,SPC 5362, Ann Arbor, MI 48109 USA. EM espeliot@med.umich.edu OI Seshadri, Sudha/0000-0001-6135-2622 FU National Institutes of Health [K23DK080145-01]; Doris Duke Medical Foundation; University of Michigan Internal Medicine Department, Division of Gastroenterology, and Biological Sciences Scholars Program; National Institute of Neurological Disorders and Stroke [NS17950]; National Institute of Aging [AG08122, AG033193]; [T32DK062708] FX JLM is supported by a T32DK062708 educational grant. EKS was supported by National Institutes of Health grant K23DK080145-01, the Doris Duke Medical Foundation, and the University of Michigan Internal Medicine Department, Division of Gastroenterology, and Biological Sciences Scholars Program. SS was supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute of Aging (AG08122, AG033193). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, the NHLBI or the NIH. NR 34 TC 27 Z9 27 U1 0 U2 7 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 2015 VL 63 IS 2 BP 470 EP 476 DI 10.1016/j.jhep.2015.02.045 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CM8YX UT WOS:000357991700025 PM 25776891 ER PT J AU Stukova, M Hall, MD Tsotsoros, SD Madigan, JP Farrell, NP Gottesman, MM AF Stukova, Marina Hall, Matthew D. Tsotsoros, Samantha D. Madigan, James P. Farrell, Nicholas P. Gottesman, Michael M. TI Reduced accumulation of platinum drugs is not observed in drug-resistant ovarian cancer cell lines derived from cisplatin-treated patients SO JOURNAL OF INORGANIC BIOCHEMISTRY LA English DT Article DE Metals in medicine; Drug resistance; Ovarian cancer; Mechanism ID BRCA1/2 MUTATION; CHEMOTHERAPY; COMPLEXES; CARCINOMA; MECHANISM; CARBOPLATIN; SENSITIVITY; EVOLUTION AB The resistance of ovarian cancer towards front-line chemotherapy, usually cisplatin or carboplatin in combination with paclitaxel or docetaxel, remains a major clinical challenge. Resistance to these agents has been largely studied using cell lines selected for resistance to agents in vitro. We examined a series of paired cell lines derived from patients with ovarian cancer prior to chemotherapy (PEO1, PEO4, PEO14 and PEA1), and following the acquisition of resistance to a platinum-based chemotherapy regimen (PEO6, PEO23 and PEA2, respectively). All resistant patient lines showed resistance to cisplatin (2-5-fold), but this did not correspond with lowered accumulation. No general cross-resistance was observed for oxaliplatin, paclitaxel or docetaxel, and paclitaxel accumulation was not affected. PEO1 cells carrying BRCA2 mutations were hypersensitive to the PARP inhibitors olaparib and velaparib, but all other cell lines expressing functional forms of BRCA2 were less sensitive. While reduced drug accumulation was not observed, we believe these pairs of lines are of use to researchers studying Pt drug resistance and experimental therapeutics against drug-resistant ovarian cancer. Published by Elsevier Inc. C1 [Stukova, Marina; Hall, Matthew D.; Madigan, James P.; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Tsotsoros, Samantha D.; Farrell, Nicholas P.] Virginia Commonwealth Univ, Dept Chem, Richmond, VA 23284 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Rm 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU National Institutes of Health (National Cancer Institute); National Institutes of Health [RO1CA78754] FX This research was supported by the Intramural Research Program of the National Institutes of Health (National Cancer Institute). We thank George Leiman for editorial assistance. NPF acknowledges support of National Institutes of Health RO1CA78754. NR 30 TC 0 Z9 0 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0162-0134 EI 1873-3344 J9 J INORG BIOCHEM JI J. Inorg. Biochem. PD AUG PY 2015 VL 149 BP 45 EP 48 DI 10.1016/j.jinorgbio.2015.05.003 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA CM6YC UT WOS:000357836600006 PM 26021697 ER PT J AU Nolte-'t Hoen, ENM Van Rooij, E Bushell, M Zhang, CY Dashwood, RH James, WPT Harris, C Baltimore, D AF Nolte-'t Hoen, E. N. M. Van Rooij, E. Bushell, M. Zhang, C. -Y. Dashwood, R. H. James, W. P. T. Harris, C. Baltimore, D. TI The role of microRNA in nutritional control SO JOURNAL OF INTERNAL MEDICINE LA English DT Review DE development; metabolic control; miRNA; nutrition; pathology; signalling ID IMPAIRS GLUCOSE-METABOLISM; EXTRACELLULAR VESICLES; GENE-EXPRESSION; POOR-PROGNOSIS; ADIPOSE-TISSUE; IMMUNE-SYSTEM; LUNG-CANCER; BROWN; RNA; DIET AB MicroRNAs (miRNAs) are one of a growing class of noncoding RNAs that are involved in the regulation of a wide range of metabolic processes including cellular differentiation, cell proliferation and apoptosis. The generation of miRNA is regulated in complex ways, for example by small interfering RNAs (small nucleolar and nuclear RNAs) and various other metabolites. This complexity of control is likely to explain how a relatively small part of the DNA that codes for proteins has enabled the evolution of such complex organisms as mammals. Non-protein-coding DNA is therefore thought to carry the memory of early evolutionary steps that led to progressively complex metabolic controls. Clinically, miRNAs are becoming increasingly important following the recognition that some congenital abnormalities can be traced to defects in miRNA processing. The potential for manipulating metabolism and affecting disease processes by the pharmaceutical or biological targeting of specific miRNA pathways is now being tested. miRNAs are also released into the extracellular milieu after packaging by cells into nano-sized extracellular vesicles. Such vesicles can be taken up by adjacent and possibly more distant cells, thereby allowing coordinated intercellular communication in specific tissues. Extracellular miRNAs found in the blood stream may also serve as novel biomarkers for both diagnosing specific forms of cancer and assessing the likelihood of metastasis, and as powerful prognostic indices for various cancers. Here, we discuss the role of intracellular and extracellular miRNAs in nutritional control of various (patho)physiological processes. In this review, we provide an update of the presentations from the 25th Marabou Symposium (Stockholm, 14-16 June 2013) entitled Role of miRNA in health and nutrition', attended by 50 international experts. C1 [Nolte-'t Hoen, E. N. M.] Univ Utrecht, Fac Vet Med, Dept Biochem & Cell Biol, Utrecht, Netherlands. [Van Rooij, E.] Univ Med Ctr Utrecht, KNAW, Hubrecht Inst, Utrecht, Netherlands. [Bushell, M.] Univ Leicester, MRC, Toxicol Unit, Leicester, Leics, England. [Zhang, C. -Y.] Nanjing Univ, Jiangsu Engn Res Ctr microRNA Biol & Biotechnol, State Key Lab Pharmaceut Biotechnol, Sch Life Sci, Nanjing 210008, Jiangsu, Peoples R China. [Dashwood, R. H.] Texas A&M Hlth Sci Ctr, Inst Biosci & Technol, Ctr Epigenet & Dis Prevent, Houston, TX USA. [James, W. P. T.] London Sch Hyg & Trop Med, London WC1, England. [Harris, C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Baltimore, D.] CALTECH, Dept Biol, Pasadena, CA 91125 USA. RP Nolte-'t Hoen, ENM (reprint author), Univ Utrecht, Fac Vet Med, Dept Biochem & Cell Biol, Utrecht, Netherlands. EM e.n.m.nolte@uu.nl FU Nutricia Research [11676]; Dutch Technology Foundation STW, which is part of the Netherlands Organization for Scientific Research (NWO) [11676]; Ministry of Economic Affairs; Ministry of Science and Technology of the People's Republic of China; National Natural Science Foundation of China; miRagen Therapeutics; Regulus Therapeutics FX Drs Dashwood, Bushell, James, and Harris have nothing to disclose. Dr Nolte-'t Hoen reports a grant (11676) from a partnership programme jointly funded by Nutricia Research and the Dutch Technology Foundation STW, which is part of the Netherlands Organization for Scientific Research (NWO), and is partly funded by the Ministry of Economic Affairs, during the conduct of the study. Dr Zhang reports grants from Ministry of Science and Technology of the People's Republic of China, grants from National Natural Science Foundation of China, during the conduct of the study. Dr van Rooij reports personal fees from miRagen Therapeutics, related to the subject matter and has several issued patents. Dr Baltimore reports personal fees from Regulus Therapeutics as a board member, outside the submitted work. NR 58 TC 4 Z9 5 U1 3 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0954-6820 EI 1365-2796 J9 J INTERN MED JI J. Intern. Med. PD AUG PY 2015 VL 278 IS 2 BP 99 EP 109 DI 10.1111/joim.12372 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CM9FL UT WOS:000358012700001 PM 25832550 ER PT J AU Grabowski, MK Gray, RH Makumbi, F Kagaayi, J Redd, AD Kigozi, G Reynolds, SJ Nalugoda, F Lutalo, T Wawer, MJ Serwadda, D Quinn, TC Tobian, AAR AF Grabowski, Mary K. Gray, Ronald H. Makumbi, Fred Kagaayi, Joseph Redd, Andrew D. Kigozi, Godfrey Reynolds, Steven J. Nalugoda, Fred Lutalo, Tom Wawer, Maria J. Serwadda, David Quinn, Thomas C. Tobian, Aaron A. R. TI Use of injectable hormonal contraception and women's risk of herpes simplex virus type 2 acquisition: a prospective study of couples in Rakai, Uganda SO LANCET GLOBAL HEALTH LA English DT Article ID SIV VAGINAL TRANSMISSION; HIV ACQUISITION; MALE CIRCUMCISION; RANDOMIZED-TRIAL; DENDRITIC CELLS; PROGESTERONE INCREASES; CERVICAL EPITHELIUM; FEMALE PARTNERS; GENITAL HERPES; SOUTH-AFRICA AB Background The injectable hormonal contraceptive depo-medroxyprogesterone acetate (DMPA) has been associated with increased risk of HIV acquisition, but findings are inconsistent. Whether DMPA increases the risk of other sexually transmitted viral infections is unknown. We assessed the association between DMPA use and incident herpes simplex virus type 2 (HSV2) infection in women. Methods In this prospective study, we enrolled HIV-negative and HSV2-negative women aged 15-49 years whose HIV-negative male partners were concurrently enrolled in a randomised trial of male circumcision in Rakai, Uganda. We excluded women if either they or their male partners HIV seroconverted. The primary outcome was HSV2 seroconversion, assessed annually. The male circumcision trial was registered with ClinicalTrials.gov, number NCT00425984. Findings Between Aug 11, 2003, and July 6, 2006, we enrolled 682 women in this study. We noted HSV2 seroconversions in 70 (10%) women. Incidence was 13.5 per 100 person-years in women consistently using DMPA (nine incident infections per 66.5 person-years), 4.3 per 100 person-years in pregnant women who were not using hormonal contraception (18 incident infections per 423.5 person-years), and 6.6 per 100 person-years in women who were neither pregnant nor using hormonal contraception (35 incident infections per 529.5 person-years). Women consistently using DMPA had an adjusted hazard ratio for HSV2 seroconversion of 2.26 (95% CI 1.09-4.69; p=0.029) compared with women who were neither pregnant nor using hormonal contraception. Of 132 women with HSV2-seropositive partners, seroconversion was 36.4 per 100 person-years in consistent DMPA users (four incident infections per 11 person-years) and 10.7 per 100 person-years in women who were neither pregnant nor using hormonal contraception (11 incident infections per 103 person-years; adjusted hazard ratio 6.23, 95% CI 1.49-26.3; p=0.012). Interpretation Consistent DMPA use might increase risk of HSV2 seroconversion; however, study power was low. These findings should be assessed in larger populations with more frequent follow-up than in this study, and other contraceptive methods should also be assessed. Access to a wide range of highly effective contraceptive methods is needed for women, particularly in sub-Saharan Africa. Copyright (C) Grabowski et al. Open Access article distributed under the terms of CC BY-NC-ND. C1 [Grabowski, Mary K.; Gray, Ronald H.; Wawer, Maria J.] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Gray, Ronald H.; Makumbi, Fred; Kagaayi, Joseph; Kigozi, Godfrey; Reynolds, Steven J.; Nalugoda, Fred; Lutalo, Tom; Wawer, Maria J.; Serwadda, David; Tobian, Aaron A. R.] Johns Hopkins Univ, Baltimore, MD 21287 USA. [Gray, Ronald H.; Makumbi, Fred; Kagaayi, Joseph; Kigozi, Godfrey; Reynolds, Steven J.; Nalugoda, Fred; Lutalo, Tom; Wawer, Maria J.; Serwadda, David; Tobian, Aaron A. R.] Rakai Hlth Sci Program, Entebbe, Uganda. [Redd, Andrew D.; Reynolds, Steven J.; Quinn, Thomas C.] NIAID, Div Intramural Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu FU Doris Duke Charitable Foundation [2011036]; Bill and Melinda Gates Foundation [22006.03]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health [U1AI51171]; Fogarty International Center [1D43TWOO9578-01]; NIH [T32AI102623, 1K23AI093152-01A1]; Doris Duke Charitable Foundation; Doris Duke Charitable Foundation Clinician Scientist Development Award FX This study was supported by the Doris Duke Charitable Foundation (#2011036), Bill and Melinda Gates Foundation (22006.03), Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health (#U1AI51171), and Fogarty International Center (1D43TWOO9578-01). MKG was supported by NIH T32AI102623 and the Doris Duke Charitable Foundation. AART was supported by NIH 1K23AI093152-01A1 and the Doris Duke Charitable Foundation Clinician Scientist Development Award. We are most grateful to the study participants and Rakai Community Advisory Board whose commitment and cooperation made this study possible. NR 54 TC 8 Z9 8 U1 2 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD AUG PY 2015 VL 3 IS 8 BP E478 EP E486 DI 10.1016/S2214-109X(15)00086-8 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CM9DM UT WOS:000358006700022 PM 26094162 ER PT J AU Simuni, T Kieburtz, K Tilley, B Elm, JJ Ravina, B Babcock, D Emborg, M Hauser, R Kamp, C Morgan, JC Ross, GW Simon, DK Bainbridge, J Baker, L Bodis-Wollner, I Boyd, J Cambi, F Carter, J Chou, K Dahodwala, N Dewey, RB Dhall, R Fang, J Farrow, B Feigin, A Glazman, S Goudreau, J LeBlanc, P Lee, S Leehey, M Lew, MF Lowenhaupt, S Luo, S Pahwa, R Perez, A Schneider, J Scott, B Shah, B Shannon, KM Sharma, S Singer, C Truong, D Wagner, R Williams, K Wills, AM Wong, PS Zadikoff, C Zweig, R AF Simuni, Tanya Kieburtz, Karl Tilley, Barbara Elm, Jordan J. Ravina, Bernard Babcock, Debra Emborg, Marina Hauser, Robert Kamp, Cornelia Morgan, John C. Ross, G. Webster Simon, David K. Bainbridge, Jacci Baker, Liana Bodis-Wollner, Ivan Boyd, James Cambi, Franca Carter, Julie Chou, Kelvin Dahodwala, Nabila Dewey, Richard B., Jr. Dhall, Rohit Fang, John Farrow, Buff Feigin, Andrew Glazman, Sofya Goudreau, John LeBlanc, Pauline Lee, Stephen Leehey, Maureen Lew, Mark F. Lowenhaupt, Stephanie Luo, Sheng Pahwa, Rajesh Perez, Adriana Schneider, Jay Scott, Burton Shah, Binit Shannon, Kathleen M. Sharma, Saloni Singer, Carlos Truong, Daniel Wagner, Renee Williams, Karen Wills, Anne Marie Wong, Pei Shieen Zadikoff, Cindy Zweig, Richard CA Ninds Exploratory Trials Parkinson TI Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial SO LANCET NEUROLOGY LA English DT Article ID ACTIVATED-RECEPTOR-GAMMA; HEALTH-EXPLORATORY-TRIALS; NET-PD EXPERIENCE; CLINICAL-TRIAL; ALZHEIMERS-DISEASE; RATING-SCALE; FUTILITY; NEUROPROTECTION; PROGRESSION; VALIDATION AB Background A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Methods Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0.10. The study is registered at ClinicalTrials.gov, number NCT01280123. Findings 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4.42 (95% CI 2.55-6.28) for 15 mg pioglitazone, 5.13 (95% CI 3.17-7.08) for 45 mg pioglitazone, and 6.25 (95% CI 4.35-8.15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was -1.83 (80% CI -3.56 to -0.10) and the null hypothesis could not be rejected (p=0.19). The mean difference between the 45 mg and placebo groups was -1.12 (80% CI -2.93 to 0.69)and the null hypothesis was rejected in favour of futility (p=0.09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0.09 for LVCF, p= 0.09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0.12 for LVCF, p=0.19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. Interpretation These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended. C1 [Simuni, Tanya; Williams, Karen; Zadikoff, Cindy] Northwestern Univ, Chicago, IL 60611 USA. [Kieburtz, Karl] Univ Rochester, Coordinat Ctr, Rochester, NY USA. [Tilley, Barbara] Univ Texas Hlth Sci Ctr Houston, Ctr Stat, Houston, TX 77030 USA. [Elm, Jordan J.] Med Univ S Carolina, Charleston, SC 29425 USA. [Ravina, Bernard] Voyager Therapeut, Cambridge, MA USA. [Babcock, Debra] NINDS, NIH, Bethesda, MD 20892 USA. [Emborg, Marina] Univ Wisconsin, Madison, WI USA. [Hauser, Robert] Univ S Florida, Tampa, FL USA. [Kamp, Cornelia; Baker, Liana; Sharma, Saloni] Univ Rochester, Rochester, NY USA. [Morgan, John C.; Farrow, Buff] Georgia Regents Univ, Augusta, GA USA. [Ross, G. Webster] Vet Affairs Pacific Hlth Care Syst, Honolulu, HI USA. [Simon, David K.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Simon, David K.; Wills, Anne Marie] Harvard Univ, Sch Med, Boston, MA USA. [Bainbridge, Jacci] Univ Colorado Denver, Skaggs Sch Pharm & Pharmaceut Sci, Dept Clin Pharm & Neurol, Aurora, CO USA. [Bodis-Wollner, Ivan; Glazman, Sofya] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Boyd, James] Univ Vermont, Burlington, VT USA. [Cambi, Franca; Wagner, Renee] Univ Kentucky, Lexington, KY USA. [Carter, Julie] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Chou, Kelvin] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [Chou, Kelvin] Univ Michigan, Dept Neurosurg, Ann Arbor, MI USA. [Dahodwala, Nabila] Univ Penn, Philadelphia, PA 19104 USA. [Dewey, Richard B., Jr.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Dhall, Rohit] Barrow Neurol Inst, Phoenix, AZ 85013 USA. [Fang, John] Vanderbilt Univ, Nashville, TN 37235 USA. [Feigin, Andrew] North Shore LIJ Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. [Goudreau, John] Michigan State Univ, Dept Neurol, E Lansing, MI 48824 USA. [LeBlanc, Pauline; Lee, Stephen] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Leehey, Maureen] Univ Colorado Denver, Aurora, CO USA. [Lew, Mark F.] Univ So Calif, Los Angeles, CA USA. [Lowenhaupt, Stephanie; Shah, Binit] Univ Virginia, Charlottesville, VA USA. [Luo, Sheng] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Pahwa, Rajesh] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Perez, Adriana] Univ Texas Hlth Sci Ctr Houston, Austin, TX USA. [Schneider, Jay] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Scott, Burton] Duke Univ, Durham, NC USA. [Shannon, Kathleen M.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Singer, Carlos] Univ Miami, Miami, FL USA. [Truong, Daniel] Parkinsons & Movement Disorder Inst, Fountain Valley, CA USA. [Wills, Anne Marie] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wong, Pei Shieen] Univ Colorado Denver, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO USA. [Wong, Pei Shieen] Singapore Gen Hosp, Singapore, Singapore. [Zweig, Richard] LSU Hlth Shreveport, Shreveport, LA USA. RP Simuni, T (reprint author), Northwestern Univ, Feinberg Sch Med, Abbott Hall,11th Floor,710 North Lake Shore Dr, Chicago, IL 60611 USA. EM tsimuni@nmff.org FU National Institute of Neurological Disorders and Stroke FX National Institute of Neurological Disorders and Stroke. NR 35 TC 15 Z9 15 U1 0 U2 7 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 2015 VL 14 IS 8 BP 795 EP 803 DI 10.1016/S1474-4422(15)00144-1 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA CM7MZ UT WOS:000357879200009 ER PT J AU Dehay, B Bourdenx, M Gorry, P Przedborski, S Vila, M Hunot, S Singleton, A Olanow, CW Merchant, KM Bezard, E Petsko, GA Meissner, WG AF Dehay, Benjamin Bourdenx, Mathieu Gorry, Philippe Przedborski, Serge Vila, Miquel Hunot, Stephane Singleton, Andrew Olanow, C. Warren Merchant, Kalpana M. Bezard, Erwan Petsko, Gregory A. Meissner, Wassilios G. TI Targeting alpha-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations SO LANCET NEUROLOGY LA English DT Article ID CHAPERONE-MEDIATED AUTOPHAGY; PROLYL OLIGOPEPTIDASE INHIBITOR; MODERATE ALZHEIMERS-DISEASE; MULTIPLE-SYSTEM ATROPHY; IN-VIVO; MOUSE MODEL; DOPAMINE NEURONS; LEWY BODIES; RAT MODEL; OLIGOMER MODULATOR AB Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the alpha-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes alpha-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of alpha-synuclein in the pathogenesis of Parkinson's disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of alpha-synuclein toxicity. We critically assess the potential of experimental therapies targeting alpha-synuclein, and discuss steps that need to be taken for target validation and drug development. C1 [Dehay, Benjamin; Bourdenx, Mathieu; Bezard, Erwan; Meissner, Wassilios G.] Univ Bordeaux, Inst Neurodegenerat Dis, CNRS, UMR, F-33076 Bordeaux, France. [Gorry, Philippe] Univ Bordeaux, Res Unit Theoret & Appl Econ, CNRS, UMR, Pessac, France. [Przedborski, Serge] Columbia Univ, Dept Neurol, New York, NY USA. [Przedborski, Serge] Columbia Univ, Dept Pathol, New York, NY USA. [Przedborski, Serge] Columbia Univ, Dept Cell Biol, New York, NY USA. [Przedborski, Serge] Columbia Univ, Ctr Motor Neuron Biol & Dis, New York, NY USA. [Vila, Miquel] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Vall dHebron Res Inst, Neurodegenerat Dis Res Grp, Barcelona, Spain. [Vila, Miquel] Autonomous Univ Barcelona, Dept Biochem & Mol Biol, Barcelona, Spain. [Vila, Miquel] Catalan Inst Res & Adv Studies, Barcelona, Spain. [Hunot, Stephane] Univ Paris 04, Inst Commun & Medias, Paris, France. [Hunot, Stephane] Univ Paris, Univ Paris 06, Inst Commun & Medias, F-75252 Paris, France. [Hunot, Stephane] CNRS, Inst Commun Medias, Paris, France. [Hunot, Stephane] Inst Commun & Medias, INSERM, Paris, France. [Singleton, Andrew] NIA, Mol Genet Sect, NIH, Bethesda, MD 20892 USA. [Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Olanow, C. Warren] Mt Sinai Sch Med, Dept Neurol, New York, NY USA. [Olanow, C. Warren] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. [Merchant, Kalpana M.] TransThera Consulting, Zionsville, IN USA. [Petsko, Gregory A.] Weill Cornell Med Coll, Dept Neurol, New York, NY USA. [Petsko, Gregory A.] Weill Cornell Med Coll, Feil Family Brain & Mind Res Inst, New York, NY USA. RP Bezard, E (reprint author), Univ Bordeaux, Inst Malad Neurodegenerat, F-33076 Bordeaux, France. EM erwan.bezard@u-bordeaux.fr RI Singleton, Andrew/C-3010-2009; Meissner, Wassilios/C-7817-2015 OI Meissner, Wassilios/0000-0003-2172-7527 FU Fondation pour la Recherche Medicale; Agence Nationale de la Recherche grants [ANR-12-BSV4-0001-01, LABEX BRAIN ANR-10-LABX-43]; Intramural Research Program of the National Institute on Ageing, National Institutes of Health, Department of Health and Human Services project [ZO1 AG000949]; Fondo de Investigacion Sanitaria-Instituto de Salud Carlos III, Spain; Ministere de l'Enseignement Superieur et de la Recherche fellowship (France); "Investissements d'avenir" program [ANR-10-IAIHU-06]; [ANR-13-BSV1-0013-01] FX The University of Bordeaux and the Centre National de la Recherche Scientifique provided infrastructural support during the preparation of this Personal View. Our work is supported by a grant from the Fondation pour la Recherche Medicale (to BD); by Agence Nationale de la Recherche grants ANR-12-BSV4-0001-01 and LABEX BRAIN ANR-10-LABX-43 (to EB); ANR-13-BSV1-0013-01 and "Investissements d'avenir" program ANR-10-IAIHU-06 (to SH); by the Intramural Research Program of the National Institute on Ageing, National Institutes of Health, Department of Health and Human Services project ZO1 AG000949 (to AS); and by Fondo de Investigacion Sanitaria-Instituto de Salud Carlos III, Spain (to MV). MB is a recipient of a Ministere de l'Enseignement Superieur et de la Recherche fellowship (France). NR 121 TC 51 Z9 52 U1 9 U2 31 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 2015 VL 14 IS 8 BP 855 EP 866 DI 10.1016/S1474-4422(15)00006-X PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA CM7MZ UT WOS:000357879200015 PM 26050140 ER PT J AU Steeves, JA Murphy, RA Zipunnikov, V Strath, SJ Harris, TB AF Steeves, Jeremy A. Murphy, Rachel A. Zipunnikov, Vadim Strath, Scott J. Harris, Tamara B. TI Women Workers and Women at Home Are Equally Inactive: NHANES 2003-2006 SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article ID PHYSICAL-ACTIVITY; UNITED-STATES; PATTERNS; ADULTS; ACCELEROMETRY; INTENSITY; DISEASE; RISK; AGE AB Purpose The prevalence of female homemakers (those who stay at home to care for the home or family) has increased to 29%. Homemakers may be more active than employed women (EW). Limited data are available for domestic-related activity; therefore, the assessment of the activity levels of homemakers has been sparse. This study compared objectively measured activity (total activity counts, counts per minute, and percent time in various activity intensity levels) of homemakers and EW. Methods Women's (18-60 yr) accelerometer data from the 2003-2006 National Health and Nutrition Examination Survey were analyzed in 2014 (n = 1763). Daily (hour-by-hour) profiles of activity were compared between homemakers and EW. Results Women spent most of their day in sedentary (similar to 55%) and light (similar to 32%) activity, with limited lifestyle (similar to 11%) and moderate vigorous physical activity (MVPA; similar to 2%); and there were no differences between the homemakers and EW. Hour-by-hour analysis showed that the homemakers had more light and less sedentary activity than EW during the afternoon (P < 0.002), whereas EW had more MVPA at times corresponding to commuting to and from work and midday (P < 0.002). On weekdays, EW initiated activity earlier than homemakers but not on weekends. On weekends, both groups had less MVPA than weekdays. Employed women with child(ren) younger than 18 yr had greater counts per minute and lifestyle activity and less sedentary activity than EW without child(ren) younger than 18 yr. Conclusion Our hourly analysis delineated important differences in activity between the groups. Homemakers accumulate enough light activity throughout the day to be as active as EW who are highly sedentary during the workday, but seem to acquire activity through commuting. Interventions to reduce sedentary behavior and increase activity are highly desirable and should take into consideration the temporality of homemakers and EW activity patterns. C1 [Steeves, Jeremy A.] NCI, Canc Prevent Fellowship Program, Div Canc Control & Populat Sci, Rockville, MD 20892 USA. [Murphy, Rachel A.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Zipunnikov, Vadim] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Strath, Scott J.] Univ Wisconsin, Dept Kinesiol, Milwaukee, WI 53201 USA. [Strath, Scott J.] Univ Wisconsin, Ctr Aging & Translat Res, Milwaukee, WI 53201 USA. RP Steeves, JA (reprint author), NCI, Canc Prevent Fellowship Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,MSC 9762, Rockville, MD 20892 USA. EM steevesja@mail.nih.gov FU National Institute on Aging, National Institutes of Health (NIH) FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH). NR 34 TC 2 Z9 2 U1 3 U2 8 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 2015 VL 47 IS 8 BP 1635 EP 1642 DI 10.1249/MSS.0000000000000582 PG 8 WC Sport Sciences SC Sport Sciences GA CM8IF UT WOS:000357942200010 PM 25412296 ER PT J AU Baltabekova, AZ Shagyrova, ZS Kamzina, AS Voykov, M Zhiyenbay, Y Ramanculov, EM Shustov, AV AF Baltabekova, A. Zh Shagyrova, Zh S. Kamzina, A. S. Voykov, M. Zhiyenbay, Ye Ramanculov, E. M. Shustov, A. V. TI SplitCore Technology Allows Efficient Production of Virus-Like Particles Presenting a Receptor-Contacting Epitope of Human IgE SO MOLECULAR BIOTECHNOLOGY LA English DT Article DE Allergy; Therapeutic vaccine; Immunoglobulin E; SplitCore; Hepatitis B capsid protein; Virus-like particles ID FC-EPSILON-RI; AUTOIMMUNE ARTHRITIS; ACTIVE IMMUNIZATION; AIRWAY INFLAMMATION; CORE PARTICLES; CELL EPITOPES; VACCINE; AUTOANTIBODIES; IMMUNOTHERAPY; INDUCTION AB Immunoglobulin E (IgE) plays a central role in type I hypersensitivity including allergy and asthma. Novel treatment strategy envisages development of a therapeutic vaccine designed to elicit autologous blocking antibodies against the IgE. We sought to develop an IgE-epitope antigen that induces antibodies against a receptor-contacting epitope on human IgE molecule. We designed the VLP immunogens which utilize hepatitis B virus core protein (HBcAg) as a carrier, and present arrays of the receptor-contacting epitopes of the human IgE on their surfaces. FG loop from the IgE domain C epsilon 3 was engineered into the HBcAg. Two constructs explore a well-established approach of insertion into a main immunodominant region of the HBcAg. Third construct is different in that the carrier is produced in a form of an assembly of two polypeptide chains which upon expression remain associated in a stable VLP-forming subunit (SplitCore technology). No VLPs were isolated from E.coli expressing the IgE-epitope antigens with contiguous sequences. On the contrary, the SplitCore antigen carrying the FG loop efficiently formed the VLPs. Immunization of mice with the VLPs presenting receptor-contacting epitope of the IgE elicited antibodies recognizing the human IgE in ELISA. C1 [Baltabekova, A. Zh; Shagyrova, Zh S.; Kamzina, A. S.; Ramanculov, E. M.; Shustov, A. V.] Natl Biotechnol Ctr, Astana 010000, Kazakhstan. [Voykov, M.; Zhiyenbay, Ye] AOE Nazarbayev Univ, Nazarbayev Univ Res & Innovat Syst NURIS, Astana 010000, Kazakhstan. RP Shustov, AV (reprint author), Natl Biotechnol Ctr, Valikhanova 13-1, Astana 010000, Kazakhstan. EM shustov@biocenter.kz RI Shustov, Alexander/K-1148-2013; OI Alexandr, Shustov/0000-0001-9880-9382 FU Ministry of Education and Science (MES) of the Republic of Kazakhstan [0112RK00352] FX This work was supported by Grant #0112RK00352 "Study of immunogenicity of virus-like particles carrying epitopes of human immunoglobulin E" from the Ministry of Education and Science (MES) of the Republic of Kazakhstan. NR 35 TC 1 Z9 2 U1 2 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1073-6085 EI 1559-0305 J9 MOL BIOTECHNOL JI Mol. Biotechnol. PD AUG PY 2015 VL 57 IS 8 BP 746 EP 755 DI 10.1007/s12033-015-9867-0 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA CM9SL UT WOS:000358049200008 PM 25837568 ER PT J AU Freed, EO AF Freed, Eric O. TI HIV-1 assembly, release and maturation SO NATURE REVIEWS MICROBIOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEIN INCORPORATION; ESCRT PROTEIN RECRUITMENT; SMALL-MOLECULE INHIBITION; GP41 CYTOPLASMIC TAIL; TYPE-1 MATRIX PROTEIN; N-TERMINAL DOMAIN; PLASMA-MEMBRANE; CAPSID PROTEIN; CRYOELECTRON MICROSCOPY AB Major advances have occurred in recent years in our understanding of HIV-1 assembly, release and maturation, as work in this field has been propelled forwards by developments in imaging technology, structural biology, and cell and molecular biology. This increase in basic knowledge is being applied to the development of novel inhibitors designed to target various aspects of virus assembly and maturation. This Review highlights recent progress in elucidating the late stages of the HIV-1 replication cycle and the related interplay between virology, cell and molecular biology, and drug discovery. C1 NCI, Ctr Canc Res, HIV Dynam & Replicat Program, Virus Cell Interact Sect, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI, Ctr Canc Res, HIV Dynam & Replicat Program, Virus Cell Interact Sect, Bg 535,Room 110,1050 Boyles St, Frederick, MD 21702 USA. EM efreed@nih.gov FU Intramural Research Program of the Center for Cancer Research (National Cancer Institute, US National Institutes of Health (NIH)); Intramural AIDS Targeted Antiviral Program of the NIH FX The author thanks A. Ono, W.-S. Hu, S. Van Engelenburg and members of the Freed laboratory for critical review of the manuscript and helpful discussions. Work in the Freed laboratory is supported by the Intramural Research Program of the Center for Cancer Research (National Cancer Institute, US National Institutes of Health (NIH)) and by the Intramural AIDS Targeted Antiviral Program of the NIH. NR 118 TC 46 Z9 46 U1 22 U2 81 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 2015 VL 13 IS 8 BP 484 EP 496 DI 10.1038/nrmicro3490 PG 13 WC Microbiology SC Microbiology GA CM9BP UT WOS:000358000700007 PM 26119571 ER PT J AU Justinova, Z Panlilio, LV Moreno-Sanz, G Redhi, GH Auber, A Secci, ME Mascia, P Bandiera, T Armirotti, A Bertorelli, R Chefer, SI Barnes, C Yasar, S Piomelli, D Goldberg, SR AF Justinova, Zuzana Panlilio, Leigh V. Moreno-Sanz, Guillermo Redhi, Godfrey H. Auber, Alessia Secci, Maria E. Mascia, Paola Bandiera, Tiziano Armirotti, Andrea Bertorelli, Rosalia Chefer, Svetlana I. Barnes, Chanel Yasar, Sevil Piomelli, Daniele Goldberg, Steven R. TI Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTORS; NUCLEUS-ACCUMBENS SHELL; ENDOCANNABINOID SYSTEM; DOPAMINE NEURONS; RAT-BRAIN; ANANDAMIDE; PPAR; CANNABINOIDS; METAANALYSIS; ABSTINENCE AB Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first-and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and alpha-type peroxisome proliferator-activated (PPAR-alpha) receptors; (2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-alpha antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-alpha (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell-consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement. C1 [Justinova, Zuzana; Panlilio, Leigh V.; Redhi, Godfrey H.; Auber, Alessia; Secci, Maria E.; Mascia, Paola; Barnes, Chanel; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Moreno-Sanz, Guillermo; Piomelli, Daniele] Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92717 USA. [Bandiera, Tiziano; Armirotti, Andrea; Bertorelli, Rosalia; Piomelli, Daniele] Ist Italiano Tecnol, Drug Discovery & Dev, Genoa, Italy. [Chefer, Svetlana I.] NIAID, Div Clin Res, NIH, US Dept HHS, Frederick, MD USA. [Yasar, Sevil] Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. RP Justinova, Z (reprint author), NIDA, Preclin Pharmacol Sect, Intramural Res Program, NIH,DHHS, 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; BERTORELLI, Rosalia/0000-0002-7913-3564 FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services; NIDA Avant-Garde Award [DP1DA031387] FX This study was supported in part by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services; and by a NIDA Avant-Garde Award to Dr Piomelli (DP1DA031387). Daniele Piomelli and Tiziano Bandiera are inventors in US patent applications assigned to the University of California Irvine and the Istituto Italiano di Tecnologia that protect FAAH inhibitors and their use as medicaments. The other authors declare no conflict of interest. NR 44 TC 16 Z9 17 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2015 VL 40 IS 9 BP 2185 EP 2197 DI 10.1038/npp.2015.62 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CM8OY UT WOS:000357962700015 PM 25754762 ER PT J AU Satterthwaite, TD Kable, JW Vandekar, L Katchmar, N Bassett, DS Baldassano, CF Ruparel, K Elliott, MA Sheline, YI Gur, RC Gur, RE Davatzikos, C Leibenluft, E Thase, ME Wolf, DH AF Satterthwaite, Theodore D. Kable, Joseph W. Vandekar, Lillie Katchmar, Natalie Bassett, Danielle S. Baldassano, Claudia F. Ruparel, Kosha Elliott, Mark A. Sheline, Yvette I. Gur, Ruben C. Gur, Raquel E. Davatzikos, Christos Leibenluft, Ellen Thase, Michael E. Wolf, Daniel H. TI Common and Dissociable Dysfunction of the Reward System in Bipolar and Unipolar Depression SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID STATE FUNCTIONAL CONNECTIVITY; DOMAIN CRITERIA RDOC; MAJOR DEPRESSION; VENTRAL STRIATUM; DECISION-MAKING; FMRI; ACTIVATION; DISORDER; IMPACT; SCHIZOPHRENIA AB Unipolar and bipolar depressive episodes have a similar clinical presentation that suggests common dysfunction of the brain's reward system. Here, we evaluated the relationship of both dimensional depression severity and diagnostic category to reward system function in both bipolar and unipolar depression. In total, 89 adults were included, including 27 with bipolar depression, 25 with unipolar depression, and 37 healthy comparison subjects. Subjects completed both a monetary reward task and a resting-state acquisition during 3T BOLD fMRI. Across disorders, depression severity was significantly associated with reduced activation for wins compared with losses in bilateral ventral striatum, anterior cingulate cortex, posterior cingulate cortex, and right anterior insula. Resting-state connectivity within this reward network was also diminished in proportion to depression severity, most notably connectivity strength in the left ventral striatum. In addition, there were categorical differences between patient groups: resting-state connectivity at multiple reward network nodes was higher in bipolar than in unipolar depression. Reduced reward system task activation and resting-state connectivity therefore appear to be a brain phenotype that is dimensionally related to depression severity in both bipolar and unipolar depression. In contrast, categorical differences in reward system resting connectivity between unipolar and bipolar depression may reflect differential risk of mania. Reward system dysfunction thus represents a common brain mechanism with relevance that spans categories of psychiatric diagnosis. C1 [Satterthwaite, Theodore D.; Vandekar, Lillie; Katchmar, Natalie; Baldassano, Claudia F.; Ruparel, Kosha; Sheline, Yvette I.; Gur, Ruben C.; Gur, Raquel E.; Thase, Michael E.; Wolf, Daniel H.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Kable, Joseph W.] Univ Penn, Dept Psychol, Philadelphia, PA 19104 USA. [Bassett, Danielle S.] Univ Penn, Dept Elect Syst & Bioengn, Philadelphia, PA 19104 USA. [Elliott, Mark A.; Gur, Ruben C.; Gur, Raquel E.; Davatzikos, Christos] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Leibenluft, Ellen] NIMH, Emot & Dev Branch, Bethesda, MD 20892 USA. RP Satterthwaite, TD (reprint author), Univ Penn, Hosp Univ Penn, Dept Psychiat, 10th Floor,Gates Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. EM sattertt@upenn.edu FU Brain and Behavior Foundation through the Marc Rapport Family Investigator Grant; Sidney R Baer, Jr. Foundation; Penn Medicine Neuroscience Center; American Psychiatric Institute for Research and Education; National Institute of Mental Health [K23MH098130, K23MH085096, T32 MH019112, R01MH101111] FX Thanks to Monica Calkins for assistance with clinical assessment training, and to Chad Jackson and Larry Macy for systems support. Many thanks to Alex Smith and Ragini Verma for providing network visualization software. Support provided by the Brain and Behavior Foundation through the Marc Rapport Family Investigator Grant and the Sidney R Baer, Jr. Foundation, the Penn Medicine Neuroscience Center, the American Psychiatric Institute for Research and Education, National Institute of Mental Health Grants K23MH098130, K23MH085096, T32 MH019112, and R01MH101111. Dr Sheline reports a past relationship with Neosynch. Dr Thase reports no conflicts directly pertaining to this research. Over the past 36 months, he reports the following relationships: Alkermes, AstraZeneca, Bristol-Myers Squibb, Cerecor, Eli Lilly, Dey Pharma, Forest Laboratories, Gerson Lehman Group, Guidepoint Global, H. Lundbeck A/S, MedAvante, Merck, Neuronetics, Otsuka, Ortho-McNeil, Pamlab, Pfizer, PGx, Shire, Sunovion, Supernus, Takeda, and Transcept Pharmaceuticals. NR 61 TC 16 Z9 16 U1 5 U2 23 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 2015 VL 40 IS 9 BP 2258 EP 2268 DI 10.1038/npp.2015.75 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CM8OY UT WOS:000357962700022 PM 25767910 ER PT J AU Kagiya, G Ogawa, R Choudhuri, R Cook, JA Hatashita, M Tanaka, Y Koda, K Yamashita, K Kubo, M Kawakami, F Mitchell, JB AF Kagiya, Go Ogawa, Ryohei Choudhuri, Rajani Cook, John A. Hatashita, Masanori Tanaka, Yoshikazu Koda, Kana Yamashita, Kei Kubo, Makoto Kawakami, Fumitaka Mitchell, James B. TI Selective enhancement of hypoxic cell killing by tempol-regulated suicide gene expression SO ONCOLOGY REPORTS LA English DT Article DE tempol; hypoxia; HIF-1 alpha; hypoxic cell killing; suicide gene; gene therapy ID INDUCIBLE FACTOR-1; STEM-CELLS; CARCINOMA; HIF-1-ALPHA; RESISTANCE; ALOPECIA; THERAPY; HIF-1 AB The presence of hypoxic regions within solid tumors is caused by an imbalance between cell proliferation and angiogenesis. Such regions may facilitate the onset of recurrence after radiation therapy and chemotherapy, as hypoxic cells show resistance to these treatments. We found that tempol, a nitroxide, strongly induces the accumulation of hypoxia-inducible factor (HIF)-1 alpha, particularly under conditions of hypoxia. We, therefore, evaluated whether tempol enhances the gene expression via HIF-1 alpha, potentially leading to various applications for cancer gene therapy targeting hypoxic cells. Consequently, following treatment with tempol under hypoxia, the luciferase (Luc) activity in the cells transfected with the plasmid containing the luc gene with the oxygen-dependent degradation domain and a promoter composed of hypoxia-responsive elements increased up to approximately 10-fold compared to that observed in cells treated identically with the exception of tempol. The plasmid constructed by replacing the luc gene with the fcy:.:fur fusion gene as a suicide gene, strongly induced the accumulation of the Fcy::Fur fusion protein, only when incubated in the presence of the hypoxic mimic CoCl2 and tempol. The transfected cells were successfully killed with the addition of 5-fluorocytosine to the cell culture according to the fcy::fur fusion gene expression. As similar but lesser enhancement of the Luc activity was also observed in solid tumor tissues in nude mice, this strategy may be applied for hypoxic cancer eradication. C1 [Kagiya, Go; Kubo, Makoto; Kawakami, Fumitaka] Kitasato Univ, Sch Allied Hlth Sci, Minami Ku, Sagamihara, Kanagawa 2288555, Japan. [Ogawa, Ryohei] Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Radiol Sci, Toyama 9300194, Japan. [Choudhuri, Rajani; Cook, John A.; Mitchell, James B.] NCI, Radiat Biol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Hatashita, Masanori; Tanaka, Yoshikazu] Wakasa Wan Energy Res Ctr, Biol Grp, Tsuruga, Fukui 9140192, Japan. [Koda, Kana] Japanese Fdn Canc Res, Canc Inst Hosp, Radiat Oncol, Tokyo 1358550, Japan. [Yamashita, Kei] Chiba Univ, Grad Sch Med & Pharmaceut Sci, Inage Ku, Chiba 2368555, Japan. RP Ogawa, R (reprint author), Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Radiol Sci, Toyama 9300194, Japan. EM ogawa@med.u-toyama.ac.jp FU National Institutes of Health, National Cancer Institute; Japan Society for the Promotion of Science [21591618, 24591849]; Kitasato University School of Allied Health Sciences [2012-1018] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. In addition, this research was also supported in part by Grants-in-Aid for Scientific Research (C) (nos. 21591618 and 24591849) from the Japan Society for the Promotion of Science and by a grant from the Kitasato University School of Allied Health Sciences (Grants-in-Aid for Research Project, no. 2012-1018). NR 23 TC 0 Z9 0 U1 1 U2 6 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X EI 1791-2431 J9 ONCOL REP JI Oncol. Rep. PD AUG PY 2015 VL 34 IS 2 BP 1065 EP 1073 DI 10.3892/or.2015.4020 PG 9 WC Oncology SC Oncology GA CM8QB UT WOS:000357965600063 PM 26034980 ER PT J AU Xiong, JH AF Xiong, Jianhua TI To be EndMT or not to be, that is the question in pulmonary hypertension SO PROTEIN & CELL LA English DT News Item ID ENDOTHELIAL-MESENCHYMAL TRANSITION; MORPHOGENETIC PROTEIN-RECEPTOR; ARTERIAL-HYPERTENSION; MONOCROTALINE PYRROLE; FIBROSIS; CELLS C1 NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Xiong, JH (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jianhua.xiong@nih.gov RI Xiong, Jianhua/D-6099-2015 OI Xiong, Jianhua/0000-0002-2740-4027 FU Intramural NIH HHS NR 28 TC 3 Z9 3 U1 0 U2 0 PU HIGHER EDUCATION PRESS PI BEIJING PA SHATANHOU ST 55, BEIJING 100009, PEOPLES R CHINA SN 1674-800X EI 1674-8018 J9 PROTEIN CELL JI Protein Cell PD AUG PY 2015 VL 6 IS 8 BP 547 EP 550 DI 10.1007/s13238-015-0183-z PG 4 WC Cell Biology SC Cell Biology GA CN0FW UT WOS:000358090500001 PM 26099567 ER PT J AU Spellman, DS Wildsmith, KR Honigberg, LA Tuefferd, M Baker, D Raghavan, N Nairn, AC Croteau, P Schirm, M Allard, R Lamontagne, J Chelsky, D Hoffmann, S Potter, WZ AF Spellman, Daniel S. Wildsmith, Kristin R. Honigberg, Lee A. Tuefferd, Marianne Baker, David Raghavan, Nandini Nairn, Angus C. Croteau, Pascal Schirm, Michael Allard, Rene Lamontagne, Julie Chelsky, Daniel Hoffmann, Steven Potter, William Z. CA Alzheimer's Dis Neuroimaging Initi Fdn NIH FNIH Biomarkers Consortium TI Development and evaluation of a multiplexed mass spectrometry based assay for measuring candidate peptide biomarkers in Alzheimer's Disease Neuroimaging Initiative (ADNI) CSF SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Alzheimer's disease; Biomarkers; Mass spectrometry; Targeted proteomics ID MILD COGNITIVE IMPAIRMENT; CEREBROSPINAL-FLUID BIOMARKERS; APOLIPOPROTEIN-E LEVELS; ACID-BINDING PROTEIN; CLINICAL-DIAGNOSIS; DEMENTIA; PLASMA; TAU; PROGRESSION; DECLINE AB Purpose: We describe the outcome of the Biomarkers Consortium CSF Proteomics Project (where CSF is cerebral spinal fluid), a public-private partnership of government, academia, nonprofit, and industry. The goal of this study was to evaluate a multiplexed MS-based approach for the qualification of candidate Alzheimer's disease (AD) biomarkers using CSF samples from the AD Neuroimaging Initiative. Experimental design: Reproducibility of sample processing, analytic variability, and ability to detect a variety of analytes of interest were thoroughly investigated. Multiple approaches to statistical analyses assessed whether panel analytes were associated with baseline pathology (mild cognitive impairment (MCI), AD) versus healthy controls or associated with progression for MCI patients, and included (i) univariate association analyses, (ii) univariate prediction models, (iii) exploratory multivariate analyses, and (iv) supervised multivariate analysis. Results: A robust targetedMS-based approach for the qualification of candidate AD biomarkers was developed. The results identified several peptides with potential diagnostic or predictive utility, with the most significant differences observed for the following peptides for differentiating (including peptides from hemoglobin A, hemoglobin B, and superoxide dismutase) or predicting (including peptides from neuronal pentraxin-2, neurosecretory protein VGF (VGF), and secretogranin-2) progression versus nonprogression from MCI to AD. Conclusions and clinical relevance: These data provide potential insights into the biology of CSF in AD and MCI progression and provide a novel tool for AD researchers and clinicians working to improve diagnostic accuracy, evaluation of treatment efficacy, and early diagnosis. C1 [Spellman, Daniel S.] Merck Res Labs, Dept Pharmacokinet Pharmacodynam & Drug Metab, West Point, PA 19486 USA. [Wildsmith, Kristin R.; Honigberg, Lee A.] Genentech Inc, Dept Pharmacodynam Biomarkers Dev Sci, San Francisco, CA 94080 USA. [Tuefferd, Marianne] Janssen Res & Dev LLC, Discovery Sci, Beerse, Belgium. [Baker, David; Raghavan, Nandini] Janssen Res & Dev LLC, Titusville, NJ USA. [Nairn, Angus C.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Croteau, Pascal; Schirm, Michael; Allard, Rene; Lamontagne, Julie; Chelsky, Daniel] Caprion Pharmaceut, Montreal, PQ, Canada. [Hoffmann, Steven] Fdn Natl Inst Hlth Inc, Bethesda, MD USA. [Potter, William Z.] NIMH, Bethesda, MD 20892 USA. RP Spellman, DS (reprint author), Merck Res Labs, Dept Pharmacokinet Pharmacodynam & Drug Metab, WP75-214,770 Sumneytown Pike, West Point, PA 19486 USA. EM daniel_spellman@merck.com FU NIH; FDA; Alzheimer's Drug Discovery Foundation; Eisai, Inc.; Eli Lilly and Company; Janssen Alzheimer Immunotherapy Research Development; Merck and Company; Pfizer Inc.; Takeda Global Research and Development Center, Inc.; ADNI (National Institutes of Health) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research FX We gratefully acknowledge Leigh Anderson, Michael McCoss, Judith A. Siuciak, Mitchel A. Kling, Howard Schulman, and all participants in the Foundation for NIH (FNIH) Biomarkers Consortium CSF Proteomics Project Team for their insights and advice during the planning and execution of this work. The data described within this document represent the work of the Biomarkers Consortium Project "Use of Targeted Multiplex Proteomic Strategies to Identify Novel CSF Biomarkers in AD." This project was submitted to the Biomarkers Consortium Neuroscience Steering Committee by a subgroup of the Alzheimer's Disease Neuroimaging Initiative (ADNI) Industry Private Partner Scientific Board (PPSB) for execution and was managed by a Biomarkers Consortium Project Team. In addition to the NIH and FDA, participating and funding organizations include Alzheimer's Drug Discovery Foundation, Eisai, Inc., Eli Lilly and Company, Janssen Alzheimer Immunotherapy Research & Development, Merck and Company, Pfizer Inc., Takeda Global Research and Development Center, Inc. Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IX-ICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. NR 60 TC 10 Z9 10 U1 4 U2 18 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1862-8346 EI 1862-8354 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD AUG PY 2015 VL 9 IS 7-8 SI SI BP 715 EP 731 DI 10.1002/prca.201400178 PG 17 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CM9FG UT WOS:000358012000009 PM 25676562 ER PT J AU Buchy, L Cadenhead, KS Cannon, TD Cornblatt, BA McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, SW Heinssen, R Bearden, CE Mathalon, D Addington, J AF Buchy, L. Cadenhead, K. S. Cannon, T. D. Cornblatt, B. A. McGlashan, T. H. Perkins, D. O. Seidman, L. J. Tsuang, M. T. Walker, E. F. Woods, S. W. Heinssen, R. Bearden, C. E. Mathalon, D. Addington, J. TI Substance use in individuals at clinical high risk of psychosis SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Alcohol; cannabis; prodrome; substance use; tobacco ID ULTRA-HIGH-RISK; CANNABIS USE; 1ST-EPISODE PSYCHOSIS; ADULT PSYCHOSIS; SYMPTOMS; PEOPLE; IMPACT; DISORDERS; ONSET; ADOLESCENTS AB Background. A series of research reports has indicated that the use of substances such as cannabis, alcohol and tobacco are higher in youth at clinical high risk (CHR) of developing psychosis than in controls. Little is known about the longitudinal trajectory of substance use, and findings on the relationship between substance use and later transition to psychosis in CHR individuals are mixed. Method. At baseline and 6- and 12-month follow-ups, 735 CHR and 278 control participants completed the Alcohol and Drug Use Scale and a cannabis use questionnaire. The longitudinal trajectory of substance use was evaluated with linear mixed models. Results. CHR participants endorsed significantly higher cannabis and tobacco use severity, and lower alcohol use severity, at baseline and over a 1-year period compared with controls. CHR youth had higher lifetime prevalence and frequency of cannabis, and were significantly younger upon first use, and were more likely to use alone and during the day. Baseline substance use did not differentiate participants who later transitioned to psychosis (n = 90) from those who did not transition (n = 272). Controls had lower tobacco use than CHR participants with a prodromal progression clinical outcome and lower cannabis use than those with a psychotic clinical outcome at the 2-year assessment. Conclusions. In CHR individuals cannabis and tobacco use is higher than in controls and this pattern persists across 1 year. Evaluation of clinical outcome may provide additional information on the longitudinal impact of substance use that cannot be detected through evaluation of transition/non-transition to psychosis alone. C1 [Buchy, L.; Addington, J.] Univ Calgary, Dept Psychiat, Calgary, AB T2N 4Z6, Canada. [Cadenhead, K. S.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Cannon, T. D.; Tsuang, M. T.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Cornblatt, B. A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [McGlashan, T. H.; Woods, S. W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Perkins, D. O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Seidman, L. J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Seidman, L. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walker, E. F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, E. F.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Heinssen, R.] NIMH, Schizophrenia Spectrum Res Program, Div Adult Translat Res, Bethesda, MD 20892 USA. [Bearden, C. E.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Bearden, C. E.] Univ Calif Los Angeles, Dept Biobehav Sci & Psychol, Los Angeles, CA USA. [Mathalon, D.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Addington, J (reprint author), Univ Calgary, Mathison Ctr Mental Hlth Res & Educ, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM jmadding@ucalgary.ca FU National Institute of Mental Health (NIMH) [U01MH081984, U01 MH081928, P50 MH080272, SCDMH82101008006, R01 MH60720, U01 MH082022, K24 MH76191, U01MH081902, P50 MH066286, U01MH082004, U01MH081988, U01MH08022, UO1 MH081857-05] FX This study was supported by the National Institute of Mental Health (NIMH) [grant U01MH081984 to J.A.; grants U01 MH081928; P50 MH080272; Commonwealth of Massachusetts SCDMH82101008006 to L.J.S.; grants R01 MH60720, U01 MH082022 and K24 MH76191 to K.S.C.; grant U01MH081902 to T.D.C.; P50 MH066286 (Prodromal Core) to C.E.B.; grant U01MH082004 to D.O.P.; grant U01MH081988 to E.F.W.; grant U01MH08022 to S.W.W.; and UO1 MH081857-05 grant to B.A.C.]. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 38 TC 6 Z9 6 U1 7 U2 14 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 2015 VL 45 IS 11 BP 2275 EP 2284 DI 10.1017/S0033291715000227 PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CM5PC UT WOS:000357739400004 PM 25727300 ER PT J AU Mason, MA Kuczmarski, MF Allegro, D Zonderman, AB Evans, MK AF Mason, Marc A. Kuczmarski, Marie Fanelli Allegro, Deanne Zonderman, Alan B. Evans, Michele K. TI The impact of conventional dietary intake data coding methods on foods typically consumed by low-income African-American and White urban populations SO PUBLIC HEALTH NUTRITION LA English DT Article DE Eating occasion; Dietary assessment methods; Food coding; Food preferences; African Americans ID MULTIPLE-PASS METHOD; UNITED-STATES; BEVERAGE CONSUMPTION; US ADULTS; PATTERNS; WOMEN; MEN; CHILDREN; TRENDS AB Objective: Analysing dietary data to capture how individuals typically consume foods is dependent on the coding variables used. Individual foods consumed simultaneously, like coffee with milk, are given codes to identify these combinations. Our literature review revealed a lack of discussion about using combination codes in analysis. The present study identified foods consumed at mealtimes and by race when combination codes were or were not utilized. Design: Duplicate analysis methods were performed on separate data sets. The original data set consisted of all foods reported; each food was coded as if it was consumed individually. The revised data set was derived from the original data set by first isolating coded foods consumed as individual items from those foods consumed simultaneously and assigning a code to designate a combination. Foods assigned a combination code, like pancakes with syrup, were aggregated and associated with a food group, defined by the major food component (i.e. pancakes), and then appended to the isolated coded foods. Setting: Healthy Aging in Neighborhoods of Diversity across the Life Span study. Subjects: African-American and White adults with two dietary recalls (n 2177). Results: Differences existed in lists of foods most frequently consumed by mealtime and race when comparing results based on original and revised data sets. African Americans reported consumption of sausage/luncheon meat and poultry, while ready-to-eat cereals and cakes/doughnuts/pastries were reported by Whites on recalls. Conclusions: Use of combination codes provided more accurate representation of how foods were consumed by populations. This information is beneficial when creating interventions and exploring diet-health relationships. C1 [Mason, Marc A.; Zonderman, Alan B.; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Kuczmarski, Marie Fanelli; Allegro, Deanne] Univ Delaware, Dept Behav Hlth & Nutr, Newark, DE 19716 USA. RP Kuczmarski, MF (reprint author), Univ Delaware, Dept Behav Hlth & Nutr, 010 Carpenter Sports Bldg, Newark, DE 19716 USA. EM mfk@udel.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH) FX Financial support: This work was supported by the Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH). NIH had a role in the design, analysis or writing of this article. NR 25 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 2015 VL 18 IS 11 BP 1922 EP 1931 DI 10.1017/S1368980014002687 PG 10 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA CM4RY UT WOS:000357673600003 PM 25435191 ER PT J AU Smith, SMS Sonego, S Wallen, GR Waterer, G Cheng, AC Thompson, P AF Smith, Sheree M. S. Sonego, Sandra Wallen, Gwenyth R. Waterer, Grant Cheng, Allen C. Thompson, Philip TI Use of non-pharmaceutical interventions to reduce the transmission of influenza in adults: A systematic review SO RESPIROLOGY LA English DT Review DE epidemic; influenza; non-pharmaceutical; pandemic; seasonal ID HEALTH-CARE WORKERS; PANDEMIC INFLUENZA; RANDOMIZED-TRIAL; A H1N1; RESPIRATORY ILLNESS; HAND HYGIENE; VIRUS A/H1N1; HOUSEHOLDS; INFECTION; PREVENTION AB During seasonal influenza epidemics and pandemics, virus transmission causes significant public health concern. Reduction of viral transmission by non-pharmaceutical interventions (NPI) has a significant appeal and is often recommended. However, the efficacy of such interventions is unclear. A systematic literature review was undertaken to identify and evaluate the published literature on NPI efficacy to prevent human transmission of influenza virus in adults. Reviewers assessed the quality of eligible studies utilizing the Critical Appraisal Skills Programme for bias and the Scottish Intercollegiate Guidelines Network for methodological quality. Studies were assessed for risk of bias domains of random sequence generation, allocation concealment, attribution bias, selective reporting and blinding. Relevant citations of 2247 were reduced to 100 for full-text evaluation. Only seven met all selection criteria and pooled analysis was not feasible. Of the seven studies, two were randomized controlled trials (RCT) and five were cluster RCT. The main NPI studied were disinfection and hygiene; barriers; and combined NPI. However, these seven RCT had significant design flaws. Only two studies used laboratory confirmed influenza and poor statistical power was a major problem. Positive significant interventions included professional oral hygiene intervention in the elderly and hand washing. Despite the potential for NPI in preventing influenza transmission, there is very limited data available. Hand washing and dental hygiene may be useful, but other interventions have not been fully assessed. Properly designed studies evaluating large populations including at risk' patients and in a variety of communities are needed. C1 [Smith, Sheree M. S.; Sonego, Sandra] Univ Western Sydney, Sch Nursing & Midwifery, Sydney, NSW 2751, Australia. [Waterer, Grant] Univ Western Australia, Sch Med & Pharmacol, Royal Perth Unit, Perth, WA 6009, Australia. [Thompson, Philip] Univ Western Australia, Sch Med & Pharmacol, Queen Elizabeth II Unit, Perth, WA 6009, Australia. [Thompson, Philip] Hollywood Hosp, Lung Hlth Clin, Perth, WA, Australia. [Thompson, Philip] Sir Charles Gairdner Hosp, Dept Resp Med, Perth, WA, Australia. [Cheng, Allen C.] Monash Univ, Dept Epidemiol & Preventat Med, Fac Med Nursing & Hlth Sci, Infect Dis Unit, Melbourne, Vic 3004, Australia. [Smith, Sheree M. S.] Univ London Imperial Coll Sci Technol & Med, Ctr Pharmacol & Therapeut, London, England. [Wallen, Gwenyth R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Smith, SMS (reprint author), Univ Western Sydney, Sch Nursing & Midwifery, Locked Bag 1797, Sydney, NSW 2751, Australia. EM sheree.smith@uws.edu.au OI Cheng, Allen/0000-0003-3152-116X FU Intramural NIH HHS [Z99 CL999999] NR 49 TC 2 Z9 2 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 EI 1440-1843 J9 RESPIROLOGY JI Respirology PD AUG PY 2015 VL 20 IS 6 BP 896 EP 903 DI 10.1111/resp.12541 PG 8 WC Respiratory System SC Respiratory System GA CM7MY UT WOS:000357879100008 PM 25873071 ER PT J AU Straughan, DM Neychev, VK Sadowski, SM Ellis, RJ Thomas, F Patronas, NJ Pacak, K Kebebew, E Nilubol, N AF Straughan, David M. Neychev, Vladimir K. Sadowski, Samira M. Ellis, Ryan J. Thomas, Francine Patronas, Nicholas J. Pacak, Karel Kebebew, Electron Nilubol, Naris TI Preoperative Imaging Features are Associated with Surgical Complications Following Carotid Body Tumor Resection SO WORLD JOURNAL OF SURGERY LA English DT Article ID PARAGANGLIOMAS; EXPERIENCE; MANAGEMENT; PREDICT AB Surgical resection remains the treatment of choice for carotid body tumors (CBTs). Although perioperative complications such as carotid artery injury and neurological deficits occur infrequently, they can be devastating. The aim of this study was to evaluate whether clinical factors or preoperative imaging findings can accurately predict perioperative complications. Twenty CBTs were resected from 19 patients. Preoperative computed tomography (CT) and magnetic resonance imaging (MRI) of the neck were used to measure the degree of circumferential involvement of the CBT to the internal carotid artery (ICA), carotid artery narrowing, tumor length, tumor volume, and the distance from the tip of the C2 dens to the superior aspect of the CBT (dens-CBT). Operative reports and Shamblin classification (I-III) of each tumor were independently reviewed. Preoperative imaging features were compared to perioperative cranial nerve injury (CNI), rates of carotid artery injury, and major carotid artery repairs, as well as Shamblin classifications a parts per thousand yenII. CNI was associated with a high-lying CBT (dens-CBT = 1.8 vs. 2.9 cm, p < 0.01). All four patients with CNI had a dens-CBT of < 3 cm. Neither tumor length and tumor volume nor the involvement of the ICA (a parts per thousand yen180A degrees as measured by CT or MRI) was associated with CNI, carotid artery injury, major carotid artery repair, or Shamblin II or III classification. No carotid artery narrowing was observed in any of the cases. Preoperative measurement of the dens-CBT is helpful in identifying CBTs at risk for CNI after surgical resection. C1 [Straughan, David M.] NCI, Thorac & GI Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Neychev, Vladimir K.; Sadowski, Samira M.; Ellis, Ryan J.; Kebebew, Electron; Nilubol, Naris] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Thomas, Francine; Patronas, Nicholas J.] NCI, Dept Diagnost Radiol, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Nilubol, Naris] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH Clin Res Ctr, Bethesda, MD 20892 USA. RP Straughan, DM (reprint author), NCI, Thorac & GI Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM david.m.straughan@gmail.com; niluboln@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX The research activities performed in this manuscript were supported in part by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 17 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD AUG PY 2015 VL 39 IS 8 BP 2084 EP 2089 DI 10.1007/s00268-015-3058-9 PG 6 WC Surgery SC Surgery GA CM4XW UT WOS:000357690700033 PM 25840820 ER PT J AU Rivera, DR Tran, Q Freedman, AN AF Rivera, D. R. Tran, Q. Freedman, A. N. TI ASSESSING HUMAN PAPILLOMAVIRUS (HPV) VACCINATION UTILIZATION AND ACCESS TO CARE IN THE UNITED STATES: A CROSS SECTNATIONAL ANALYSIS USING THE NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES) SO CLINICAL THERAPEUTICS LA English DT Meeting Abstract CT 12th Congress of the European-Association-for-Clinical-Pharmacology-and-Therapeutics CY JUN 27-30, 2015 CL Madrid, SPAIN SP European Assoc Clin Pharmacol & Therapeut C1 [Rivera, D. R.; Tran, Q.; Freedman, A. N.] NCI, Rockville, MD 20850 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER PI BRIDGEWATER PA 685 ROUTE 202-206, BRIDGEWATER, NJ 08807 USA SN 0149-2918 EI 1879-114X J9 CLIN THER JI Clin. Ther. PD AUG PY 2015 VL 37 IS 8 SU S BP E17 EP E18 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DY2VW UT WOS:000384951200051 ER PT J AU Mima, K Sukawa, Y Nishihara, R Qian, ZR Yamauchi, M Inamura, K Kim, SA Masuda, A Nowak, JA Nosho, K Kostic, AD Giannakis, M Watanabe, H Bullman, S Milner, DA Harris, CC Giovannucci, E Garraway, LA Freeman, GJ Dranoff, G Chan, AT Garrett, WS Huttenhower, C Fuchs, CS Ogino, S AF Mima, Kosuke Sukawa, Yasutaka Nishihara, Reiko Qian, Zhi Rong Yamauchi, Mai Inamura, Kentaro Kim, Sun A. Masuda, Atsuhiro Nowak, Jonathan A. Nosho, Katsuhiko Kostic, Aleksandar D. Giannakis, Marios Watanabe, Hideo Bullman, Susan Milner, Danny A. Harris, Curtis C. Giovannucci, Edward Garraway, Levi A. Freeman, Gordon J. Dranoff, Glenn Chan, Andrew T. Garrett, Wendy S. Huttenhower, Curtis Fuchs, Charles S. Ogino, Shuji TI Fusobacterium nucleatum and T Cells in Colorectal Carcinoma SO JAMA ONCOLOGY LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; MICROSATELLITE INSTABILITY; COLON-CANCER; IMMUNE MICROENVIRONMENT; MOLECULAR-FEATURES; PATIENT SURVIVAL; PIK3CA MUTATION; HUMAN GUT; MICROBIOTA; TUMORS AB IMPORTANCE Evidence indicates a complex link between gut microbiome, immunity, and intestinal tumorigenesis. To target the microbiota and immunity for colorectal cancer prevention and therapy, a better understanding of the relationship between microorganisms and immune cells in the tumor microenvironment is needed. Experimental evidence suggests that Fusobacterium nucleatum may promote colonic neoplasia development by downregulating antitumor T cell-mediated adaptive immunity. OBJECTIVE To test the hypothesis that a greater amount of F nucleatum in colorectal carcinoma tissue is associated with a lower density of T cells in tumor tissue. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional analysis was conducted on 598 rectal and colon carcinoma cases in 2 US nationwide prospective cohort studies with follow-up through 2006, the Nurses' Health Study (participants enrolled in 1976) and the Health Professionals Follow-up Study (participants enrolled in 1986). Tissue collection and processing were performed from 2002 through 2008, and immunity assessment, 2008 through 2009. From 2013 through 2014, the amount of F nucleatum in colorectal carcinoma tissue was measured by quantitative polymerase chain reaction assay; we equally dichotomized positive cases (high vs low). Multivariable ordinal logistic regression analysis was conducted in 2014 to assess associations of the amount of F nucleatum with densities (quartiles) of T cells in tumor tissue, controlling for clinical and tumor molecular features, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 (LINE-1) methylation, and KRAS, BRAF, and PIK3CA mutation status. We adjusted the 2-sided a level to.013 for multiple hypothesis testing. MAIN OUTCOMES AND MEASURES Densities of CD3(+), CD8(+), CD45RO (protein tyrosine phosphatase receptor type C [PTPRC])(+), and FOXP3(+) T cells in tumor tissue, determined by means of tissue microarray immunohistochemical analysis and computer-assisted image analysis. RESULTS F nucleatum was detected in colorectal carcinoma tissue in 76 (13%) of 598 cases. Compared with F nucleatum-negative cases, F nucleatum-high cases were inversely associated with the density of CD3(+) T cells (for a unit increase in quartile categories of CD3(+) T cells as an outcome: multivariable odds ratio, 0.47 [95% CI, 0.26-0.87]; P for trend =.006). The amount of F nucleatum was not significantly associated with the density of CD8(+), CD45RO(+), or FOXP3(+) T cells (P for trend =.24,.88, and.014, respectively). CONCLUSIONS AND RELEVANCE The amount of tissue F nucleatum is inversely associated with CD3(+) T-cell density in colorectal carcinoma tissue. On validation, our human population data may provide an impetus for further investigations on potential interactive roles of Fusobacterium and host immunity in colon carcinogenesis. C1 [Mima, Kosuke; Sukawa, Yasutaka; Qian, Zhi Rong; Yamauchi, Mai; Inamura, Kentaro; Kim, Sun A.; Masuda, Atsuhiro; Giannakis, Marios; Watanabe, Hideo; Bullman, Susan; Garraway, Levi A.; Freeman, Gordon J.; Dranoff, Glenn; Garrett, Wendy S.; Fuchs, Charles S.; Ogino, Shuji] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. [Nishihara, Reiko; Giovannucci, Edward] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Nishihara, Reiko; Giovannucci, Edward; Ogino, Shuji] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Inamura, Kentaro; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Nowak, Jonathan A.; Milner, Danny A.; Ogino, Shuji] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Nosho, Katsuhiko] Sapporo Med Univ, Sch Med, Dept Gastroenterol Rheumatol & Clin Immunol, Sapporo, Hokkaido, Japan. [Kostic, Aleksandar D.; Huttenhower, Curtis] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kostic, Aleksandar D.; Garrett, Wendy S.; Huttenhower, Curtis] Massachusetts Inst Technol & Harvard, Broad Inst, Cambridge, MA USA. [Milner, Danny A.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Freeman, Gordon J.; Dranoff, Glenn] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Chan, Andrew T.; Fuchs, Charles S.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Ogino, S (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu FU National Institutes of Health (NIH) [P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552, K07 CA190673, R01 CA137178, P50 CA127003, R01 CA151993]; Paula and Russell Agrusa Fund for Colorectal Cancer Research; Friends of the Dana-Farber Cancer Institute; Bennett Family Fund; Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance; Uehara Memorial Foundation; Asan Medical Center FX This work was supported by National Institutes of Health (NIH) grants (P01 CA87969 to S. E. Hankinson, UM1 CA186107 to M. J. Stampfer, P01 CA55075 and UM1 CA167552 to W. C. Willett, K07 CA190673 to Dr Nishihara, R01 CA137178 to Dr Chan, P50 CA127003 to Dr Fuchs, R01 CA151993 to Dr Ogino) and by grants from the Paula and Russell Agrusa Fund for Colorectal Cancer Research, the Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance. Dr Mima is supported by a fellowship grant from Uehara Memorial Foundation. Dr Kim is supported by an Early Exchange Postdoctoral Fellowship Grant from Asan Medical Center. NR 49 TC 39 Z9 39 U1 6 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD AUG PY 2015 VL 1 IS 5 BP 653 EP 661 DI 10.1001/jamaoncol.2015.1377 PG 9 WC Oncology SC Oncology GA DW5HA UT WOS:000383673100020 PM 26181352 ER PT J AU Esnault, C Levin, HL AF Esnault, Caroline Levin, Henry L. TI The Long Terminal Repeat Retrotransposons Tf1 and Tf2 of Schizosaccharomyces pombe SO MICROBIOLOGY SPECTRUM LA English DT Article ID PRIMED REVERSE TRANSCRIPTION; REPLICATION FORK ARREST; VIRUS-LIKE PARTICLES; NUCLEAR-PORE FACTOR; POL-II PROMOTERS; FISSION YEAST; TRANSPOSABLE ELEMENTS; CENP-B; HETEROCHROMATIN FORMATION; CHROMOSOME SEGREGATION AB The long terminal repeat (LTR) retrotransposons Tf1 and Tf2 of Schizosaccharomyces pombe are active mobile elements of the Ty3/gypsy family. The mobilization of these retrotransposons depends on particle formation, reverse transcription and integration, processes typical of other LTR retrotransposons. However, Tf1 and Tf2 are distinct from other LTR elements in that they assemble virus-like particles from a single primary translation product, initiate reverse transcription with an unusual self-priming mechanism, and, in the case of Tf1, integrate with a pattern that favors specific promoters of RNA pol II-transcribed genes. To avoid the chromosome instability and genome damage that results from increased copy number, S. pombe applies a variety of defense mechanisms that restrict Tf1 and Tf2 activity. The mRNA of the Tf elements is eliminated by an exosome-based pathway when cells are in favorable conditions whereas nutrient deprivation triggers an RNA interference-dependent pathway that results in the heterochromatization of the elements. Interestingly, Tf1 integrates into the promoters of stress-induced genes and these insertions are capable of increasing the expression of adjacent genes. These properties of Tf1 transposition raise the possibility that Tf1 benefits cells with specific insertions by providing resistance to environmental stress. C1 [Esnault, Caroline; Levin, Henry L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Eukaryot Transposable Elements, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. RP Levin, HL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Eukaryot Transposable Elements, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. EM henry_levin@nih.gov NR 99 TC 2 Z9 2 U1 0 U2 1 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 2015 VL 3 IS 4 AR UNSP MDNA3-0040-2014 DI 10.1128/microbiolspec.MDNA3-0040-2014 PG 13 WC Microbiology SC Microbiology GA DT9EI UT WOS:000381798100018 ER PT J AU He, S Corneloup, A Guynet, C Lavatine, L Caumont-Sarcos, A Siguier, P Marty, B Dyda, F Chandler, M Hoang, BT AF He, S. Corneloup, A. Guynet, C. Lavatine, L. Caumont-Sarcos, A. Siguier, P. Marty, B. Dyda, F. Chandler, M. Hoang, B. Ton TI The IS200/IS605 Family and "Peel and Paste" Single-strand Transposition Mechanism SO MICROBIOLOGY SPECTRUM LA English DT Article ID REPETITIVE EXTRAGENIC PALINDROMES; COORDINATED LEADING-STRAND; DNA-REPLICATION FORK; GROUP-I INTRONS; ESCHERICHIA-COLI; INSERTION-SEQUENCE; TRANSPOSABLE ELEMENTS; HELICOBACTER-PYLORI; DEINOCOCCUS-RADIODURANS; FUNCTIONAL-ORGANIZATION AB This chapter presents an analysis of the organization and distribution of the IS200/IS605 family of insertion sequences (IS). Members of this family are widespread in both bacteria and archaea. They are unusual because they use obligatory single-strand DNA intermediates, which distinguishes them from classical IS. We summarize studies of the experimental model systems IS608 (from Helicobacter pylori) and ISDra2 (from Deinococcus radiodurans) and present biochemical, genetic, and structural data that describe their transposition pathway and the way in which their transposase (an HuH rather than a DDE enzyme) catalyzes this process. The transposition of IS200/IS605 family members can be described as a "Peel-and-Paste" mechanism. We also address the probable domestication of IS200/IS605 family transposases as enzymes involved in multiplication of repeated extragenic palindromes and as potential homing endonucleases in intron-IS chimeras. C1 [He, S.; Corneloup, A.; Guynet, C.; Lavatine, L.; Caumont-Sarcos, A.; Siguier, P.; Marty, B.; Chandler, M.; Hoang, B. Ton] CNRS, Lab Microbiol & Genet Mol, Toulouse, France. [Dyda, F.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hoang, BT (reprint author), CNRS, Lab Microbiol & Genet Mol, Toulouse, France. EM tonhoang@ibcg.biotoul.fr NR 66 TC 2 Z9 2 U1 0 U2 0 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 2015 VL 3 IS 4 AR UNSP MDNA3-0039-2014 DI 10.1128/microbiolspec.MDNA3-0039-2014 PG 21 WC Microbiology SC Microbiology GA DT9EI UT WOS:000381798100017 ER PT J AU Skolnick, P Kos, T Czekaj, J Popik, P AF Skolnick, Phil Kos, Tomasz Czekaj, Janusz Popik, Piotr TI Effect of NMDAR antagonists in the tetrabenazine test for antidepressants: comparison with the tail suspension test SO ACTA NEUROPSYCHIATRICA LA English DT Article DE antidepressant; NMDAR antagonist; ptosis; tail suspension test; tetrabenazine ID FORCED SWIMMING TEST; MAJOR DEPRESSIVE DISORDER; D-ASPARTATE ANTAGONIST; CHRONIC MILD STRESS; RECEPTOR ANTAGONISTS; PARKINSONS-DISEASE; PREFRONTAL CORTEX; CHANNEL BLOCKER; ANIMAL-MODELS; KETAMINE AB Objective The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine, produces rapid and enduring antidepressant effect in patients with treatment-resistant depression. Similar dramatic effects have not been observed in clinical trials with other NMDAR antagonists indicating ketamine may possess unique pharmacological properties. Tetrabenazine induces ptosis (a drooping of the eyelids), and the reversal of this effect, attributed to a sympathomimetic action, has been used to detect first-generation antidepressants, as well as ketamine. Because the actions of other NMDAR antagonists have not been reported in this measure, we examined whether reversal of tetrabenazine-induced ptosis was unique to ketamine, or a class effect of NMDAR antagonists. Methods The effects of ketamine and other NMDAR antagonists to reverse tetrabenazine-induced ptosis were examined and compared with their antidepressant-like effects in the tail suspension test (TST) in mice. Results All the NMDAR antagonists tested produced a partial reversal of tetrabenazine-induced ptosis and, as expected, reduced immobility in the TST. Ketamine, memantine, MK-801 and AZD6765 were all about half as potent in reversing tetrabenazine-induced ptosis compared to reducing immobility in the TST, while an NR2B antagonist (Ro 25-6981) and a glycine partial agonist (ACPC) were equipotent in both tests. Conclusion The ability to reverse tetrabenazine-induced ptosis is a class effect of NMDAR antagonists. These findings are consistent with the hypothesis that the inability of memantine, AZD6765 (lanicemine) and MK-0657 to reproduce the rapid and robust antidepressant effects of ketamine in the clinic result from insufficient dosing rather than a difference in mechanism of action among these NMDAR antagonists. C1 [Skolnick, Phil] NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. [Kos, Tomasz; Popik, Piotr] Polish Acad Sci, Inst Pharmacol, Behav Neurosci & Drug Dev, Krakow, Poland. [Czekaj, Janusz; Popik, Piotr] Jagiellonian Univ, Coll Med, Fac Hlth Sci, Krakow, Poland. RP Popik, P (reprint author), Polish Acad Sci, Inst Pharmacol, Krakow, Poland. EM nfpopik@cyf-kr.edu.pl RI Popik, Piotr/R-5383-2016 OI Popik, Piotr/0000-0003-0722-1263 FU Statutory Activity of Institute of Pharmacology, Polish Academy of Sciences FX This work was funded by the Statutory Activity of Institute of Pharmacology, Polish Academy of Sciences. The authors thank Dr. A. Bespalov for the generous gift of tetrabenazine. P.S. and P.P. designed the study and wrote the manuscript. T.K. carried out the experiments, analysed the data and wrote parts of the manuscript. J.C. provided important intellectual content, assisted with the interpretation of results and approved the final version. NR 50 TC 3 Z9 3 U1 4 U2 10 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1601-5215 J9 ACTA NEUROPSYCHIATR JI Acta Neuropsychiatr. PD AUG PY 2015 VL 27 IS 4 BP 228 EP 234 DI 10.1017/neu.2015.14 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CM2SY UT WOS:000357533600005 PM 25858023 ER PT J AU Prasad, V AF Prasad, Vinay TI Use of the Word "Cure" in the Oncology Literature SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Editorial Material DE cure; oncology; language; cancer care; excellence ID METASTATIC COLORECTAL-CANCER; BREAST-CANCER; STAGE; SURVIVAL; RATES; CHALLENGES; PREVENTION; EXPERIENCE; DIAGNOSIS; DISEASE AB Purpose: Cure is an important word in oncology but its use in the published literature has not been examined. I investigated all oncology articles using cure in the title field and published in 2012. The definition of cure was examined, specifically whether or not authors use the word to connote some surviving subset of patients who go on to experience outcomes similar to age-matched, normal controlsa definition favored by researchers and employed in survival function analyses. Methods: All articles published between January 1, 2012, and December 31, 2012, with the word cure in the title field were retrieved from Thompson Reuters' Web of Science. After exclusions, articles were read in full to examine what definitions of cure was used. Additionally, for each situation (type of cancer, stage/grade) where the word cure was used, a literature search was performed to ascertain whether there existed documented cases of cure. Results: Twenty-nine oncology articles used the word cure in their title in 2012. Nearly half, 14 (48%) of 29, used the term in situations (cancer type, stage/grade) currently considered incurable. Approximately one-third (34.5%) of the articles used the word consistent with the definition that, after a set period of time, some surviving subset of patients experience survival similar to normal controls. Conclusion: There is heterogeneity in the use of the word cure in the literature. C1 [Prasad, Vinay] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr 10-12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov NR 32 TC 1 Z9 1 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 EI 1938-2715 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD AUG PY 2015 VL 32 IS 5 BP 477 EP 483 DI 10.1177/1049909114524477 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CM5QZ UT WOS:000357745000001 PM 24558172 ER PT J AU Taber, JM Klein, WMP Ferrer, RA Lewis, KL Harris, PR Shepperd, JA Biesecker, LG AF Taber, Jennifer M. Klein, William M. P. Ferrer, Rebecca A. Lewis, Katie L. Harris, Peter R. Shepperd, James A. Biesecker, Leslie G. TI Information Avoidance Tendencies, Threat Management Resources, and Interest in Genetic Sequencing Feedback SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Information avoidance; Genomics; Genetics; Self-affirmation; Threat; Optimism ID SELF-AFFIRMATION; IMPLEMENTATION INTENTIONS; RISK; DISEASE; OPTIMISM; CLINSEQ; CANCER AB Information avoidance is a defensive strategy that undermines receipt of potentially beneficial but threatening health information and may especially occur when threat management resources are unavailable. We examined whether individual differences in information avoidance predicted intentions to receive genetic sequencing results for preventable and unpreventable (i.e., more threatening) disease and, secondarily, whether threat management resources of self-affirmation or optimism mitigated any effects. Participants (N = 493) in an NIH study (ClinSeqA (R)) piloting the use of genome sequencing reported intentions to receive (optional) sequencing results and completed individual difference measures of information avoidance, self-affirmation, and optimism. Information avoidance tendencies corresponded with lower intentions to learn results, particularly for unpreventable diseases. The association was weaker among individuals higher in self-affirmation or optimism, but only for results regarding preventable diseases. Information avoidance tendencies may influence decisions to receive threatening health information; threat management resources hold promise for mitigating this association. C1 [Taber, Jennifer M.; Klein, William M. P.; Ferrer, Rebecca A.] NCI, NIH, Bethesda, MD 20892 USA. [Lewis, Katie L.; Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Harris, Peter R.] Univ Sussex, Sch Psychol, Brighton BN1 9RH, E Sussex, England. [Shepperd, James A.] Univ Florida, Dept Psychol, Gainesville, FL 32611 USA. RP Taber, JM (reprint author), NCI, NIH, 9609 Med Ctr Dr,Room 3E642, Bethesda, MD 20892 USA. EM jennifer.taber@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 38 TC 5 Z9 5 U1 9 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD AUG PY 2015 VL 49 IS 4 BP 616 EP 621 DI 10.1007/s12160-014-9679-7 PG 6 WC Psychology, Multidisciplinary SC Psychology GA CM4ZJ UT WOS:000357695400012 PM 25582989 ER PT J AU Kelly, NR Shomaker, LB Pickworth, CK Grygorenko, MV Radin, RM Vannucci, A Shank, LM Brady, SM Courville, AB Tanofsky-Kraff, M Yanovski, JA AF Kelly, Nichole R. Shomaker, Lauren B. Pickworth, Courtney K. Grygorenko, Mariya V. Radin, Rachel M. Vannucci, Anna Shank, Lisa M. Brady, Sheila M. Courville, Amber B. Tanofsky-Kraff, Marian Yanovski, Jack A. TI Depressed affect and dietary restraint in adolescent boys' and girls' eating in the absence of hunger SO APPETITE LA English DT Article DE Eating in the absence of hunger; Dietary restraint; Mood; Negative affect; Emotional eating ID ECOLOGICAL MOMENTARY ASSESSMENT; SENSORY-SPECIFIC SATIETY; ENERGY-INTAKE; FOOD CHOICE; CONSTRUCT-VALIDITY; PUBERTAL CHANGES; NEGATIVE AFFECT; OBESE ADULTS; ACUTE STRESS; CHILDREN AB Data suggest that depressed affect and dietary restraint are related to disinhibited eating patterns in children and adults. Yet, experimental research has not determined to what extent depressed affect acutely affects eating in the absence of physiological hunger (EAH) in adolescents. In the current between-subjects experimental study, we measured EAH in 182 adolescent (13-17 y) girls (65%) and boys as ad libitum palatable snack food intake after youth ate to satiety from a buffet meal. Just prior to EAH, participants were randomly assigned to view either a sad or neutral film clip. Dietary restraint was measured with the Eating Disorder Examination. Adolescents who viewed the sad film clip reported small but significant increases in state depressed affect relative to adolescents who viewed the neutral film clip (p <.001). Yet, there was no main effect of film condition on EAH (p =.26). Instead, dietary restraint predicted greater EAH among girls, but not boys (p <.001). These findings provide evidence that adolescent girls' propensity to report restrained eating is associated with their greater disinhibited eating in the laboratory. Additional experimental research, perhaps utilizing a more potent laboratory stressor and manipulating both affective state and dietary restraint, is required to elucidate how state affect may interact with dietary restraint to influence EAH during adolescence. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Kelly, Nichole R.; Radin, Rachel M.; Vannucci, Anna; Shank, Lisa M.; Tanofsky-Kraff, Marian] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Kelly, Nichole R.; Shomaker, Lauren B.; Pickworth, Courtney K.; Grygorenko, Mariya V.; Radin, Rachel M.; Vannucci, Anna; Shank, Lisa M.; Brady, Sheila M.; Tanofsky-Kraff, Marian; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Kelly, Nichole R.; Shomaker, Lauren B.] Colorado State Univ, Ft Collins, CO 80523 USA. [Courville, Amber B.] NIH, Dept Nutr, Ctr Clin, Bethesda, MD 20892 USA. RP Shomaker, LB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, US Dept HHS,NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM lauren.shomaker@colostate.edu OI , Amber/0000-0002-1419-3937; Shank, Lisa/0000-0002-6922-7946 FU NIH from National Institute of Child Health and Human Development [1ZIAH0000641]; NIH [Y1CH8385858]; Office of Behavioral and Social Sciences Research; NIH National Research Service Award [F32HD056762]; Pathway to Independence Award from NICHD [K99/R00HD069516] FX NIH Intramural Research Program Grant 1ZIAH0000641 (J. Yanovski) from National Institute of Child Health and Human Development with supplemental funding from the NIH Bench to Bedside Program Y1CH8385858 and the Office of Behavioral and Social Sciences Research; NIH National Research Service Award F32HD056762 and Pathway to Independence Award K99/R00HD069516 (L. Shomaker) from NICHD. NR 77 TC 1 Z9 1 U1 4 U2 13 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD AUG 1 PY 2015 VL 91 BP 343 EP 350 DI 10.1016/j.appet.2015.04.072 PG 8 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA CM2XW UT WOS:000357546600045 PM 25936291 ER PT J AU Hotaling, NA Bharti, K Kriel, H Simon, CG AF Hotaling, Nathan A. Bharti, Kapil Kriel, Haydn Simon, Carl G., Jr. TI DiameterJ: A validated open source nanofiber diameter measurement tool SO BIOMATERIALS LA English DT Article DE ImageJ; Image analysis; FIJI; Scaffold; Morphology; Structure ID IMAGE-ANALYSIS; BIOSENSOR APPLICATIONS; MECHANICAL-PROPERTIES; FIBER DIAMETER; IN-VITRO; ELECTROSPUN; CELL; SCAFFOLD; TISSUE; DIFFERENTIATION AB Despite the growing use of nanofiber scaffolds for tissue engineering applications, there is not a validated, readily available, free solution for rapid, automated analysis of nanofiber diameter from scanning electron microscope (SEM) micrographs. Thus, the goal of this study was to create a user friendly ImageJ/FIJI plugin that would analyze SEM micrographs of nanofibers to determine nanofiber diameter on a desktop computer within 60 s. Additional design goals included 1) compatibility with a variety of existing segmentation algorithms, and 2) an open source code to enable further improvement of the plugin. Using existing algorithms for centerline determination, Euclidean distance transforms and a novel pixel transformation technique, a plugin called "DiameterJ" was created for ImageJ/FIJI. The plugin was validated using 1) digital synthetic images of white lines on a black background and 2) SEM images of nominally monodispersed steel wires of known diameters. DiameterJ analyzed SEM micrographs in 20 s, produced diameters not statistically different from known values, was over 10-times closer to known diameter values than other open source software, provided hundreds of times the sampling of manual measurement, and was hundreds of times faster than manual assessment of nanofiber diameter. DiameterJ enables users to rapidly and thoroughly determine the structural features of nanofiber scaffolds and could potentially allow new insights to be formed into fiber diameter distribution and cell response. Published by Elsevier Ltd. C1 [Hotaling, Nathan A.; Simon, Carl G., Jr.] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Bharti, Kapil] NEI, Unit Ocular & Stem Cell Translat Res, NIH, Bethesda, MD 20892 USA. [Kriel, Haydn] Stellenbosch Nanofiber Co Pty Ltd, Cape Town, South Africa. RP Hotaling, NA (reprint author), NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. EM Nathan.Hotaling@gmail.com OI Hotaling, Nathan/0000-0001-8423-6464 FU Intramural NIH HHS [ZIA EY000531-02, Z99 EY999999] NR 56 TC 25 Z9 25 U1 5 U2 22 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2015 VL 61 BP 327 EP 338 DI 10.1016/j.biomaterials.2015.05.015 PG 12 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CL8MX UT WOS:000357229900031 PM 26043061 ER PT J AU Felix, AS Arem, H Trabert, B Gierach, GL Park, Y Pfeiffer, RM Brinton, LA AF Felix, Ashley S. Arem, Hannah Trabert, Britton Gierach, Gretchen L. Park, Yikyung Pfeiffer, Ruth M. Brinton, Louise A. TI Menopausal hormone therapy and mortality among endometrial cancer patients in the NIH-AARP Diet and Health Study SO CANCER CAUSES & CONTROL LA English DT Article DE Estrogen plus progestin; Endometrial cancer; Survival ID ESTROGEN PLUS PROGESTIN; REPLACEMENT THERAPY; POSTMENOPAUSAL WOMEN; CARCINOMA; SURVIVAL; COHORT; USERS; RISK; ADENOCARCINOMA; NONUSERS AB While menopausal hormone therapy (MHT) is an established endometrial cancer risk factor, its relationship with mortality among endometrial cancer patients is understudied. Within the NIH-AARP Diet and Health Study, we examined the associations of pre-diagnosis MHT use with 10-year all-cause and endometrial cancer-specific mortality among 890 endometrial cancer patients. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) adjusted for tumor characteristics, treatment, and other risk factors. Endometrial cancer cases were diagnosed a median of 4.6 years (range 0.0-10.1 years) after the second risk factor questionnaire was completed. We identified a total of 241 deaths, of which 104 were due to endometrial cancer. Compared with non-MHT use, pre-diagnosis use of estrogen plus progestin therapy (EPT)-only was associated with lower 10-year all-cause (HR 0.65, 95 % CI 0.43-0.99, based on 29 deaths) and endometrial cancer-specific mortality (HR 0.51, 95 % CI 0.26-0.98, based on 11 deaths). Recency of MHT use, assessed approximately 5 years prior to the endometrial cancer diagnosis, was associated with mortality. Compared with non-MHT users, former ET users had higher all-cause (HR 1.71, 95 % CI 1.02-2.88, based on 18 deaths) and endometrial cancer-specific mortality (HR 2.17, 95 % CI 0.96-4.90, based on 8 deaths), whereas current EPT users had nonsignificant lower risks of death. Based on small numbers, we observed that pre-diagnosis use of EPT was related to lower mortality among endometrial cancer patients. Future studies examining the biological mechanisms underlying this association are warranted. C1 [Felix, Ashley S.; Trabert, Britton; Gierach, Gretchen L.; Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Felix, Ashley S.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Arem, Hannah; Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Felix, AS (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 7E214, Bethesda, MD 20892 USA. EM ashley.felix@nih.gov RI Trabert, Britton/F-8051-2015; Gierach, Gretchen/E-1817-2016; Felix, Ashley/A-3240-2016; OI Gierach, Gretchen/0000-0002-0165-5522; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute FX This research was supported (in part) by the Intramural Research Program of the National Cancer Institute. NR 27 TC 1 Z9 1 U1 0 U2 1 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 2015 VL 26 IS 8 BP 1055 EP 1063 DI 10.1007/s10552-015-0598-0 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CM4LX UT WOS:000357657200001 PM 25962764 ER PT J AU Kent, EE Breen, N Lewis, DR de Moor, JS Smith, AW Seibel, NL AF Kent, Erin E. Breen, Nancy Lewis, Denise R. de Moor, Janet S. Smith, Ashley Wilder Seibel, Nita L. TI US trends in survival disparities among adolescents and young adults with non-Hodgkin lymphoma SO CANCER CAUSES & CONTROL LA English DT Article DE Non-Hodgkin lymphoma; Adolescents and young adults; Relative survival; Cancer health disparities; Surveillance ID LARGE B-CELL; UNITED-STATES; CANCER; HEALTH; CARE; EPIDEMIOLOGY; INEQUALITIES; MORTALITY; DIAGNOSIS; RATES AB Improvement in US survival rates among adolescents and young adults (AYAs, ages 15 through 39 years inclusive) diagnosed with non-Hodgkin lymphoma (NHL) has been documented over the last two decades. We examined national trends in survival disparities for AYAs with NHL by race/ethnicity and socioeconomic status (SES, county-level poverty) to further understand NHL and to begin monitoring health outcome disparities for this disease. Surveillance Epidemiology and End Results data were used to calculate 5-year relative survival rates of AYAs diagnosed with NHL from 1992 to 2007 and followed through 2011. Absolute and relative disparities were computed using HD*Calc. Whether a significant linear trend was present was evaluated using Joinpoint. Analyses were replicated after excluding individuals with known HIV infection. The study sample included 9,573 total and 7,121 non-HIV cases of NHL. Five-year survival rates improved for all groups over time. Significant decreases were found in absolute disparities for race/ethnicity (non-HIV), in relative disparities for SES (total) and race/ethnicity (total and non-HIV) (all p < 0.05). Survival rates of non-Hispanic Blacks and Hispanics remained below than those of non-Hispanic Whites throughout the time period. Absolute and relative disparities in 5-year survival narrowed for AYAs with NHL over the time period. To continue to promote this trend, future research should investigate factors, particularly diagnostic delays and barriers to care, which continue to contribute to SES and racial/ethnic differences in survival. These factors may be particularly relevant to identify given the recent Affordable Care Act, which is designed to increase access to medical services, particularly for young adults. C1 [Kent, Erin E.; Smith, Ashley Wilder] NCI, Outcomes Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Breen, Nancy] NCI, Hlth Syst & Intervent Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Lewis, Denise R.] NCI, Data Qual Anal & Interpretat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [de Moor, Janet S.] NCI, Healthcare Assessment Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Seibel, Nita L.] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD 20850 USA. RP Kent, EE (reprint author), NCI, Outcomes Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM Erin.Kent@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 38 TC 3 Z9 3 U1 1 U2 10 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 2015 VL 26 IS 8 BP 1153 EP 1162 DI 10.1007/s10552-015-0609-1 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CM4LX UT WOS:000357657200010 PM 26084209 ER PT J AU Fedick, AM Shi, L Jalas, C Treff, NR Ekstein, J Kornreich, R Edelmann, L Mehta, L Savage, SA AF Fedick, A. M. Shi, L. Jalas, C. Treff, N. R. Ekstein, J. Kornreich, R. Edelmann, L. Mehta, L. Savage, S. A. TI Carrier screening of RTEL1 mutations in the Ashkenazi Jewish population SO CLINICAL GENETICS LA English DT Article DE Ashkenazi Jewish; carrier screening; dyskeratosis congenita; Hoyeraal-Hreidarsson syndrome; RTEL1 ID DYSKERATOSIS-CONGENITA; TELOMERE; HELICASE; REPLICATION AB Hoyeraal-Hreidarsson syndrome (HH) is a clinically severe variant of dyskeratosis congenita (DC), characterized by cerebellar hypoplasia, microcephaly, intrauterine growth retardation, and severe immunodeficiency in addition to features of DC. Germline mutations in the RTEL1 gene have recently been identified as causative of HH. In this study, the carrier frequency for five RTEL1 mutations that occurred in individuals of Ashkenazi Jewish descent was investigated in order to advise on including them in existing clinical mutation panels for this population. Our screening showed that the carrier frequency for c.3791G>A (p.R1264H) was higher than expected, 1% in the Ashkenazi Orthodox and 0.45% in the general Ashkenazi Jewish population. Haplotype analyses suggested the presence of a common founder. We recommend that the c.3791G>A RTEL1 mutation be considered for inclusion in carrier screening panels in the Ashkenazi population. C1 [Fedick, A. M.; Treff, N. R.] Rutgers Robert Wood Johnson Med Sch, Dept Microbiol & Mol Genet, Piscataway, NJ USA. [Fedick, A. M.; Treff, N. R.] Reprod Med Associates New Jersey, Basking Ridge, NJ USA. [Shi, L.; Kornreich, R.; Edelmann, L.; Mehta, L.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Jalas, C.] Bonei Olam, Ctr Rare Jewish Genet Disorders, Brooklyn, NY USA. [Ekstein, J.] Dor Yeshorim, Comm Prevent Jewish Dis, Brooklyn, NY USA. [Savage, S. A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E456,MSC 9772, Rockville, MD 20850 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 NR 17 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 EI 1399-0004 J9 CLIN GENET JI Clin. Genet. PD AUG PY 2015 VL 88 IS 2 BP 177 EP 181 DI 10.1111/cge.12459 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA CM4YG UT WOS:000357692000014 PM 25047097 ER PT J AU Kukke, SN de Campos, AC Damiano, D Alter, KE Patronas, N Hallett, M AF Kukke, Sahana N. de Campos, Ana Carolina Damiano, Diane Alter, Katharine E. Patronas, Nicholas Hallett, Mark TI Cortical activation and inter-hemispheric sensorimotor coherence in individuals with arm dystonia due to childhood stroke SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Childhood stroke; Dystonia; Electroencephalography; Cortical activation; Coherence; Cerebral palsy ID TRANSCRANIAL MAGNETIC STIMULATION; EVENT-RELATED DESYNCHRONIZATION; HEMIPARETIC CEREBRAL-PALSY; WRITERS CRAMP; CONGENITAL HEMIPARESIS; SECONDARY DYSTONIA; MOVEMENT-DISORDERS; PERINATAL STROKE; CORPUS-CALLOSUM; MIRROR DYSTONIA AB Objective: Dystonia is a disabling motor disorder often without effective therapies. To better understand the genesis of dystonia after childhood stroke, we analyzed electroencephalographic (EEG) recordings in this population. Methods: Resting spectral power of EEG signals over bilateral sensorimotor cortices (Powrest), resting inter-hemispheric sensorimotor coherence (Coh(rest)), and task-related changes in power (TRPow) and coherence (TRCoh) during wrist extension were analyzed in individuals with dystonia (age 20 +/- 3 years) and healthy volunteers (age 17 +/- 5 years). Results: Ipsilesional TRPow decrease was significantly lower in patients than controls during the more affected wrist task. Force deficits of the affected wrist correlated with reduced alpha TRPow decrease on the ipsilesional and not the contralesional hemisphere. Coh(rest) was significantly lower in patients than controls, and correlated with more severe dystonia and poorer hand function. Powrest and TRCoh were similar between groups. Conclusions: The association between weakness and cortical activation during wrist extension highlights the importance of ipsilesional sensorimotor activation on function. Reduction of Coh(rest) in patients reflects a loss of inter-hemispheric connectivity that may result from structural changes and neuroplasticity, potentially contributing to the development of dystonia. Significance: Cortical and motor dysfunction are correlated in patients with childhood stroke and may in part explain the genesis of dystonia. Published by Elsevier Ltd. on behalf of International Federation of Clinical Neurophysiology. C1 [Kukke, Sahana N.] Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA. [Kukke, Sahana N.; de Campos, Ana Carolina; Damiano, Diane; Alter, Katharine E.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD USA. [Kukke, Sahana N.; Hallett, Mark] NINDS, NIH, Bethesda, MD 20892 USA. [Alter, Katharine E.] Mt Washington Pediat Hosp, Washington, DC USA. [Patronas, Nicholas] NIH, Dept Radiol, Ctr Clin, Bethesda, MD USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 7D37,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov RI de Campos, Ana Carolina/J-3676-2015; Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU NIH, National Institute of Neurological Disorders and Stroke; NIH Clinical Center FX The authors acknowledge the assistance of Sherry Vorbach in all data collection sessions, and Sophia Francis and Francesca Gajofatto in preliminary data analysis. This work was supported by the Intramural Research Programs of the NIH, National Institute of Neurological Disorders and Stroke, and the NIH Clinical Center. NR 58 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD AUG PY 2015 VL 126 IS 8 BP 1589 EP 1598 DI 10.1016/j.clinph.2014.11.002 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CM2DA UT WOS:000357488800020 PM 25499610 ER PT J AU Kutty, RK Samuel, W Abay, R Cherukuri, A Nagineni, CN Duncan, T Jaworski, C Vijayasarathy, C Redmond, TM AF Kutty, R. Krishnan Samuel, William Abay, Rebecca Cherukuri, Aswini Nagineni, Chandrasekharam N. Duncan, Todd Jaworski, Cynthia Vijayasarathy, Camasamudram Redmond, T. Michael TI Resveratrol attenuates CXCL11 expression induced by proinflammatory cytokines in retinal pigment epithelial cells SO CYTOKINE LA English DT Article DE Resveratrol; Retinal pigment epithelium; Age-related macular degeneration; CXCL11; Nuclear factor-kappa B ID ACTIVATED T-CELLS; NF-KAPPA-B; MACULAR DEGENERATION; CHEMOKINE; DISEASES; ARPE-19; ALPHA AB Dysfunction of the retinal pigment epithelium (RPE) resulting from chronic inflammation is implicated in the pathogenesis of age-related macular degeneration (AMD). RPE cells adjacent to drusen deposits in the AMD eye are known to contain CXCLI I, a chemokine involved in inflammatory cell recruitment. We investigated the CXCL11 production by the human RPE (ARPE-19) cells under inflammatory conditions and tested its response to resveratrol, a naturally occurring anti-inflammatory antioxidant. A proinflammatory cytokine mixture consisting of IFN-gamma, IL-1 beta and TNF-alpha highly increased CXCL11 mRNA expression and CXCLI I protein secretion by ARPE-19 cells. Resveratrol substantially inhibited the proinflammatory cytokines-induced CXCL11 production while partially blocking nuclear factor-kappa B activation. This inhibitory action of resveratrol was also observed for the cytokines-induced expression of chemokines CXCL9, CCL2 and CCL5. Our results indicate that resveratrol could potentially attenuate RPE inflammatory response implicated in the pathogenesis of AMD. Published by Elsevier Ltd. C1 [Kutty, R. Krishnan; Samuel, William; Abay, Rebecca; Cherukuri, Aswini; Duncan, Todd; Jaworski, Cynthia; Redmond, T. Michael] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Nagineni, Chandrasekharam N.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Vijayasarathy, Camasamudram] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Kutty, RK (reprint author), NEI, Lab Retinal Cell & Mol Biol, NIH, Bldg 6,Room 112,6 Ctr Dr,MSC 0608, Bethesda, MD 20892 USA. EM kuttyk@nei.nih.gov FU National Eye Institute, NIH FX This study was supported by the Intramural Research Program of the National Eye Institute, NIH. NR 14 TC 3 Z9 3 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD AUG PY 2015 VL 74 IS 2 BP 335 EP 338 DI 10.1016/j.cyto.2015.03.016 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CM5CM UT WOS:000357704400024 PM 25890876 ER PT J AU Matherne, CE Tanofsky-Kraff, M Altschul, AM Shank, LM Schvey, NA Brady, SM Galescu, O Demidowich, AP Yanovski, SZ Yanovski, JA AF Matherne, Camden E. Tanofsky-Kraff, Marian Altschul, Anne M. Shank, Lisa M. Schvey, Natasha A. Brady, Sheila M. Galescu, Ovidiu Demidowich, Andrew P. Yanovski, Susan Z. Yanovski, Jack A. TI A preliminary examination of Loss of Control Eating Disorder (LOC-ED) in middle childhood SO EATING BEHAVIORS LA English DT Article DE Binge eating; Loss of control eating; Obesity; Prevention ID CHILDRENS DEPRESSION INVENTORY; RISK-FACTORS; WEIGHT-GAIN; DSM-V; ADOLESCENTS; OVERWEIGHT; BEHAVIORS; YOUNGSTERS; GENDER; ONSET AB Loss of Control Eating Disorder (LOC-ED) has been proposed as a diagnostic category for children 6-12 years with binge-type eating. However, characteristics of youth with LOC-ED have not been examined. We tested the hypothesis that the proposed criteria for LOC-ED would identify children with greater adiposity, more disordered eating attitudes, and greater mood disturbance than those without LOC-ED. Participants were 251 youth (10.29 years +/-1.54, 53.8% female, 57.8% White, 35.5% Black, 2.0% Asian, 4.8% Hispanic, 53.0% overweight). Youth were interviewed regarding eating attitudes and behaviors, completed questionnaires to assess general psychopathology, and underwent measurements of body fat mass. Using previously proposed criteria for LOCED, children were classified as LOC-ED (n=19), LOC in the absence of the full disorder (subLOC, n = 33), and youth not reporting LOC (noLOC, n = 199). LOC-ED youth had higher BMIz (p = 0.001) and adiposity (p = 0.003) and reported greater disordered eating concerns (p < 0.001) compared to noLOC youth. Compared to subLOC youth, LOC-ED youth had non-significantly higher BMIz (p = 0.11), and significantly higher adiposity (p = 0.04) and disordered eating attitudes (p = 0.02). SubLOC youth had greater disordered eating concerns (p < 0.001) and BMIz (p = 0.03) but did not differ in adiposity (p = 0.33) compared to noLOC youth. These preliminary data suggest that LOC-ED youth are elevated on disordered eating cognitions and anthropometric measures compared to youth without LOC-ED. Longitudinal studies are needed to determine if those with LOC-ED are at particularly increased risk for progression of disordered eating and excess weight gain. Published by Elsevier Ltd. C1 [Matherne, Camden E.; Tanofsky-Kraff, Marian; Shank, Lisa M.; Schvey, Natasha A.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Matherne, Camden E.; Tanofsky-Kraff, Marian; Altschul, Anne M.; Shank, Lisa M.; Schvey, Natasha A.; Brady, Sheila M.; Galescu, Ovidiu; Demidowich, Andrew P.; Yanovski, Susan Z.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Baltimore, MD USA. [Yanovski, Susan Z.] NIDDK, Obes & Eating Disorders Program, NIH, DHHS, Baltimore, MD USA. RP Tanofsky-Kraff, M (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM marian.tanofsky-kraff@usuhs.edu OI Galescu, Ovidiu/0000-0003-0948-645X; Shank, Lisa/0000-0002-6922-7946 FU Intramural Research Program, NIH from the NICHD [Z1A-HD-00641]; NIMHD; USUHS [R072IC] FX Funding for this study was provided by Intramural Research Program, NIH, grant Z1A-HD-00641 from the NICHD, with supplemental funding from NIMHD to J. Yanovski; USUHS grant R072IC to M. Tanofsky-Kraff. None of these institutions had a role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. NR 40 TC 3 Z9 3 U1 2 U2 9 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 2015 VL 18 BP 57 EP 61 DI 10.1016/j.eatbeh.2015.04.001 PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CM5PP UT WOS:000357740900011 PM 25913008 ER PT J AU Tertipis, N Hammar, U Nasman, A Vlastos, A Nordfors, C Grun, N Ahrlund-Richter, A Sivars, L Haeggblom, L Marklund, L Hammarstedt-Nordenvall, L Chaturvedi, AK Munck-Wikland, E Ramqvist, T Bottai, M Dalianis, T AF Tertipis, Nikolaos Hammar, Ulf Nasman, Anders Vlastos, Andrea Nordfors, Cecilia Grun, Nathalie Ahrlund-Richter, Andreas Sivars, Lars Haeggblom, Linnea Marklund, Linda Hammarstedt-Nordenvall, Lalle Chaturvedi, Anil K. Munck-Wikland, Eva Ramqvist, Torbjorn Bottai, Matteo Dalianis, Tina TI A model for predicting clinical outcome in patients with human papillomavirus-positive tonsillar and base of tongue cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE HPV; Tonsillar cancer; Base of tongue cancer; Biomarkers; Survival ID SQUAMOUS-CELL CARCINOMA; OROPHARYNGEAL CANCER; SURVIVAL; RISK; PREVALENCE; HEAD; VALIDATION; EXPRESSION; BIOMARKERS; EPIDEMIC AB Aim: To combine clinical and molecular markers into an algorithm for predicting outcome for individual patients with human papillomavirus (HPV) DNA/p16(INK4a) positive tonsillar and base of tongue squamous cell carcinoma (TSCC and BOTSCC). Background: Head-neck cancer treatment has become more intensified, comprising not only surgery and radiotherapy, but also induction/concomitant chemotherapy and targeted therapy. With less treatment, 3-year disease free survival (DFS) is 80% for HPV-positive TSCC and BOTSCC. An 85-100% 3-year DFS is observed for HPV+ TSCC and BOTSCC with absence of HLA class I, or CD44 expression, or high CD8(+) tumour-infiltrating lymphocyte (TIL) counts suggesting that therapy could be tapered for many if patients could be identified individually. Patients and methods: Patients treated curatively, with HPV DNA/p16(INK4a) positive tumours examined for HLA class I and II, CD44 and CD8(+) TILs, were included. An L1-regularised logistic regression was used to evaluate the effect of the biomarker data, age, stage, diagnosis, smoking and treatment on 3-year risk of death or relapse on a training cohort of 197 patients diagnosed 2000-2007 and validated on a cohort of 118 patients diagnosed 2008-2011. Results: The variables finally included in the model were HLA class I, CD8(+) TILs, age, stage and diagnosis (TSCC or BOTSCC). The model showed acceptable discrimination and calibration. The discriminative ability of the model did not diminish after validation (AUC = 0.77). Conclusion: To our knowledge, this is the first model to utilise information from several markers to predict an individual probability of clinical outcome for patients with HPV DNA/p16(INK4a) positive tumours. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Tertipis, Nikolaos; Nasman, Anders; Vlastos, Andrea; Nordfors, Cecilia; Grun, Nathalie; Ahrlund-Richter, Andreas; Sivars, Lars; Haeggblom, Linnea; Ramqvist, Torbjorn; Dalianis, Tina] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Hammar, Ulf; Bottai, Matteo] Karolinska Inst, Dept Environm Med, Stockholm, Sweden. [Vlastos, Andrea; Marklund, Linda; Hammarstedt-Nordenvall, Lalle; Munck-Wikland, Eva] Karolinska Inst, Dept Clin Sci & Technol, Stockholm, Sweden. [Vlastos, Andrea; Marklund, Linda; Hammarstedt-Nordenvall, Lalle; Munck-Wikland, Eva] Karolinska Univ Hosp, Dept Otorhinolaryngol Head & Neck Surg, Stockholm, Sweden. [Chaturvedi, Anil K.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Dalianis, T (reprint author), Karolinska Univ Hosp, Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, R8 01, S-17176 Stockholm, Sweden. EM tina.dalianis@ki.se RI Chaturvedi, Anil/J-2024-2015; Marklunf, Linda/L-1913-2015; OI Chaturvedi, Anil/0000-0003-2696-8899; Hammarstedt-Nordenvall, Lalle/0000-0003-1660-9737; Nasman, Anders/0000-0003-4602-4297 FU Swedish Cancer Foundation; Stockholm Cancer Society; Swedish Cancer and Allergy Foundation; Henning and Ida Persson's Research Foundation; Stockholm City Council; Karolinska Institutet, Sweden FX This work was supported by the Swedish Cancer Foundation, the Stockholm Cancer Society, the Swedish Cancer and Allergy Foundation, Henning and Ida Persson's Research Foundation, the Stockholm City Council and Karolinska Institutet, Sweden. NR 35 TC 4 Z9 4 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD AUG PY 2015 VL 51 IS 12 BP 1580 EP 1587 DI 10.1016/j.ejca.2015.04.024 PG 8 WC Oncology SC Oncology GA CM4MN UT WOS:000357658900010 PM 26025766 ER PT J AU Temiz, NA Donohue, DE Bacolla, A Vasquez, KM Cooper, DN Mudunuri, U Ivanic, J Cer, RZ Yi, M Stephens, RM Collins, JR Luke, BT AF Temiz, Nuri A. Donohue, Duncan E. Bacolla, Albino Vasquez, Karen M. Cooper, David N. Mudunuri, Uma Ivanic, Joseph Cer, Regina Z. Yi, Ming Stephens, Robert M. Collins, Jack R. Luke, Brian T. TI The somatic autosomal mutation matrix in cancer genomes SO HUMAN GENETICS LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; HUMAN INHERITED DISEASE; ONE-ELECTRON OXIDATION; DNA-DAMAGE; SKIN-CANCER; DENSITY FUNCTIONALS; CPG DINUCLEOTIDES; PYRIMIDINE DIMERS; EXCITED-STATES; MUTAGENESIS AB DNA damage in somatic cells originates from both environmental and endogenous sources, giving rise to mutations through multiple mechanisms. When these mutations affect the function of critical genes, cancer may ensue. Although identifying genomic subsets of mutated genes may inform therapeutic options, a systematic survey of tumor mutational spectra is required to improve our understanding of the underlying mechanisms of mutagenesis involved in cancer etiology. Recent studies have presented genome-wide sets of somatic mutations as a 96-element vector, a procedure that only captures the immediate neighbors of the mutated nucleotide. Herein, we present a 32 x 12 mutation matrix that captures the nucleotide pattern two nucleotides upstream and downstream of the mutation. A somatic autosomal mutation matrix (SAMM) was constructed from tumor-specific mutations derived from each of 909 individual cancer genomes harboring a total of 10,681,843 single-base substitutions. In addition, mechanistic template mutation matrices (MTMMs) representing oxidative DNA damage, ultraviolet-induced DNA damage, (5m)CpG deamination, and APOBEC-mediated cytosine mutation, are presented. MTMMs were mapped to the individual tumor SAMMs to determine the maximum contribution of each mutational mechanism to the overall mutation pattern. A Manhattan distance across all SAMM elements between any two tumor genomes was used to determine their relative distance. Employing this metric, 89.5 % of all tumor genomes were found to have a nearest neighbor from the same tissue of origin. When a distance-dependent 6-nearest neighbor classifier was used, 86.9 % of all SAMMs were assigned to the correct tissue of origin. Thus, although tumors from different tissues may have similar mutation patterns, their SAMMs often display signatures that are characteristic of specific tissues. C1 [Temiz, Nuri A.; Donohue, Duncan E.; Bacolla, Albino; Mudunuri, Uma; Ivanic, Joseph; Cer, Regina Z.; Yi, Ming; Stephens, Robert M.; Collins, Jack R.; Luke, Brian T.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Silico Res Ctr Excellence, Adv Biomed Comp Ctr,Informat Syst Program, Frederick, MD 21702 USA. [Bacolla, Albino; Vasquez, Karen M.] Univ Texas Austin, Div Pharmacol & Toxicol, Austin, TX 78723 USA. [Cooper, David N.] Cardiff Univ, Inst Med Genet, Sch Med, Cardiff CF14 4XN, S Glam, Wales. RP Luke, BT (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Silico Res Ctr Excellence, Adv Biomed Comp Ctr,Informat Syst Program, POB B, Frederick, MD 21702 USA. EM Brian.Luke@nih.gov OI Cooper, David N./0000-0002-8943-8484 FU National Cancer Institute (NCI)/National Institutes of Health (NIH) [HHSN261200800001E]; NCI/NIH [CA093729]; BIOBASE/Qiagen; Cardiff University FX This work was supported in part by funds from the National Cancer Institute (NCI)/National Institutes of Health (NIH) contract No. HHSN261200800001E and NCI/NIH grant CA093729 (to K.M.V.). The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We are unaware of any financial conflicts. DNC is in receipt of financial support from BIOBASE/Qiagen through a License Agreement with Cardiff University. NR 82 TC 3 Z9 3 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD AUG PY 2015 VL 134 IS 8 BP 851 EP 864 DI 10.1007/s00439-015-1566-1 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA CM4OZ UT WOS:000357665600004 PM 26001532 ER PT J AU Temiz, NA Donohue, DE Bacolla, A Vasquez, KM Cooper, DN Mudunuri, U Ivanic, J Cer, RZ Yi, M Stephens, RM Collins, JR Luke, BT AF Temiz, Nuri A. Donohue, Duncan E. Bacolla, Albino Vasquez, Karen M. Cooper, David N. Mudunuri, Uma Ivanic, Joseph Cer, Regina Z. Yi, Ming Stephens, Robert M. Collins, Jack R. Luke, Brian T. TI The somatic autosomal mutation matrix in cancer genomes (vol 134, pg 851, 2015) SO HUMAN GENETICS LA English DT Correction C1 [Temiz, Nuri A.; Donohue, Duncan E.; Bacolla, Albino; Mudunuri, Uma; Ivanic, Joseph; Cer, Regina Z.; Yi, Ming; Stephens, Robert M.; Collins, Jack R.; Luke, Brian T.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Silico Res Ctr Ex3ellence, Adv Biomed Comp Ctr,Informat Syst Program, Frederick, MD 21702 USA. [Bacolla, Albino; Vasquez, Karen M.] Univ Texas Austin, Div Pharmacol & Toxicol, Austin, TX 78723 USA. [Cooper, David N.] Cardiff Univ, Inst Med Genet, Sch Med, Cardiff CF14 4XN, S Glam, Wales. RP Luke, BT (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Silico Res Ctr Ex3ellence, Adv Biomed Comp Ctr,Informat Syst Program, POB B, Frederick, MD 21702 USA. EM Brian.Luke@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 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 2015 VL 134 IS 8 BP 865 EP 867 DI 10.1007/s00439-015-1576-z PG 3 WC Genetics & Heredity SC Genetics & Heredity GA CM4OZ UT WOS:000357665600005 PM 26071096 ER PT J AU Wang, B Lu, F Cheng, Y Chen, JH Jeon, HY Ha, KS Cao, J Nyunt, MH Han, JH Lee, SK Kyaw, MP Sattabongkot, J Takashima, E Tsuboi, T Han, ET AF Wang, Bo Lu, Feng Cheng, Yang Chen, Jun-Hu Jeon, Hye-Yoon Ha, Kwon-Soo Cao, Jun Nyunt, Myat Htut Han, Jin-Hee Lee, Seong-Kyun Kyaw, Myat Phone Sattabongkot, Jetsumon Takashima, Eizo Tsuboi, Takafumi Han, Eun-Taek TI Immunoprofiling of the Tryptophan-Rich Antigen Family in Plasmodium vivax SO INFECTION AND IMMUNITY LA English DT Article ID MEROZOITE SURFACE PROTEIN-1; CAVEOLA-VESICLE COMPLEXES; HUMORAL IMMUNE-RESPONSES; INFECTED ERYTHROCYTES; ANTIBODY-RESPONSES; SCHUFFNERS DOTS; MALARIA; FALCIPARUM; VACCINE; IDENTIFICATION AB Tryptophan-rich antigens (TRAgs) are an antigen family that has been identified in human and rodent malaria parasites. TRAgs have been proposed as candidate antigens for potential vaccines. The Plasmodium vivax TRAg (PvTRAg) family includes 36 members. Each PvTRAg contains a tryptophan-rich (TR) domain in the C-terminal region. In this study, we recombinantly expressed all 36 PvTRAgs using a cell-free expression system, and, for the first time, profiled the IgG antibody responses against all PvTRAgs in the sera from 96 vivax malaria patients and 40 healthy individuals using protein microarray technology. The mean seropositive rate for all PvTRAgs was 60.3%. Among them, nine PvTRAgs were newly identified in this study and showed a seropositive rate of >50%. Five of them, PvTRAg_13, PvTRAg_15, PvTRAg_16, PvTRAg_26, and PvTRAg_29, produced higher levels of IgG antibody, even in low-endemicity countries. In addition, the results of an immunofluorescence analysis suggest that PvTRAgs are, at least in part, associated with caveola-vesicle complexes, a unique structure of P. vivax-infected erythrocytes. The mechanism of formation and the function of these abundant membrane structures are not known. Further investigation aimed at determining the functions of these proteins would lead to a better understanding of the blood-stage biology of P. vivax. C1 [Wang, Bo; Lu, Feng; Cheng, Yang; Chen, Jun-Hu; Nyunt, Myat Htut; Han, Jin-Hee; Lee, Seong-Kyun; Han, Eun-Taek] Kangwon Natl Univ, Sch Med, Dept Med Environm Biol & Trop Med, Chunchon, Gangwon Do, South Korea. [Wang, Bo] Anhui Med Univ, Affiliated Hosp 1, Dept Clin Lab, Hefei, Anhui, Peoples R China. [Lu, Feng; Cao, Jun] Jiangsu Inst Parasit Dis, Minist Hlth, Key Lab Parasit Dis Control & Prevent, Wuxi, Jiangsu, Peoples R China. [Lu, Feng; Cao, Jun] Jiangsu Inst Parasit Dis, Jiangsu Prov Key Lab Parasite Mol Biol, Wuxi, Jiangsu, Peoples R China. [Cheng, Yang] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Jeon, Hye-Yoon; Ha, Kwon-Soo] Kangwon Natl Univ, Sch Med, Dept Mol & Cellular Biochem, Chunchon, Gangwon Do, South Korea. [Nyunt, Myat Htut; Kyaw, Myat Phone] Dept Med Res, Yangon, Myanmar. [Sattabongkot, Jetsumon] Mahidol Univ, Fac Trop Med, Mahidol Vivax Res Unit, Bangkok, Thailand. [Takashima, Eizo; Tsuboi, Takafumi] Ehime Univ, Proteosci Ctr, Div Malaria Res, Matsuyama, Ehime, Japan. RP Tsuboi, T (reprint author), Ehime Univ, Proteosci Ctr, Div Malaria Res, Matsuyama, Ehime, Japan. EM tsuboi.takafumi.mb@ehime-u.ac.jp; ethan@kangwon.ac.kr FU Korea Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea [A121180]; MEXT [23117008]; JSPS, Japan [26670202, 26253026] FX This work was supported by a grant from the Korea Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A121180). This work was also supported in part by MEXT KAKENHI (23117008) and JSPS KAKENHI (26670202, 26253026), Japan. NR 40 TC 3 Z9 3 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2015 VL 83 IS 8 BP 3083 EP 3095 DI 10.1128/IAI.03067-14 PG 13 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CM3XI UT WOS:000357618300008 PM 25987709 ER PT J AU Do, K Speranza, G Chang, LC Polley, EC Bishop, R Zhu, WM Trepel, JB Lee, S Lee, MJ Kinders, RJ Phillips, L Collins, J Lyons, J Jeong, W Antony, R Chen, AP Neckers, L Doroshow, JH Kummar, S AF Khanh Do Speranza, Giovanna Chang, Lun-Ching Polley, Eric C. Bishop, Rachel Zhu, Weimin Trepel, Jane B. Lee, Sunmin Lee, Min-Jung Kinders, Robert J. Phillips, Larry Collins, Jerry Lyons, John Jeong, Woondong Antony, Ramya Chen, Alice P. Neckers, Len Doroshow, James H. Kummar, Shivaani TI Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Molecular chaperones; Proteolysis; Hsp90 inhibitor; Hsp70 heat-shock proteins; Hsp27 heat-shock proteins ID CANCER; RESISTANCE AB Inhibition of heat shock 90 (Hsp90) molecular chaperones allows targeting of multiple proteins involved in tumorigenesis. We investigated the safety, recommended phase 2 dose (RP2D), and pharmacokinetic and pharmacodynamic profile of onalespib (AT13387), a potent synthetic Hsp90 inhibitor, administered on days 1, 2, 8, 9, 15, and 16 of 28 day cycles (QDx2/week) in a phase I trial. This study followed an accelerated titration design with a starting dose of 20 mg/m(2)/dose and a standard 3 + 3 dose escalation design for dose level 4 (120 mg/m(2)/dose) and above. Additional patients were enrolled at the RP2D with mandatory paired tumor biopsies to assess modulation of 210 client proteins using reverse phase protein array analysis. Thirty-one patients were treated; RP2D was established at 160 mg/m(2)/dose on the QDx2/week schedule. Common toxicities were gastrointestinal, hepatic, and hematologic. Pharmacokinetic profile was linear and plasma levels increased proportionally with dose (T-A1/2 similar to 8 h). No responses were observed; eight patients had stable disease for > 2 cycles with one patient remaining on study for 6 cycles. Target engagement was demonstrated by transcriptional upregulation of Hsp70 and Hsp27 in PBMCs. Statistically significant modulation of client proteins was not achieved in the 9 paired tumor biopsies evaluated; however, hierarchical clustering revealed two subgroups of patients with differential patterns of protein expression. Further combination studies are needed in order to target prospective driver oncoproteins. C1 [Khanh Do; Speranza, Giovanna; Chang, Lun-Ching; Polley, Eric C.; Phillips, Larry; Collins, Jerry; Jeong, Woondong; Chen, Alice P.; Doroshow, James H.; Kummar, Shivaani] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Bishop, Rachel] NEI, Bethesda, MD 20892 USA. [Zhu, Weimin; Kinders, Robert J.; Antony, Ramya] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Trepel, Jane B.; Lee, Sunmin; Lee, Min-Jung; Neckers, Len; Doroshow, James H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Lyons, John] Astex Pharmaceut, Cambridge, England. RP Kummar, S (reprint author), NCI, Div Canc Treatment & Diag, 31 Ctr Dr,Bldg 31,Rm 3A44, Bethesda, MD 20892 USA. EM kummars@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E, CA16672] FX The authors thank Dr. Andrea Regier Voth, Leidos Biomedical Research, Inc., for medical writing support in the preparation of this manuscript, and Ms. Tracy Webb, Leidos Biomedical Research, Inc., for pharmacokinetic technical assistance. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and Core grant #CA16672. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. John Lyons is an employee of Astex Pharmaceuticals; no potential conflicts of interest were disclosed by the other authors. NR 15 TC 3 Z9 3 U1 1 U2 5 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 2015 VL 33 IS 4 BP 921 EP 930 DI 10.1007/s10637-015-0255-1 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA CM1TH UT WOS:000357462700015 PM 26082332 ER PT J AU Putnick, DL Bornstein, MH Lansford, JE Malone, PS Pastorelli, C Skinner, AT Sorbring, E Tapanya, S Tirado, LM Zelli, A Alampay, LP Al-Hassan, SM Bacchini, D Bombi, AS Chang, L Deater-Deckard, K Di Giunta, L Dodge, KA Oburu, P AF Putnick, Diane L. Bornstein, Marc H. Lansford, Jennifer E. Malone, Patrick S. Pastorelli, Concetta Skinner, Ann T. Sorbring, Emma Tapanya, Sombat Uribe Tirado, Liliana Maria Zelli, Arnaldo Alampay, Liane Pena Al-Hassan, Suha M. Bacchini, Dario Bombi, Anna Silvia Chang, Lei Deater-Deckard, Kirby Di Giunta, Laura Dodge, Kenneth A. Oburu, Paul TI Perceived mother and father acceptance-rejection predict four unique aspects of child adjustment across nine countries SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Parental acceptance-rejection; behavior problems; school performance; prosocial behavior; social competence; cross-cultural ID PARENTAL ACCEPTANCE; ACADEMIC-ACHIEVEMENT; SOCIAL COMPETENCE; PSYCHOLOGICAL ADJUSTMENT; INTERNALIZING SYMPTOMS; MATERNAL ACCEPTANCE; EARLY ADOLESCENCE; MIDDLE SCHOOL; FIT INDEXES; WARMTH AB BackgroundIt is generally believed that parental rejection of children leads to child maladaptation. However, the specific effects of perceived parental acceptance-rejection on diverse domains of child adjustment and development have been incompletely documented, and whether these effects hold across diverse populations and for mothers and fathers are still open questions. MethodsThis study assessed children's perceptions of mother and father acceptance-rejection in 1,247 families from China, Colombia, Italy, Jordan, Kenya, the Philippines, Sweden, Thailand, and the United States as antecedent predictors of later internalizing and externalizing behavior problems, school performance, prosocial behavior, and social competence. ResultsHigher perceived parental rejection predicted increases in internalizing and externalizing behavior problems and decreases in school performance and prosocial behavior across 3years controlling for within-wave relations, stability across waves, and parental age, education, and social desirability bias. Patterns of relations were similar across mothers and fathers and, with a few exceptions, all nine countries. ConclusionsChildren's perceptions of maternal and paternal acceptance-rejection have small but nearly universal effects on multiple aspects of their adjustment and development regardless of the family's country of origin. C1 [Putnick, Diane L.; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Bethesda, MD 20892 USA. [Lansford, Jennifer E.; Malone, Patrick S.; Skinner, Ann T.; Dodge, Kenneth A.] Duke Univ, Ctr Child & Family Policy, Durham, NC USA. [Pastorelli, Concetta; Uribe Tirado, Liliana Maria; Bombi, Anna Silvia; Di Giunta, Laura] Univ Roma La Sapienza, Dept Psychol, I-00185 Rome, Italy. [Sorbring, Emma] Univ West, Dept Psychol, Trollhattan, Sweden. [Tapanya, Sombat] Chiang Mai Univ, Chiang Mai 50000, Thailand. [Uribe Tirado, Liliana Maria] Univ San Buenaventura, Dept Psychol, Medellin, Colombia. [Zelli, Arnaldo] Foro Italico Univ Rome, Dept Sports Psychol, Rome, Italy. [Alampay, Liane Pena] Ateneo Manila Univ, Quezon City, Metro Manila, Philippines. [Al-Hassan, Suha M.] Hashemite Univ, Zarqa, Jordan. [Bacchini, Dario] Univ Naples 2, Naples, Italy. [Chang, Lei] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Deater-Deckard, Kirby] Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. [Oburu, Paul] Maseno Univ, Maseno, Kenya. RP Putnick, DL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM putnickd@mail.nih.gov RI ZELLI, ARNALDO/N-2333-2015; OI ZELLI, ARNALDO/0000-0003-4020-8159; Bacchini, Dario/0000-0001-6140-9377; Putnick, Diane/0000-0002-6323-749X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [RO1-HD054805]; Fogarty International Center [RO3-TW008141]; NIH, NICHD FX This research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development grant RO1-HD054805, Fogarty International Center grant RO3-TW008141, and the intramural program of the NIH, NICHD. NR 49 TC 5 Z9 5 U1 6 U2 30 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD AUG PY 2015 VL 56 IS 8 BP 923 EP 932 DI 10.1111/jcpp.12366 PG 10 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA CM1WZ UT WOS:000357472500011 PM 25492267 ER PT J AU Thouennon, E Cheng, Y Falahatian, V Cawley, NX Loh, YP AF Thouennon, Erwan Cheng, Yong Falahatian, Vida Cawley, Niamh X. Loh, Yoke Peng TI Rosiglitazone-activated PPAR gamma induces neurotrophic factor-alpha 1 transcription contributing to neuroprotection SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE BCL-2; hippocampus; neuroprotection; neurotrophic factor-alpha 1; rosiglitazone ID ENZYME CARBOXYPEPTIDASE-E; TRAUMATIC BRAIN-INJURY; RECEPTOR-GAMMA; AGONIST ROSIGLITAZONE; NEURONS; ISCHEMIA; PROTEIN; MECHANISMS; EXPRESSION; STRESS AB Brain peroxisome proliferator-activated receptor gamma (PPAR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, is involved in neuroprotection. It is activated by the drug rosiglitazone, which then can increase the pro-survival protein B-cell lymphoma 2 (BCL-2), to mediate neuroprotection. However, the mechanism underlying this molecular cascade remains unknown. Here, we show that the neuroprotective protein neurotrophic factor-1 (NF-1), which also induces the expression of BCL-2, has a promoter that contains PPAR-binding sites that are activated by rosiglitazone. Treatment of Neuro2a cells and primary hippocampal neurons with rosiglitazone increased endogenous NF-1 expression and prevented H2O2-induced cytotoxicity. Concomitant with the increase in NF-1, BCL-2 was also increased in these cells. When siRNA against NF-1 was used, the induction of BCL-2 by rosiglitazone was prevented, and the neuroprotective effect of rosiglitazone was reduced. These results demonstrate that rosiglitazone-activated PPAR directly induces the transcription of NF-1, contributing to neuroprotection in neurons. C1 [Thouennon, Erwan; Cheng, Yong; Falahatian, Vida; Cawley, Niamh X.; Loh, Yoke Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bethesda, MD USA. RP Loh, YP (reprint author), NIH, 49 Convent Dr,Bldg 49,Room 6C10, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA. The authors declare no conflicts of interest. NR 29 TC 5 Z9 5 U1 1 U2 3 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 2015 VL 134 IS 3 BP 463 EP 470 DI 10.1111/jnc.13152 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CM5JS UT WOS:000357724700007 PM 25940785 ER PT J AU Torkko, KC Wilson, RS Smith, EE Kusek, JW van Bokhoven, A Lucia, MS AF Torkko, Kathleen C. Wilson, R. Storey Smith, Elizabeth E. Kusek, John W. van Bokhoven, Adrie Lucia, M. Scott TI Prostate Biopsy Markers of Inflammation are Associated with Risk of Clinical Progression of Benign Prostatic Hyperplasia: Findings from the MTOPS Study SO JOURNAL OF UROLOGY LA English DT Article DE prostatic hyperplasia; inflammation; disease progression; anti-inflammatory agents ID URINARY-TRACT SYMPTOMS; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; BPH; CANCER; TISSUE; TRIAL; PATHOGENESIS; ETIOLOGY; THERAPY; IMPACT AB Purpose: Factors associated with worsening of benign prostatic hyperplasia are not well understood. We measured inflammatory markers from prostate biopsies to study if inflammation is related to clinical progression of benign prostatic hyperplasia. Materials and Methods: We measured inflammatory cell markers CD45, CD4, CD8 and CD68 in transition zone biopsies from 859 men in the MTOPS biopsy substudy. Using novel imaging techniques we quantified amounts of moderate/severe inflammation. Benign prostatic hyperplasia clinical progression was defined as a confirmed 4-point or greater increase in the AUA symptom score from baseline, or the occurrence of urinary incontinence or acute urinary retention. Baseline clinical parameters including concomitant medication use were determined. Kaplan-Meier curves and multivariate Cox proportional hazard models were used to determine the risk of progression. Results: Inflammation as measured by CD45, CD4 and CD68 increased the risk of clinical progression of benign prostatic hyperplasia. CD4 showed the highest risk where men in the highest tertile of moderate/severe inflammation were at twice the risk of progression compared to men in the lower 2 tertiles combined (HR 2.03, p=0.001). Inflammation was more strongly associated with progression defined by acute urinary retention or incontinence (HR ranging from 2.39 [CD8, p=0.03] to 3.08 [CD4, p=0.01]) than an AUA symptom score increase (CD4, HR 1.86, p=0.01). Men who reported use of nonsteroidal anti-inflammatory drugs or steroids at baseline tended to be at higher risk for progression. Conclusions: Although our data show that inflammation increases the risk of progression, our findings suggest that inflammation has a greater role in men who have conditions requiring anti-inflammatory medications. C1 [Torkko, Kathleen C.; Wilson, R. Storey; Smith, Elizabeth E.; van Bokhoven, Adrie; Lucia, M. Scott] Univ Colorado Denver, Dept Pathol, Aurora, CO 80045 USA. [Kusek, John W.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. RP Torkko, KC (reprint author), Univ Colorado Denver, Dept Pathol, Anschutz Med Campus,MS 8104 RC1 North, Aurora, CO 80045 USA. EM kathleen.torkko@ucdenver.edu FU NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) [5R01DK84991-2, SUB-05-B15, P50 DK082998] FX Supported by NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) Grant 5R01DK84991-2, SUB-05-B15 and P50 DK082998. The data and samples from the MTOPS study reported here were supplied by the NIDDK Central Repositories. This manuscript does not necessarily reflect the opinions or views of the MTOPS study, the NIDDK Central Repositories or the NIDDK. NR 28 TC 11 Z9 11 U1 1 U2 4 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 2015 VL 194 IS 2 BP 454 EP 461 DI 10.1016/j.juro.2015.03.103 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CM5QA UT WOS:000357742000059 PM 25828974 ER PT J AU Baio, G Rescinito, G Rosa, F Pace, D Boccardo, S Basso, L Salvi, S Calabrese, M Truini, M Neumaier, CE AF Baio, Gabriella Rescinito, Giuseppe Rosa, Francesca Pace, Daniele Boccardo, Simona Basso, Luca Salvi, Sandra Calabrese, Massimo Truini, Mauro Neumaier, Carlo Emanuele TI Correlation between Choline Peak at MR Spectroscopy and Calcium-Sensing Receptor Expression Level in Breast Cancer: A Preliminary Clinical Study SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Calcium-sensing receptor; MR spectroscopy; Breast cancer; Posphocholine; 3T MR; Magnetic resonance imaging; G protein-coupled receptor; Calcium channels; MRI breast; Molecular imaging cancer ID HIGH-RISK; WOMEN AB The calcium-sensing receptor (CaSR) is overexpressed in many pathological states including breast cancer. Since choline kinase may be activated in breast cancer cells by CaSR resulting in increased phosphocholine production, we sought to correlate the total choline peak in breast lesions as measured by in vivo proton magnetic resonance spectroscopy (H-1-MRS) with the CaSR expression levels in surgical specimens. Thirty-six patients with breast lesions were MR scanned at 3T scanner. Tumour morphology and DCE-MR kinetics were evaluated. H-1-MRS was applied for Cho detection and compared with the CaSR immunohistochemistry analysis (score 0-5) on surgical breast specimens. Thirty-four lesions demonstrated a DCE malignant kinetics curve (types 2 and 3), while two lesions showed a benign (type 1). Twenty of the 23 breast cancer lesions (87 %) with a consistent Cho peak expressed a CaSR score of 3-5, and ten of the 11 breast lesions negative for Cho (91 %) had a CaSR score of 1-2. The two benign lesions showed a non-uniform/weak intense expression of the CaSR (score 3) with a consistent Cho peak. The presence or absence of choline peak evaluated by H-1-MRS, well correlated with the expression of CaSR in patients with breast lesions (p < 0.01), supports the hypothesis that CaSR may play an important role in the production of choline in breast cancer. C1 [Baio, Gabriella; Rescinito, Giuseppe; Rosa, Francesca; Pace, Daniele; Basso, Luca; Calabrese, Massimo; Neumaier, Carlo Emanuele] IRCCS Azienda Osped Univ AOU San Martino, IST, Natl Canc Inst, Diagnost Imaging & Senol Unit, I-16132 Genoa, Italy. [Baio, Gabriella] Univ Aberdeen, Aberdeen Biomed Imaging Ctr, Aberdeen, Scotland. [Boccardo, Simona; Salvi, Sandra; Truini, Mauro] IRCCS Azienda Osped Univ AOU San Martino, IST, Natl Canc Inst, Dept Pathol, I-16132 Genoa, Italy. RP Baio, G (reprint author), IRCCS Azienda Osped Univ AOU San Martino, IST, Natl Canc Inst, Diagnost Imaging & Senol Unit, I-16132 Genoa, Italy. EM gabriella.baio@abdn.ac.uk; giuseppe.rescinito@hsanmartino.it; francescarosa892@gmail.com; daniele.pace@hsanmartino.it; simona.boccardo@hsanmartino.it; lukabasso89@gmail.com; sandra.salvi@hsanmartino.it; massimo.calabrese@hsanmartino.it; mauro.truini@hsanmartino.it; carlo.neumaier@hsanmartino.it RI Baio, Gabriella/M-7621-2015 OI Baio, Gabriella/0000-0002-8397-5318 NR 21 TC 2 Z9 2 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD AUG PY 2015 VL 17 IS 4 BP 548 EP 556 DI 10.1007/s11307-015-0823-y PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CM2IV UT WOS:000357504300014 PM 25613673 ER PT J AU Cheng, Q Yaker, JL AF Cheng, Qing Yaker, Jerrel L. TI Activation of alpha 7 nicotinic acetylcholine receptors increases intracellular cAMP levels via activation of AC1 in hippocampal neurons SO NEUROPHARMACOLOGY LA English DT Article DE alpha 7 nAChRs; Calcium; AC1; cAMP; Synapsin ID LONG-TERM POTENTIATION; PROTEIN-KINASE-A; CYCLASE MUTANT MICE; SYNAPTIC PLASTICITY; ADENYLYL CYCLASES; NEUROTRANSMITTER RELEASE; TRANSMITTER RELEASE; CORTICAL-NEURONS; FIBER SYNAPSES; MOUSE-BRAIN AB The activation of alpha 7 nAChRs has been shown to improve hippocampal-dependent learning and memory. However, the molecular mechanism of alpha 7 nAChRs' action remains elusive. We previously reported that activation of alpha 7 nAChRs induced a prolonged enhancement of glutamatergic synaptic transmission in a PICA-dependent manner. Here, we investigated any connection between the activation of the alpha 7 nAChR and cAMP signaling in hippocampal neurons. To address this question, we employed a FRET-based biosensor to measure the intracellular cAMP levels directly via live cell imaging. We found that application of the alpha 7 nAChR-selective agonist choline, in the presence of the alpha 7 nAChR positive allosteric modulator PNU-120596, induced a significant change in emission ratio of F535/F470, which indicated an increase in intracellular cAMP levels. This choline-induced increase was abolished by the alpha 7 nAChR antagonist MLA and the calcium chelator BAPTA, suggesting that the cAMP increase depends on the alpha 7 nAChR activation and subsequent intracellular calcium rise. The selective AC1 inhibitor CB-6673567 and siRNA-mediated deletion of AC1 both blocked the choline-induced cAMP increase, suggesting that calcium-dependent AC1 is required for choline's action. Furthermore, alpha 7 nAChR activation stimulated the phosphorylation of synapsin, which serves as a downstream effector to regulate neurotransmitter release. Our findings provide the first direct evidence to link activation of alpha 7 nAChRs to a cAMP rise via AC1, which defines a new signaling pathway employed by alpha 7 nAChRs. Our study sheds light into potential molecular mechanisms of the positive cognitive actions of alpha 7 nAChR agonists and development of therapeutic treatments for cognitive impairments. Published by Elsevier Ltd. C1 [Cheng, Qing; Yaker, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Yaker, JL (reprint author), NIEHS, Neurobiol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov FU NIEHS Intramural Research Program/NIH FX We thank Pattie Lamb and Jeff Tucker for technical support. We appreciate Drs. Georgia Alexander and Shannon Farris for the helpful reading and suggestions on our manuscript. This research was funded by the NIEHS Intramural Research Program/NIH. The authors declare no competing financial interests. NR 70 TC 3 Z9 4 U1 3 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD AUG PY 2015 VL 95 BP 405 EP 414 DI 10.1016/j.neuropharm.2015.04.016 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CM0DR UT WOS:000357349100040 PM 25937212 ER PT J AU Freeman, R AF Freeman, Robert TI Introduction SO VIOLENCE AGAINST WOMEN LA English DT Editorial Material ID WOMENS ALCOHOL-CONSUMPTION; INTIMATE PARTNER VIOLENCE; SEXUAL AGGRESSION; MARITAL AGGRESSION; RISK; VICTIMIZATION; PERPETRATION; EXPERIENCES; PERCEPTION; COUPLES C1 NIH, Bethesda, MD 20892 USA. RP Freeman, R (reprint author), NIH, 5635 Fishers Lane,Room 2073 MSC 9304, Bethesda, MD 20892 USA. EM rfreeman@mail.nih.gov NR 33 TC 0 Z9 0 U1 7 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1077-8012 EI 1552-8448 J9 VIOLENCE AGAINST WOM JI Violence Against Women PD AUG PY 2015 VL 21 IS 8 SI SI BP 911 EP 916 DI 10.1177/1077801215589374 PG 6 WC Women's Studies SC Women's Studies GA CM2QV UT WOS:000357527700001 PM 26139835 ER PT J AU Levine, KE Young, DJ Afton, SE Harrington, JM Essader, AS Weber, FX Fernando, RA Thayer, K Hatch, EE Robinson, VG Waidyanatha, S AF Levine, Keith E. Young, Daniel J. Afton, Scott E. Harrington, James M. Essader, Amal S. Weber, Frank X. Fernando, Reshan A. Thayer, Kristina Hatch, Elizabeth E. Robinson, Veronica G. Waidyanatha, Suramya TI Development, validation, and application of an ultra-performance liquid chromatography-sector field inductively coupled plasma mass spectrometry method for simultaneous determination of six organotin compounds in human serum SO TALANTA LA English DT Article DE Organotin compounds; Metallomics; Speciation; Ultra high pressure liquid chromatography; Inductively coupled plasma mass spectrometry; Serum; Biomonitoring ID SOLID-PHASE MICROEXTRACTION; GAS-CHROMATOGRAPHY; BUTYLTIN COMPOUNDS; SPECIATION ANALYSIS; ENVIRONMENTAL FATE; WATER SAMPLES; EXTRACTION; TRIBUTYLTIN; SEDIMENT; TOXICITY AB Organotin compounds (OTCs) are heavily employed by industry for a wide variety of applications, including the production of plastics and as biocides. Reports of environmental prevalence, differential toxicity between OTCs, and poorly characterized human exposure have fueled the demand for sensitive, selective speciation methods. The objective of this investigation was to develop and validate a rapid, sensitive, and selective analytical method for the simultaneous determination of a suite of organotin compounds, including butyl (mono-, di-, and tri-substituted) and phenyl (mono-, di-, and tri-substituted) species in human serum. The analytical method utilized ultra-performance liquid chromatography (UPLC) coupled with sector field inductively coupled plasma mass spectrometry (SF-ICP-MS). The small (sub-2 mu m) particle size of the UPLC column stationary phase and the sensitivity of the SF-ICP-MS enabled separation and sensitive determination of the analyte suite with a runtime of approximately 3 min. Validation activities included demonstration of method linearity over the concentration range of approximately 0.250-13.661 ng mL(-1), depending on the species; intraday precision of less than 21%, interday precision of less than 18%, intraday accuracy of -5.3% to 19%, and interday accuracy of -14% to 15% for all species; specificity, and matrix impact. In addition, sensitivity, and analyte stability under different storage scenarios were evaluated. Analyte stability was found to be limited for most species in freezer, refrigerator, and freeze-thaw conditions. The validated method was then applied for the determination of the OTCs in human serum samples from women participating in the Snart-Foraeldre/Miljo (Soon-Parents/Environment) Study. The concentration of each OTC ranged from below the experimental limit of quantitation to 10.929 ng tin (Sn) mL(-1) serum. Speciation values were confirmed by a total Sn analysis. (C) 2015 Elsevier B.V. All rights reserved. C1 [Levine, Keith E.; Young, Daniel J.; Afton, Scott E.; Harrington, James M.; Essader, Amal S.; Weber, Frank X.; Fernando, Reshan A.] RTI Int, Res Triangle Pk, NC 27709 USA. [Thayer, Kristina; Robinson, Veronica G.; Waidyanatha, Suramya] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Hatch, Elizabeth E.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Levine, KE (reprint author), RTI Int, Res Triangle Pk, NC 27709 USA. FU National Institute of Health/National Institute of Environmental Health Sciences (NIH/NIEHS) [HHSN27320110003C] FX This research was supported by the National Institute of Health/National Institute of Environmental Health Sciences (NIH/NIEHS; HHSN27320110003C). The authors would like to acknowledge Mr. Bradley J. Collins, Dr. Michelle Hooth, and Dr. Esra Mutlu for their review of this manuscript prior to formal submission. NR 36 TC 3 Z9 3 U1 5 U2 46 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0039-9140 EI 1873-3573 J9 TALANTA JI Talanta PD AUG 1 PY 2015 VL 140 BP 115 EP 121 DI 10.1016/j.talanta.2015.03.022 PG 7 WC Chemistry, Analytical SC Chemistry GA CL5GI UT WOS:000356987400018 PM 26048832 ER PT J AU Cui, CH Noronha, A Warren, KR Koob, GF Sinha, R Thakkar, M Matochik, J Crews, FT Chandler, LJ Pfefferbaum, A Becker, HC Lovinger, D Everitt, BJ Egli, M Mandyam, CD Fein, G Potenza, MN Harris, RA Grant, KA Roberto, M Meyerhoff, DJ Sullivan, EV AF Cui, Changhai Noronha, Antonio Warren, Kenneth R. Koob, George F. Sinha, Rajita Thakkar, Mahesh Matochik, John Crews, Fulton T. Chandler, L. Judson Pfefferbaum, Adolf Becker, Howard C. Lovinger, David Everitt, Barry J. Egli, Mark Mandyam, Chitra D. Fein, George Potenza, Marc N. Harris, R. Adron Grant, Kathleen A. Roberto, Marisa Meyerhoff, Dieter J. Sullivan, Edith V. TI Brain pathways to recovery from alcohol dependence SO ALCOHOL LA English DT Article DE Alcohol dependence; Recovery; Withdrawal; Abstinence; Neuroadaptation; Neurocircuitry ID CORTICOTROPIN-RELEASING-FACTOR; ANXIETY-LIKE BEHAVIOR; WITHDRAWAL-INDUCED ANXIETY; TERM ABSTINENT ALCOHOLICS; RESTING-STATE SYNCHRONY; INTERMITTENT ETHANOL EXPOSURE; DRUG MEMORY RECONSOLIDATION; BETA-ADRENERGIC-RECEPTORS; PROMOTING BASAL FOREBRAIN; MEDIAL PREFRONTAL CORTEX AB This article highlights the research presentations at the satellite symposium on "Brain Pathways to Recovery from Alcohol Dependence" held at the 2013 Society for Neuroscience Annual Meeting. The purpose of this symposium was to provide an up to date overview of research efforts focusing on understanding brain mechanisms that contribute to recovery from alcohol dependence. A panel of scientists from the alcohol and addiction research field presented their insights and perspectives on brain mechanisms that may underlie both recovery and lack of recovery from alcohol dependence. The four sessions of the symposium encompassed multilevel studies exploring mechanisms underlying relapse and craving associated with sustained alcohol abstinence, cognitive function deficit and recovery, and translational studies on preventing relapse and promoting recovery. Gaps in our knowledge and research opportunities were also discussed. Published by Elsevier Inc. C1 [Cui, Changhai; Noronha, Antonio; Warren, Kenneth R.; Koob, George F.; Matochik, John; Egli, Mark] NIAAA, Bethesda, MD 20892 USA. [Koob, George F.; Mandyam, Chitra D.; Roberto, Marisa] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Sinha, Rajita; Potenza, Marc N.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Thakkar, Mahesh] Univ Missouri, Dept Neurol, Columbia, MO USA. [Crews, Fulton T.] Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC USA. [Chandler, L. Judson; Becker, Howard C.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Pfefferbaum, Adolf] SRI Int, Ctr Hlth Sci, Neurosci Program, Menlo Pk, CA 94025 USA. [Lovinger, David] NIAAA, Lab Integrat Neurosci, Bethesda, MD 20892 USA. [Everitt, Barry J.] Univ Cambridge, Dept Psychol, Behav & Clin Neurosci Inst, Cambridge, England. [Fein, George] Neurobehav Res Inc, Ala Moana Pacific Ctr, Honolulu, HI USA. [Harris, R. Adron] Univ Texas Austin, Waggoner Ctr Alcohol & Addict, Austin, TX 78712 USA. [Grant, Kathleen A.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Meyerhoff, Dieter J.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Sullivan, Edith V.] Stanford Univ, Dept Psychiat & Behav Sci, Sch Med, Stanford, CA 94305 USA. RP Cui, CH (reprint author), NIAAA, 5635 Fishers Lane,Suite 2067, Bethesda, MD 20892 USA. EM Changhai.cui@nih.gov RI koob, george/P-8791-2016 FU National Institutes of Health from the National Institute on Alcohol Abuse and Alcoholism [AA006420, AA020608, AA012602, AA008459, AA013892, AA020334, AA0174720, AA11605, AA020022, AA020024, AA010983, AA022701]; National Institute on Drug Abuse [DA010072, DA004043, DA023597, DA004398, DA024859, DA020908, DA035058, DA027844, DA09241]; National Institute of Diabetes and Digestive and Kidney Diseases [DK26741]; National Institute of Dental and Craniofacial Research [DE19586]; Pearson Center for Alcoholism and Addiction Research; Bowles UNC Center for Alcohol Studies; NIAAA Division of Intramural Clinical and Biological Research [ZIA AA000407]; UK Medical Research Council Program [G1002231]; Alcohol Beverage Medical Research Foundation; Center of Excellence grant from the National Center for Responsible Gaming; [AA019967]; [AA010761]; [AA022475]; [AA021642]; [AA005965]; [AA012388]; [AA013521]; [AA017168]; [AA014095]; [AA020929]; [AA019138]; [AA013885]; [AA020098]; [AA06420]; [AA013659]; [AA016944]; [AA017539] FX George Koob would like to thank Michael Arends for assistance with manuscript preparation. Research was supported by National Institutes of Health grants AA006420, AA020608, AA012602, AA008459, AA013892, AA020334, AA0174720, AA11605, AA020022, AA020024, AA010983, AA022701, AA019967, AA010761, AA022475, AA021642, AA005965, AA012388, AA013521, AA017168, AA010761, AA014095, AA020929, AA019138, AA013885, AA020098, AA06420, AA013659, AA016944, and AA017539 from the National Institute on Alcohol Abuse and Alcoholism, DA010072, DA004043, DA023597, DA004398, DA024859, DA020908, DA035058, DA027844, DA09241 from the National Institute on Drug Abuse, DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases, DE19586 from National Institute of Dental and Craniofacial Research. Research was also supported by the Pearson Center for Alcoholism and Addiction Research, Bowles UNC Center for Alcohol Studies, NIAAA Division of Intramural Clinical and Biological Research (ZIA AA000407), UK Medical Research Council Program (G1002231), Alcohol Beverage Medical Research Foundation, and a Center of Excellence grant from the National Center for Responsible Gaming. NR 168 TC 8 Z9 8 U1 7 U2 34 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD AUG PY 2015 VL 49 IS 5 BP 435 EP 452 DI 10.1016/j.alcohol.2015.04.006 PG 18 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA CL4FE UT WOS:000356907200001 PM 26074423 ER PT J AU Xiao, S Chen, YC Betenbaugh, MJ Martin, SE Shiloach, J AF Xiao, Su Chen, Yu-Chi Betenbaugh, Michael J. Martin, Scott E. Shiloach, Joseph TI MiRNA mimic screen for improved expression of functional neurotensin receptor from HEK 293 cells SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE microRNA screen; neurotensin receptor; HEK293; protein expression ID MEMBRANE-PROTEIN OVEREXPRESSION; HIGH-LEVEL EXPRESSION; HAMSTER OVARY CELLS; SEROTONIN TRANSPORTER; TUMOR-SUPPRESSOR; MAMMALIAN-CELLS; CANCER CELLS; CHO-CELLS; GENES; TRANSCRIPTION AB Obtaining adequate quantities of functional mammalian membrane proteins has been a bottleneck in their structural and functional studies because the expression of these proteins from mammalian cells is relatively low. To explore the possibility of enhancing expression of these proteins using miRNA, a stable T-REx-293 cell line expressing the neurotensin receptor type 1 (NTSR1), a hard-to-express G protein-coupled receptor (GPCR), was constructed. The cell line was then subjected to human miRNA mimic library screening. In parallel, an HEK293 cell line expressing luciferase was also screened with the same human miRNA mimic library. Five microRNA mimics: hsa-miR-22-5p, hsa-miR-18a-5p, hsa-miR-22-3p, hsa-miR-429, and hsa-miR-2110were identified from both screens. They led to 48% increase in the expression of functional NTSR1 and to 239% increase of luciferase expression. These miRNAs were also effective in enhancing the expression of secretedglypican-3 hFc-fusion protein from HEK293 cells.The results indicate that these molecules may have a wide role in enhancing the production of proteins with biomedical interest. Biotechnol. Bioeng. 2015;112: 1632-1643. (c) 2015 Wiley Periodicals, Inc. C1 [Xiao, Su; Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. [Xiao, Su; Betenbaugh, Michael J.] Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. [Xiao, Su; Betenbaugh, Michael J.] Johns Hopkins Univ, Dept Biomol Engn, Baltimore, MD USA. [Chen, Yu-Chi; Martin, Scott E.] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. EM martinsc@mail.nih.gov; josephs@intra.niddk.nih.gov FU Intramural Research Program of the National Institutes of Health; Intramural Research Program of the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases); Intramural Research Program of the National Institutes of Health (National Center for Advancing Translational Sciences); NIH [5R01GM095685-03] FX This work was supported by the Intramural Research Program of the National Institutes of Health (SX, JS: National Institute of Diabetes and Digestive and Kidney Diseases; YC, SM: National Center for Advancing Translational Sciences) and was partially supported by NIH grant 5R01GM095685-03. DNA sequence synthesis and analysis were performed at the Center for Biologics Evaluation and Research (Food and Drug Administration, Bethesda, MD, USA). We thank Sarah Inwood (National Institutes of Health, Bethesda, USA) for discussion and help with miRNA references. We are grateful to Dr. Reinhard Grisshammer and Jim White (National Institutes of Health, Rockville, US) for providing NTSR1 construct, ligand binding assay workstation and the kind help. We thankDr. Christopher G. Tate (MRC Laboratory of Molecular Biology, Cambridge, UK) for the kind gift of pJMA111 plasmidand Dr. Mitchell Ho (National Cancer Institute, Bethesda, US) for HEK-GPC3-hFc cell line. NR 48 TC 2 Z9 2 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3592 EI 1097-0290 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD AUG PY 2015 VL 112 IS 8 BP 1632 EP 1643 DI 10.1002/bit.25567 PG 12 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA CL5AO UT WOS:000356971500013 PM 25676429 ER PT J AU Graves, JP Gruzdev, A Bradbury, JA DeGraff, LM Li, HL House, JS Hoopes, SL Edin, ML Zeldin, DC AF Graves, Joan P. Gruzdev, Artiom Bradbury, J. Alyce DeGraff, Laura M. Li, Huiling House, John S. Hoopes, Samantha L. Edin, Matthew L. Zeldin, Darryl C. TI Quantitative Polymerase Chain Reaction Analysis of the Mouse Cyp2j Subfamily: Tissue Distribution and Regulation SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID ARACHIDONIC-ACID EPOXYGENASE; SOLUBLE EPOXIDE HYDROLASE; MOLECULAR-CLONING; EPOXYEICOSATRIENOIC ACIDS; HYPERPOLARIZING FACTORS; INFLAMMATORY RESPONSE; AIRWAY INFLAMMATION; CYTOCHROMES P450; EXPRESSION; PCR AB Members of the cytochrome P450 CYP2J subfamily are expressed in multiple tissues in mice and humans. These enzymes are active in the metabolism of fatty acids to generate bioactive compounds. Herein we report new methods and results for quantitative polymerase chain reaction (qPCR) analysis for the seven genes (Cyp2j5, Cyp2j6, Cyp2j8, Cyp2j9, Cyp2j11, Cyp2j12, and Cyp2j13) of the mouse Cyp2j subfamily. SYBR Green primer sets were developed and compared with commercially available TaqMan primer/probe assays for specificity toward mouse Cyp2j cDNA, and analysis of tissue distribution and regulation of Cyp2j genes. Each TaqMan primer/probe set and SYBR Green primer set were shown to be specific for their intended mouse Cyp2j cDNA. Tissue distribution of the mouse Cyp2j isoforms confirmed similar patterns of expression between the two qPCR methods. Cyp2j5 and Cyp2j13 were highly expressed in male kidneys, and Cyp2j11 was highly expressed in both male and female kidneys. Cyp2j6 was expressed in multiple tissues, with the highest expression in the small intestine and duodenum. Cyp2j8 was detected in various tissues, with highest expression found in the skin. Cyp2j9 was highly expressed in the brain, liver, and lung. Cyp2j12 was predominately expressed in the brain. We also determined the Cyp2j isoform expression in Cyp2j5 knockout mice to determine whether there was compensatory regulation of other Cyp2j isoforms, and we assessed Cyp2j isoform regulation during various inflammatory models, including influenza A, bacterial lipopolysaccharide, house dust mite allergen, and corn pollen. Both qPCR methods detected similar suppression of Cyp2j6 and Cyp2j9 during inflammation in the lung. C1 [Graves, Joan P.; Gruzdev, Artiom; Bradbury, J. Alyce; DeGraff, Laura M.; Li, Huiling; House, John S.; Hoopes, Samantha L.; Edin, Matthew L.; Zeldin, Darryl C.] NIEHS, Immun Inflammat & Dis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), NIEHS, NIH, 111 TW Alexander Dr,Bldg 101,Room A214, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov OI Edin, Matthew/0000-0002-7042-500X; House, John S./0000-0002-8447-7871 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES025034] FX This work was funded by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES025034]. NR 38 TC 3 Z9 3 U1 1 U2 9 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 EI 1521-009X J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD AUG PY 2015 VL 43 IS 8 BP 1169 EP 1180 DI 10.1124/dmd.115.064139 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CL6QE UT WOS:000357091100002 PM 25994032 ER PT J AU Xin, W Bonci, A AF Xin, W. Bonci, A. TI Functional characterization of astrocytes within the ventral midbrain SO GLIA LA English DT Meeting Abstract CT 12th European Meeting on Glial Cell Function in Health and Disease CY JUL 15-18, 2015 CL Bilbao, SPAIN C1 [Xin, W.] Natl Inst Drug Abuse, Johns Hopkins, Neurosci, Baltimore, MD USA. [Bonci, A.] Natl Inst Drug Abuse, Synapt Plast, Baltimore, 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 0894-1491 EI 1098-1136 J9 GLIA JI Glia PD AUG PY 2015 VL 63 SU 1 MA T15-10A BP E448 EP E449 PG 2 WC Neurosciences SC Neurosciences & Neurology GA CK7CA UT WOS:000356386700745 ER PT J AU Song, SB Gotts, SJ Dayan, E Cohen, LG AF Song, Sunbin Gotts, Stephen J. Dayan, Eran Cohen, Leonardo G. TI Practice Structure Improves Unconscious Transitional Memories by Increasing Synchrony in a Premotor Network SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID AUTISM SPECTRUM DISORDERS; SUPPLEMENTARY MOTOR AREA; CONTEXTUAL INTERFERENCE; CEREBRAL-CORTEX; SKILL; ACQUISITION; RETENTION; REPRESENTATION; PROBABILITIES; EXPLICIT AB Sequence learning relies on formation of unconscious transitional and conscious ordinal memories. The influence of practice type on formation of these memories that compose skill and systems level neural substrates is not known. Here, we studied learning of transitional and ordinal memories in participants trained on motor sequences while scanned using fMRI. Practice structure was varied or grouped (mixing or grouping sequences during training, respectively). Memory was assessed 30 min and 1 week later. Varied practice improved transitional memory and enhanced coupling of the dorsal premotor cortex with thalamus, cerebellum, and lingual and cingulate regions and greater transitional memory correlated with this coupling. Thus, varied practice improves unconscious transitional memories in proportion to coupling within a cortico-subcortical network linked to premotor cortex. This result indicates that practice structure influences unconscious transitional memory formation and identifies underlying systems level mechanisms. C1 Natl Inst Hlth, Bethesda, MD USA. [Song, Sunbin; Gotts, Stephen J.; Dayan, Eran; Cohen, Leonardo G.] NIH, Bethesda, MD 20892 USA. RP Song, SB (reprint author), NINDS, Human Cort Physiol & Neurorehabilitat Sect, NIH, Bethesda, MD 20892 USA. EM songss@ninds.nih.gov; cohenl@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX The authors thank Richard Reynolds and Gang Chen of the NIH AFNI Core Staff and Marco Sandrini for helpful comments on the manuscript. This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health and utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (http://biowulf.nih.gov). NR 59 TC 4 Z9 4 U1 0 U2 5 PU MIT PRESS PI CAMBRIDGE PA ONE ROGERS ST, CAMBRIDGE, MA 02142-1209 USA SN 0898-929X EI 1530-8898 J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD AUG PY 2015 VL 27 IS 8 BP 1503 EP 1512 DI 10.1162/jocn_a_00796 PG 10 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA CL4NV UT WOS:000356930600003 PM 25761004 ER PT J AU Wang, XQ Wei, YX Liu, XL Xing, C Han, GC Chen, GJ Hou, CM Dambuza, IM Shen, BF Li, Y Xiao, H Wang, RX AF Wang, Xiaoqian Wei, Yinxiang Liu, Xiaoling Xing, Chen Han, Gencheng Chen, Guojiang Hou, Chunmei Dambuza, Ivy M. Shen, Beifen Li, Yan Xiao, He Wang, Renxi TI IL-15-secreting gamma delta T cells induce memory T cells in experimental allergic encephalomyelitis (EAE) mice SO MOLECULAR IMMUNOLOGY LA English DT Article DE Multiple sclerosis; EAE; gamma delta T Cells; IL-15; Th17 ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; MULTIPLE-SCLEROSIS; DEMYELINATING DISEASE; GENE-EXPRESSION; NATURAL-HISTORY; KNOCKOUT MICE; ANIMAL-MODELS; LYMPHOCYTE-T; IL-15 AB With the most recent data suggesting gamma delta T cells as primary producers of the pro-inflammatory autoimmune-associated cytokine, the relationship between gamma delta T cells and Th17 in experimental allergic encephalitis (EAE) mice requires more extensive investigation. By flow cytometry and qPCR, we identified a new subset of IL-15-secreting gamma delta T (gamma delta T15) cells that increased in EAE mice. The capacity of IL-15-secreting gamma delta T cells inducing memory T cells and memory T cells inducing IL-17(+)Th17 was examined by transferring into EAE mice and 7-week-old female nude mice, respectively. We found that gamma delta T15 induced CD44(hi) memory T cells by secreting IL-15. gamma delta T15-induced memory T cells induced EAE by transforming into pathogenic Th17 cells. The data suggest that a new subset of IL-15-secreting gamma delta T cells mediated the production of memory T cells which transformed into pathogenic Th17 cells in EAE mice. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Wang, Xiaoqian; Wei, Yinxiang; Liu, Xiaoling; Xing, Chen; Han, Gencheng; Chen, Guojiang; Hou, Chunmei; Shen, Beifen; Li, Yan; Xiao, He; Wang, Renxi] Inst Basic Med Sci, Immunol Lab, Beijing 100850, Peoples R China. [Wei, Yinxiang] Zhejiang Univ, Sch Med, Inst Immunol, Hangzhou 310013, Zhejiang, Peoples R China. [Liu, Xiaoling] 307th Hosp Chinese Peoples Liberat Army, Dept Mephrol, Beijing 100850, Peoples R China. [Dambuza, Ivy M.] NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Xiao, H (reprint author), Inst Basic Med Sci, Immunol Lab, POB 130 3,Taiping Rd 27, Beijing 100850, Peoples R China. EM yinher2001@yahoo.com; wang_renxi@yahoo.com FU National Natural Science Foundation of China [81471529, 81272320, 81172800]; Beijing Natural Science Foundation [7132139, 7141007, 7132151]; National Basic Research Program 973 Grants [2013CB530506] FX This study was supported by National Natural Science Foundation of China (81471529, 81272320 and 81172800), Beijing Natural Science Foundation (7132139, 7141007 and 7132151) and National Basic Research Program 973 Grants (2013CB530506). NR 39 TC 2 Z9 3 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 2015 VL 66 IS 2 BP 402 EP 408 DI 10.1016/j.molimm.2015.04.021 PG 7 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA CL5JJ UT WOS:000356995900033 PM 25974878 ER PT J AU Saligan, LN Olson, K Filler, K Larkin, D Cramp, F Sriram, Y Escalante, CP del Giglio, A Kober, KM Kamath, J Palesh, O Mustian, K AF Saligan, Leorey N. Olson, Karin Filler, Kristin Larkin, David Cramp, Fiona Sriram, Yennu Escalante, Carmen P. del Giglio, Auro Kober, Kord M. Kamath, Jayesh Palesh, Oxana Mustian, Karen CA Multinatl Assoc Supportive Care Biomarker Working Grp TI The biology of cancer-related fatigue: a review of the literature SO SUPPORTIVE CARE IN CANCER LA English DT Review DE Cancer-related fatigue; Inflammation; Metabolic; Neuroendocrine; Genetic ID METHYLTRANSFERASE GENOTYPE VAL158MET; ANDROGEN DEPRIVATION THERAPY; NECROSIS-FACTOR-ALPHA; BREAST-CANCER; SLEEP DISTURBANCE; PROSTATE-CANCER; OVARIAN-CANCER; INFLAMMATORY CYTOKINES; CHEMORADIATION THERAPY; COGNITIVE IMPAIRMENT AB Understanding the etiology of cancer-related fatigue (CRF) is critical to identify targets to develop therapies to reduce CRF burden. The goal of this systematic review was to expand on the initial work by the National Cancer Institute CRF Working Group to understand the state of the science related to the biology of CRF and, specifically, to evaluate studies that examined the relationships between biomarkers and CRF and to develop an etiologic model of CRF to guide researchers on pathways to explore or therapeutic targets to investigate. This review was completed by the Multinational Association of Supportive Care in Cancer Fatigue Study Group-Biomarker Working Group. The initial search used three terms (biomarkers, fatigue, cancer), which yielded 11,129 articles. After removing duplicates, 9145 articles remained. Titles were assessed for the keywords "cancer" and "fatigue" resulting in 3811 articles. Articles published before 2010 and those with samples < 50 were excluded, leaving 75 articles for full-text review. Of the 75 articles, 28 were further excluded for not investigating the associations of biomarkers and CRF. Of the 47 articles reviewed, 25 were cross-sectional and 22 were longitudinal studies. More than half (about 70 %) were published recently (2010-2013). Almost half (45 %) enrolled breast cancer participants. The majority of studies assessed fatigue using self-report questionnaires, and only two studies used clinical parameters to measure fatigue. The findings from this review suggest that CRF is linked to immune/inflammatory, metabolic, neuroendocrine, and genetic biomarkers. We also identified gaps in knowledge and made recommendations for future research. C1 [Saligan, Leorey N.; Filler, Kristin] NINR, NIH, Bethesda, MD 20892 USA. [Olson, Karin] Univ Alberta, Fac Nursing, Edmonton, AB, Canada. [Larkin, David] Univ Canberra, Australian Capital Terr Hlth, Canberra, ACT 2601, Australia. [Cramp, Fiona] Univ W England, Bristol BS16 1QY, Avon, England. [Sriram, Yennu; Escalante, Carmen P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [del Giglio, Auro] Brazilian Albert Einstein Jewish Hosp, Sao Paulo, Brazil. [Kober, Kord M.] Univ Calif San Francisco, Dept Physiol Nursing, San Francisco, CA USA. [Kamath, Jayesh] Univ Connecticut Hlth Ctr, Farmington, CT USA. [Palesh, Oxana] Stanford Univ Med Ctr, Psychiat & Behav Sci, Stanford, CA USA. [Mustian, Karen] Univ Rochester Med Ctr, Wilmot Canc Inst, Rochester, NY USA. RP Saligan, LN (reprint author), NINR, NIH, 9000 Rockville Pike,Bldg 3,Room 5E14, Bethesda, MD 20892 USA. EM saliganl@mail.nih.gov RI Kamath, Jayesh/J-7491-2013; OI Cramp, Fiona/0000-0001-8035-9758 FU Multinational Association of Supportive Care in Cancer; Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health; NCI [K07CA120025, UG1 CA189961, R01 CA181064] FX This research was supported by the Multinational Association of Supportive Care in Cancer and the Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health, and Grants NCI K07CA120025, UG1 CA189961 and R01 CA181064. NR 90 TC 22 Z9 22 U1 5 U2 27 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD AUG PY 2015 VL 23 IS 8 BP 2461 EP 2478 DI 10.1007/s00520-015-2763-0 PG 18 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA CL4ZQ UT WOS:000356968100033 PM 25975676 ER PT J AU Loohuis, NFMO Kole, K Glennon, JC Karel, P Van der Borg, G Van Gemert, Y Van den Bosch, D Meinhardt, J Kos, A Shahabipour, F Tiesinga, P van Bokhoven, H Martens, GJM Kaplan, BB Homberg, JR Aschrafi, A AF Loohuis, N. F. M. Olde Kole, K. Glennon, J. C. Karel, P. Van der Borg, G. Van Gemert, Y. Van den Bosch, D. Meinhardt, J. Kos, A. Shahabipour, F. Tiesinga, P. van Bokhoven, H. Martens, G. J. M. Kaplan, B. B. Homberg, J. R. Aschrafi, A. TI Elevated microRNA-181c and microRNA-30d levels in the enlarged amygdala of the valproic acid rat model of autism SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Autism spectrum disorder; Valproic acid; Amygdala; MicroRNA; Gene networks; Neurodevelopmental disorder; Rat model of autism ID MENTAL-RETARDATION PROTEIN; SYNAPTIC PLASTICITY; SPECTRUM DISORDERS; BEHAVIORAL ALTERATIONS; BASOLATERAL AMYGDALA; PRENATAL EXPOSURE; ANIMAL-MODEL; IN-VIVO; HIPPOCAMPUS; EXPRESSION AB Autism spectrum disorders are severe neurodevelopmental disorders, marked by impairments in reciprocal social interaction, delays in early language and communication, and the presence of restrictive, repetitive and stereotyped behaviors. Accumulating evidence suggests that dysfunction of the amygdala may be partially responsible for the impairment of social behavior that is a hallmark feature of ASD. Our studies suggest that a valproic acid (VPA) rat model of ASD exhibits an enlargement of the amygdala as compared to controls rats, similar to that observed in adolescent ASD individuals. Since recent research suggests that altered neuronal development and morphology, as seen in ASD, may result from a common post-transcriptional process that is under tight regulation by microRNAs (miRs), we examined genome-wide transcriptomics expression in the amygdala of rats prenatally exposed to VPA, and detected elevated miR-181c and miR-30d expression levels as well as dysregulated expression of their cognate mRNA targets encoding proteins involved in neuronal system development. Furthermore, selective suppression of miR-181c function attenuates neurite outgrowth and branching, and results in reduced synaptic density in primary amygdalar neurons in vitro. Collectively, these results implicate the small non-coding miR-181c in neuronal morphology, and provide a framework of understanding how dysregulation of a neurodevelopmentally relevant miR in the amygdala may contribute to the pathophysiology of ASD. (C) 2015 Elsevier Inc. All rights reserved. C1 [Loohuis, N. F. M. Olde; Glennon, J. C.; Karel, P.; Kos, A.; van Bokhoven, H.; Homberg, J. R.] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Med Ctr, Dept Cognit Neurosci, NL-6525 AJ Nijmegen, Netherlands. [Kole, K.; Van der Borg, G.; Van Gemert, Y.; Van den Bosch, D.; Meinhardt, J.; Shahabipour, F.; Tiesinga, P.; Aschrafi, A.] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Dept Neuroinformat, NL-6525 AJ Nijmegen, Netherlands. [Martens, G. J. M.] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Dept Mol Anim Physiol, Nijmegen Ctr Mol Life Sci, NL-6525 AJ Nijmegen, Netherlands. [Kaplan, B. B.] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [van Bokhoven, H.] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 AJ Nijmegen, Netherlands. RP Aschrafi, A (reprint author), Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Dept Neuroinformat, Heyendaalseweg 135, NL-6525 AJ Nijmegen, Netherlands. EM a.aschrafi@donders.ru.nl RI Martens, Gerard/D-1925-2010; Bokhoven, J.H.L.M./H-8015-2014; Homberg, Judith/D-2473-2010; Glennon, Jeffrey/D-2379-2013 FU Donders Center for Neuroscience fellowship award of the Radboud University Nijmegen Medical Centre; FP7-Marie Curie International Reintegration Grant FX This work was supported by the Donders Center for Neuroscience fellowship award of the Radboud University Nijmegen Medical Centre and the FP7-Marie Curie International Reintegration Grant to A. Aschrafi. NR 74 TC 6 Z9 6 U1 4 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD AUG PY 2015 VL 80 BP 42 EP 53 DI 10.1016/j.nbd.2015.05.006 PG 12 WC Neurosciences SC Neurosciences & Neurology GA CK9MV UT WOS:000356565100004 ER PT J AU Peskoe, SB Joshu, CE Rohrmann, S McGlynn, KA Nyante, SJ Bradwin, G Dobs, AS Kanarek, N Nelson, WG Platz, EA AF Peskoe, Sarah B. Joshu, Corinne E. Rohrmann, Sabine McGlynn, Katherine A. Nyante, Sarah J. Bradwin, Gary Dobs, Adrian S. Kanarek, Norma Nelson, William G. Platz, Elizabeth A. TI Circulating total testosterone and PSA concentrations in a nationally representative sample of men without a diagnosis of prostate cancer SO PROSTATE LA English DT Article DE testosterone; prostate specific antigen; men ID ANTIGEN; SERUM AB BACKGROUNDThe association between serum sex steroid hormones and PSA in a general population has not been described. METHODSIncluded were 378 men aged 40-85 years who participated in the National Health and Nutrition Examination Survey in 2001-2004, who did not have a prostate cancer diagnosis, and had not had a recent biopsy, rectal examination, cystoscopy, or prostate infection or inflammation. Serum total PSA, total testosterone, androstanediol glucuronide (3-diol-G), estradiol, and sex hormone binding globulin (SHBG) concentrations were previously measured. Free testosterone was estimated by mass action. We applied sampling weights and calculated geometric mean PSA concentration by hormone quintiles adjusting for age and race/ethnicity, and also for body mass index, waist circumference, smoking, diabetes, and mutually for hormones. We estimated the OR of PSA 2.5ng/ml per hormone quintile using logistic regression. RESULTSGeometric mean PSA increased across testosterone quintiles after age and race/ethnicity (Q1: 0.80, Q5: 1.14ng/ml; P-trend=0.002) and multivariable (Q1: 0.79, Q5: 1.16ng/ml; P-trend=0.02) adjustment; patterns were similar for free testosterone and 3-diol-G. SHBG was inversely associated with PSA only after multivariable adjustment (Q1: 1.32, Q5: 0.82 nmol/L; P-trend=0.01). Estradiol and PSA were not associated. The OR of PSA 2.5ng/ml was 1.54 (95%CI 1.18-2.01) per testosterone quintile after age and race/ethnicity adjustment, and 1.78 (95%CI 1.16-2.73) after multivariable adjustment. CONCLUSIONSIn this nationally representative sample, men with higher testosterone had higher PSA even after taking into account other hormones and modifiable factors. Men with higher SHBG had lower PSA, but only after multivariable adjustment. Prostate 75: 1167-1176, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Peskoe, Sarah B.; Joshu, Corinne E.; Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Rohrmann, Sabine] Univ Zurich, EBPI, Dept Chron Dis Epidemiol, Zurich, Switzerland. [McGlynn, Katherine A.; Nyante, Sarah J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Bradwin, Gary] Harvard Univ, Sch Med, Dept Lab Med, Boston, MA USA. [Bradwin, Gary] Childrens Hosp, Boston, MA 02115 USA. [Dobs, Adrian S.] Johns Hopkins Univ, Sch Med, Dept Med, Div Endocrinol & Metab, Baltimore, MD 21205 USA. [Dobs, Adrian S.; Kanarek, Norma; Nelson, William G.; Platz, Elizabeth A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Kanarek, Norma; Nelson, William G.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 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, James Buchanan Brady Urol Inst, Sch Med, Baltimore, MD USA. RP Platz, EA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Room E6132,615 N Wolfe St, Baltimore, MD 21205 USA. EM eplatz1@jhu.edu FU Maryland Cigarette Restitution Fund at Johns Hopkins; NCI [P30 CA006973]; NIH Intramural Research Program FX Grant sponsor: The Maryland Cigarette Restitution Fund at Johns Hopkins; Grant sponsor: NCI; Grant number: P30 CA006973; Grant sponsor: The NIH Intramural Research Program. NR 16 TC 10 Z9 10 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD AUG 1 PY 2015 VL 75 IS 11 BP 1167 EP 1176 DI 10.1002/pros.22998 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA CK8AN UT WOS:000356459700006 PM 25919471 ER PT J AU Zagouri, F Liakou, P Bartsch, R Peccatori, FA Tsigginou, A Dimitrakakis, C Zografos, GC Dimopoulos, MA Azim, HA AF Zagouri, Flora Liakou, Paraskevi Bartsch, Rupert Peccatori, Fedro A. Tsigginou, Alexandra Dimitrakakis, Constantine Zografos, George C. Dimopoulos, Meletios-Athanassios Azim, H. A., Jr. TI Discrepancies between ESMO and NCCN breast cancer guidelines: An appraisal SO BREAST LA English DT Article DE Breast cancer; NCCN; ESMO; Guidelines; Metastatic; Adjuvant AB An ever growing number of medical organizations, societies, working groups and governmental agencies issue algorithms i.e. guidelines, of decision making flowcharts in diagnosis and treatment in a variety of diseases. In the field of evidence-based diagnosis and treatment of breast cancer, a large number of guidelines are available both from medical associations and national health departments. Among the most appreciated and utilized comprehensive guides is the European Society for Medical Oncology (ESMO) Breast Cancer Guidelines and from the other side of the Atlantic the National Comprehensive Cancer Network (NCCN) Guidelines in Breast Cancer. Although there is much concordance between the guidelines from these two organizations, it is intriguing to locate their discrepancies also. The aim of this report is to present a number of different points between ESMO and NCCN in the whole spectrum of breast cancer management, from prevention and diagnosis to treatment and follow up. This systematic review was performed in accordance with the PRISMA guidelines using a predefined search strategy and summarizes in detail, the differences between ESMO and NCCN guidelines regarding genetic risk evaluation and screening, surgery, chemotherapy, endocrine treatment, targeted biological agents, radiotherapy, pregnancy and fertility and follow-up. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Zagouri, Flora; Dimopoulos, Meletios-Athanassios] Univ Athens, Sch Med, Alexandra Hosp, Dept Clin Therapeut, GR-10679 Athens, Greece. [Liakou, Paraskevi; Zografos, George C.] Univ Athens, Sch Med, Hippocrateio Hosp, Propaedeut Surg Dept 1, GR-11527 Athens, Greece. [Bartsch, Rupert] Med Univ Vienna, Div Clin Oncol, Vienna, Austria. [Tsigginou, Alexandra] European Inst Oncol, Dept Gynecol Oncol, Fertil & Procreat Unit, Milan, Italy. [Peccatori, Fedro A.] Univ Athens, Sch Med, Dept Obstet & Gynecol, GR-10679 Athens, Greece. [Dimitrakakis, Constantine] NICHHD, Eunice Kennedy Shriver, NIH, Iowa City, IA USA. [Azim, H. A., Jr.] Univ Libre Bruxelles, Inst Jules Bordet, BrEAST Data Ctr, Dept Med, Brussels, Belgium. RP Azim, HA (reprint author), Inst Jules Bordet, Dept Med, BrEAST Data Ctr, Blvd Waterloo 121, B-1000 Brussels, Belgium. EM hatem.azim@bordet.be NR 17 TC 5 Z9 5 U1 0 U2 9 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 EI 1532-3080 J9 BREAST JI Breast PD AUG PY 2015 VL 24 IS 4 BP 513 EP 523 DI 10.1016/j.breast.2015.02.031 PG 11 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CK3FG UT WOS:000356101400029 PM 25818651 ER PT J AU Bae, J Kim, S Schisterman, EF Barr, DB Louis, GMB AF Bae, Jisuk Kim, Sungduk Schisterman, Enrique F. Barr, Dana Boyd Louis, Germaine M. Buck TI Maternal and paternal serum concentrations of perfluoroalkyl and polyfluoroalkyl substances and the secondary sex ratio SO CHEMOSPHERE LA English DT Article DE Endocrine disruptors; Fertility; Maternal exposure; Paternal exposure; Perfluoroalkyl and polyfluoroalkyl; substances; Sex ratio ID MITOCHONDRIAL PERMEABILITY TRANSITION; PERFLUOROOCTANE SULFONATE PFOS; HUMAN SEMEN QUALITY; PERFLUORINATED COMPOUNDS; IN-VITRO; EUROPEAN POPULATIONS; HUMAN BLOOD; BIRTH; EXPOSURE; CONCEPTION AB Select persistent environmental chemicals have been associated with a reduction in the secondary sex ratio (SSR), or the ratio of male to female live births. We evaluated preconception maternal, paternal, and couple serum concentrations of perfluoroalkyl and polyfluoroalkyl substances (PFASs) in relation to the SSR, given the absence of previous investigation. Two hundred thirty-three couples from Michigan and Texas were enrolled prior to conception and prospectively followed through delivery of a singleton birth, 2005-2009. Maternal and paternal serum concentrations (ng mL(-1)) were measured at baseline for seven PFASs. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for a male birth, after adjusting for potential confounders. When maternal and paternal PFAS concentrations were modeled jointly, five of the seven PFASs, including the two most prominent PFASs, perfluorooctane sulfonic acid and perfluorooctanoic acid, were not significantly associated with the SSR. However, paternal N-methyl-perfluorooctane sulfonamidoacetic acid (MeFOSAA) and perfluorononanoic acid (2nd versus 1st tertile, OR, 0.43, 95% CI, 0.21-0.88) were significantly associated with an excess of female births. Meanwhile, a dose-response relation was observed only for paternal MeFOSAA (2nd versus 1st tertile, OR, 0.53, 95% CI, 0.26-1.10; 3rd versus 1st tertile, OR, 0.34, 95% CI, 0.13-0.89). This study suggests a possible dose-response relation between a less prevalent PFAS and a reversal in the SSR, though the underlying mechanisms remain unknown and the findings await corroboration to eliminate other explanations including chance. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Bae, Jisuk; Kim, Sungduk; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. [Bae, Jisuk] Catholic Univ, Sch Med, Dept Prevent Med, Daegu 705718, South Korea. [Barr, Dana Boyd; Louis, Germaine M. Buck] Emory Univ, Rollins Sch Publ Hlth, Dept Environm Hlth, Atlanta, GA 30322 USA. RP Bae, J (reprint author), Catholic Univ, Sch Med, Dept Prevent Med, 33 Duryugongwon Ro 17-Gil, Daegu 705718, South Korea. EM jialove@cu.ac.kr OI Bae, Jisuk/0000-0002-5809-5394; Schisterman, Enrique/0000-0003-3757-641X; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358]; Korea-US Visiting Scientist Training Award (VSTA) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [VFTB057303] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358). J.B. was supported by the Korea-US Visiting Scientist Training Award (VSTA) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (award #VFTB057303). NR 53 TC 2 Z9 2 U1 2 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 EI 1879-1298 J9 CHEMOSPHERE JI Chemosphere PD AUG PY 2015 VL 133 BP 31 EP 40 DI 10.1016/j.chemosphere.2015.03.015 PG 10 WC Environmental Sciences SC Environmental Sciences & Ecology GA CK0GG UT WOS:000355883100005 PM 25863705 ER PT J AU Liu, X Yanagawa, T Leopold, DA Chang, C Ishida, H Fujii, N Duyn, JH AF Liu, Xiao Yanagawa, Toru Leopold, David A. Chang, Catie Ishida, Hiroaki Fujii, Naotaka Duyn, Jeff H. TI Arousal transitions in sleep, wakefulness, and anesthesia are characterized by an orderly sequence of cortical events SO NEUROIMAGE LA English DT Article DE Resting-state global signal; Consciousness; Feedback process; Alpha inhibitory gating; Sleep; Propofol anesthesia ID PROPOFOL-INDUCED UNCONSCIOUSNESS; BASAL FOREBRAIN NEURONS; GAMMA OSCILLATIONS; TOP-DOWN; FUNCTIONAL CONNECTIVITY; BAND OSCILLATIONS; VISUAL-CORTEX; EEG-VIGILANCE; FMRI ACTIVITY; BOLD SIGNAL AB Many aspects of brain function are influenced by modulatory processes, including arousal. The most abrupt changes in arousal occur at the wake-sleep transition and at the induction of anesthetic conditions. They are accompanied by major electrophysiological changes, including an emergence of low-frequency (sleep-like) activity and a loss of mid-frequency (wake-like) activity that has been linked to feedback processes of the brain. Nevertheless, the causal relationship between these two types of electrophysiological changes, as well as the cortical mechanisms underlying changes in arousal and consciousness, remain poorly understood. To address this, we studied spontaneous electro-cortical activity during arousal changes in macaques. During sleep and at loss of consciousness induced by propofol anesthesia, we identified a prototypical sequence of cortical events in which the loss of mid-frequency activity preceded, by seconds, the increases in low-frequency activity. Furthermore, in visual areas, an influence of mid-frequency change onto high-frequency activity was observed across visual hierarchy. These results are consistent with the notion that drops in arousal and consciousness are facilitated by a release of feedback cortical inhibition. Published by Elsevier Inc. C1 [Liu, Xiao; Chang, Catie; Duyn, Jeff H.] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Yanagawa, Toru; Fujii, Naotaka] RIKEN, Brain Sci Inst, Lab Adapt Intelligence, Saitama, Japan. [Leopold, David A.] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Leopold, David A.] NEI, Neurophysiol Imaging Facil, NIMH, NINDS, Bethesda, MD 20892 USA. [Ishida, Hiroaki] Tokyo Metropolitan Inst Med Sci, Frontal Lobe Funct Project, Tokyo 113, Japan. RP Liu, X (reprint author), 10 Ctr Dr,Bldg 10,Rm B1D-723A,MSC 1065, Bethesda, MD 20892 USA. EM liux15@ninds.nih.gov RI Liu, Xiao/C-5943-2016; OI Leopold, David/0000-0002-1345-6360 FU Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke [NS 003027-8] FX This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke (NS 003027-8). The authors thank Dr. Picchioni for helpful discussion. NR 76 TC 5 Z9 5 U1 1 U2 17 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 2015 VL 116 BP 222 EP 231 DI 10.1016/j.neuroimage.2015.04.003 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CK0XY UT WOS:000355930200022 PM 25865143 ER PT J AU Pelch, KE Tokar, EJ Merrick, BA Waalkes, MP AF Pelch, Katherine E. Tokar, Erik J. Merrick, B. Alex Waalkes, Michael P. TI Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Inorganic arsenic; Cadmium; DNA methylation; Prostate cancer; Gene expression ID STEM-CELL; NESTIN EXPRESSION; CANCER; EXPOSURE; CARCINOGENESIS; S100P; LINES; PROGRESSION; HYAL-1 AB Previous work shows altered methylation patterns in inorganic arsenic (iAs)- or cadmium (Cd)-transformed epithelial cells. Here, the methylation status near the transcriptional start site was assessed in the normal human prostate epithelial cell line (RWPE-1) that was malignantly transformed by 10 mu M Cd for 11 weeks (CTPE) or 5 mu M iAs for 29 weeks (CAsE-PE), at which time cells showed multiple markers of acquired cancer phenotype. Next generation sequencing of the transcriptome of CAsE-PE cells identified multiple dysregulated genes. Of the most highly dysregulated genes, five genes that can be relevant to the carcinogenic process (S100P, HYAL1, NTM, NES, ALDH1A1) were chosen for an in-depth analysis of the DNA methylation profile. DNA was isolated, bisulfite converted, and combined bisulfite restriction analysis was used to identify differentially methylated CpG sites, which was confirmed with bisulfite sequencing. Four of the five genes showed differential methylation in transformants relative to control cells that was inversely related to altered gene expression. Increased expression of HYAL1 (>25-fold) and S100P (>40-fold) in transformants was correlated with hypomethylation near the transcriptional start site. Decreased expression of NES (>15-fold) and NTM (>1000-fold) in transformants was correlated with hypermethylation near the transcriptional start site. ALDH1A1 expression was differentially expressed in transformed cells but was not differentially methylated relative to control. In conclusion, altered gene expression observed in Cd and iAs transformed cells may result from altered DNA methylation status. Published by Elsevier Inc. C1 [Pelch, Katherine E.; Tokar, Erik J.; Waalkes, Michael P.] NIEHS, Natl Toxicol Program Lab, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Merrick, B. Alex] NIEHS, Mol Toxicol & Informat Grp, Biomol Screening Branch, Div Natl Toxicol Program, Morrisville, NY 27560 USA. RP Waalkes, MP (reprint author), 111 TW Alexander Dr,E-104, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov OI Pelch, Katherine/0000-0002-4821-5153 FU National Toxicology Program of the National Institute of Environmental Health Sciences [ES 102925] FX This work was supported by the National Toxicology Program of the National Institute of Environmental Health Sciences (ES 102925). NR 43 TC 6 Z9 7 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 1 PY 2015 VL 286 IS 3 BP 159 EP 167 DI 10.1016/j.taap.2015.04.011 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CK7FN UT WOS:000356398300003 PM 25922126 ER PT J AU Resnick, SM Bilgel, M Moghekar, A An, Y Cai, Q Wang, MC Thambisetty, M Prince, JL Zhou, Y Soldan, A Wong, DF O'Brien, RJ Ferrucci, L Albert, MS AF Resnick, Susan M. Bilgel, Murat Moghekar, Abhay An, Yang Cai, Qing Wang, Mei-Cheng Thambisetty, Madhav Prince, Jerry L. Zhou, Yun Soldan, Anja Wong, Dean F. O'Brien, Richard J. Ferrucci, Luigi Albert, Marilyn S. TI Changes in A beta biomarkers and associations with APOE genotype in 2 longitudinal cohorts SO NEUROBIOLOGY OF AGING LA English DT Article DE PET amyloid imaging; CSF A beta(1-42); Biomarkers; Apolipoprotein E genotype; Longitudinal ID MILD COGNITIVE IMPAIRMENT; APOLIPOPROTEIN-E EPSILON-4; ALZHEIMERS-DISEASE; SYMPTOM ONSET; OLDER-ADULTS; AGE; BRAIN; DEPOSITION; DECLINE; INDIVIDUALS AB Apolipoprotein E (APOE) genotype influences onset age of Alzheimer's disease but effects on disease progression are less clear. We investigated amyloid-beta (A beta) levels and change in relationship to APOE genotype, using 2 different measures of Ab in 2 different longitudinal cohorts. A beta accumulation was measured using positron emission tomography (PET) imaging and C-11-Pittsburgh compound-B (PiB) in 113 Baltimore Longitudinal Study of Aging participants (mean age 77.3 years; 107 normal, 6 cognitively impaired) and cerebral spinal fluid (CSF) A beta(1-42) assays in 207 BIOCARD study participants (mean age 62 years; 195 normal, 12 cognitively impaired). Participants in both cohorts had up to 7 serial assessments (mean 2.3-2.4). PET-PiB retention increased and CSF A beta(1-42) declined longitudinally. APOE epsilon 4 was significantly associated with higher PET-PiB retention and lower CSF A beta(1-42), independent of age and sex, but APOE genotype did not significantly affect A beta change over time. APOE epsilon 4 carriers may be further along in the disease process, consistent with earlier brain A beta deposition and providing a biological basis for APOE genotype effects on onset age of Alzheimer's disease. (C) 2015 Elsevier Inc. All rights reserved. C1 [Resnick, Susan M.; Bilgel, Murat; An, Yang; Thambisetty, Madhav] NIA, Lab Behav Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Bilgel, Murat; Prince, Jerry L.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Moghekar, Abhay; Soldan, Anja; O'Brien, Richard J.; Albert, Marilyn S.] Johns Hopkins Med Inst, Dept Neurol, Baltimore, MD 21205 USA. [Cai, Qing; Wang, Mei-Cheng] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Prince, Jerry L.; Zhou, Yun; Wong, Dean F.] Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21205 USA. [Ferrucci, Luigi] NIA, Translat Gerontol Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Resnick, SM (reprint author), NIA, Lab Behav Neurosci, Intramural Res Program, Biomed Res Ctr, 251 Bayview Blvd,Room 4B335, Baltimore, MD 21224 USA. EM resnicks@mail.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging; National Institutes of Health [U01-AG03365, P50- AG005146, P41-RR015241]; [HHSN-260-2004-00012C] FX The BLSA study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging and by Research and Development Contract HHSN-260-2004-00012C. We are grateful to the BLSA participants and staff for their dedication to these studies and the staff of the Johns Hopkins PET facility for their assistance. We are especially grateful to Wendy Elkins and Brieana Viscomi for their assistance with coordination and data collection for the PET-PiB studies.; The BIOCARD study is supported in part by grants from the National Institutes of Health: U01-AG03365, P50- AG005146 and P41-RR015241. The BIOCARD Study consists of 7 cores with the following members: (1) the Administrative Core (Marilyn Albert, Barbara Rodzon, Richard Power), (2) the Clinical Core (Ola Selnes, Marilyn Albert, Rebecca Gottesman, Ned Sacktor, Guy McKhann, Scott Turner, Leonie Farrington, Maura Grega, Daniel D'Agostino, Sydney Feagen, David Dolan, Hillary Dolan), (3) the Imaging Core (Michael Miller, Susumu Mori, Tilak Ratnanather, Timothy Brown, Hayan Chi, Anthony Kolasny, Kenichi Oishi, Thomas Reigel, William Schneider, Laurent Younes), (4) the Biospecimen Core (Richard O'Brien, Abhay Moghekar, Richard Meehan), (5) the Informatics Core (Roberta Scherer, Curt Meinert, David Shade, Ann Ervin, Jennifer Jones, Matt Toepfner, Lauren Parlett, April Patterson, Lisa Lassiter), the (6) Biostatistics Core (Mei-Cheng Wang, Yi Lu, Qing Cai), and (7) the Neuropathology Core (Juan Troncoso, Barbara Crain, Olga Pletnikova, Gay Rudow, Karen Fisher). NR 30 TC 8 Z9 8 U1 0 U2 4 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 2015 VL 36 IS 8 BP 2333 EP 2339 DI 10.1016/j.neurobiolaging.2015.04.001 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CJ8RL UT WOS:000355771100001 PM 26004017 ER PT J AU Nichols, N Bras, JM Hernandez, DG Jansen, IE Lesage, S Lubbe, S Singleton, AB AF Nichols, Noah Bras, Jose M. Hernandez, Dena G. Jansen, Iris E. Lesage, Suzanne Lubbe, Steven Singleton, Andrew B. CA Int Parkinsons Dis Genomics Consor TI EIF4G1 mutations do not cause Parkinson's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Parkinson's disease; EIF4G1; Genetics; Mutation ID COMMON-CAUSE AB EIF4G1 mutations were previously reported as a cause of Parkinson's disease (PD). As a result of this finding, considerable work has been performed to test this idea and to examine the functional role of eukaryotic translation initiation factor 4-gamma in the pathogenic process underlying PD. Here, we show that the originally described mutation is likely a rare benign variant. We tested this variant in a very large series of subjects and show that it is more frequent in controls than cases. We argue here that this infers that EIF4G1 mutations are not related to PD. Published by Elsevier Inc. C1 [Nichols, Noah; Hernandez, Dena G.; Singleton, Andrew B.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Bras, Jose M.; Hernandez, Dena G.] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Jansen, Iris E.] VU Univ Med Ctr VUmc, Dept Clin Genet, Amsterdam, Netherlands. [Jansen, Iris E.] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany. [Lesage, Suzanne] Univ Paris 06, Sorbonne Univ, UMR S 1127, CNRS,INSERM,U1127,UMR 7225, Paris, France. [Lesage, Suzanne] ICM, Paris, France. [Lubbe, Steven] UCL Inst Neurol, Dept Clin Neurosci, London, England. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RI Singleton, Andrew/C-3010-2009; Lubbe, Steven/L-8261-2013; OI Bras, Jose/0000-0001-8186-0333 NR 11 TC 3 Z9 3 U1 0 U2 7 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 2015 VL 36 IS 8 AR 2444.e4 DI 10.1016/j.neurobiolaging.2015.04.017 PG 4 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CJ8RL UT WOS:000355771100014 ER PT J AU Wehrspaun, CC Haerty, W Ponting, CP AF Wehrspaun, Claudia C. Haerty, Wilfried Ponting, Chris P. TI Microglia recapitulate a hematopoietic master regulator network in the aging human frontal cortex SO NEUROBIOLOGY OF AGING LA English DT Article DE Microglia; Hematopoiesis; Aging; Immune system; Transcriptional network; Master regulator ID HUMAN TRANSCRIPTION FACTORS; HUMAN BRAIN; GENE-EXPRESSION; ALTERNATIVE ACTIVATION; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; CELLS; RUNX1; PU.1; MACROPHAGES AB Microglia form the immune system of the brain. Previous studies in cell cultures and animal models suggest altered activation states and cellular senescence in the aged brain. Instead, we analyzed 3 transcriptome data sets from the postmortem frontal cortex of 381 control individuals to show that microglia gene markers assemble into a transcriptional module in a gene coexpression network. These markers predominantly represented M1 and M1/M2b activation phenotypes. Expression of genes in this module generally declines over the adult life span. This decrease was more pronounced in microglia surface receptors for microglia and/or neuron crosstalk than in markers for activation state phenotypes. In addition to these receptors for exogenous signals, microglia are controlled by brain-expressed regulatory factors. We identified a subnetwork of transcription factors, including RUNX1, IRF8, PU. 1, and TAL1, which are master regulators (MRs) for the age-dependent microglia module. The causal contributions of these MRs on the microglia module were verified using publicly available ChIP-Seq data. Interactions of these key MRs were preserved in a protein-protein interaction network. Importantly, these MRs appear to be essential for regulating microglia homeostasis in the adult human frontal cortex in addition to their crucial roles in hematopoiesis and myeloid cell-fate decisions during embryogenesis. (C) 2015 The Authors. Published by Elsevier Inc. C1 [Wehrspaun, Claudia C.; Haerty, Wilfried; Ponting, Chris P.] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. [Wehrspaun, Claudia C.] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program,IRP,NIH, Bethesda, MD 20892 USA. [Haerty, Wilfried; Ponting, Chris P.] Univ Oxford, Dept Physiol Anat & Genet, MRC Funct Genom Unit, Oxford OX1 2JD, England. RP Wehrspaun, CC (reprint author), Univ Oxford, Dept Physiol Anat & Genet, S Parks Rd, Oxford OX1 3QX, England. EM claudia.wehrspaun@dpag.ox.ac.uk OI Haerty, Wilfried/0000-0003-0111-191X; Ponting, Chris/0000-0003-0202-7816 FU Wellcome Trust; NIMH; MRC; ERC (DARCGENs) FX authors would like to thank T. Grant Belgard, Avigail Taylor, and Andreas Heger for helpful comments on analysis and contextualization of results. Claudia C. Wehrspaun was funded by the Wellcome Trust and the NIMH. Wilfried Haerty and Chris P. Ponting were funded by the MRC and ERC (DARCGENs). NR 92 TC 4 Z9 4 U1 0 U2 3 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 2015 VL 36 IS 8 AR 2443.e20 DI 10.1016/j.neurobiolaging.2015.04.008 PG 12 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CJ8RL UT WOS:000355771100012 ER PT J AU Lin, YZ Zhang, M Zhang, DB AF Lin, Yanzhu Zhang, Min Zhang, Dabao TI Generalized orthogonal components regression for high dimensional generalized linear models SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article DE Categorical data; Classification; Collinear; Dimension reduction multicollinear ID PARTIAL LEAST-SQUARES; LOGISTIC-REGRESSION; CLASSIFICATION AB The algorithm, generalized orthogonal components regression (GOCRE), is proposed to explore the relationship between a categorical outcome and a set of massive variables. A set of orthogonal components are sequentially constructed to account for the variation of the categorical outcome, and together build up a generalized linear model (GLM). This algorithm can be considered as an extension of the partial least squares (PLS) for GLMs, but overcomes several issues of existing extensions based on iteratively reweighted least squares (IRLS). First, existing extensions construct a different set of components at each iteration and thus cannot provide a convergent set of components. Second, existing extensions are computationally intensive because of repetitively constructing a full set of components. Third, although they pursue the convergence of regression coefficients, the resultant regression coefficients may still diverge especially when building logistic regression models. GOCRE instead sequentially builds up each orthogonal component upon convergent construction, and simultaneously regresses against these orthogonal components to fit the GLM. The performance of the new method is demonstrated by both simulation studies and a real data example. (C) 20,15 Elsevier B.V. All rights reserved. C1 [Lin, Yanzhu] NHLBI, Lab Syst Genet, NIH, Bethesda, MD 20892 USA. [Zhang, Min; Zhang, Dabao] Purdue Univ, Dept Stat, W Lafayette, IN 47907 USA. RP Zhang, DB (reprint author), Purdue Univ, Dept Stat, W Lafayette, IN 47907 USA. EM zhangdb@stat.purdue.edu OI Zhang, Dabao/0000-0003-0629-8672 FU NSF CAREER award [HS-0844945]; Cancer Care Engineering project at the Oncological Science Center of Purdue University FX This work was partially supported by NSF CAREER award HS-0844945 and the Cancer Care Engineering project at the Oncological Science Center of Purdue University. NR 18 TC 0 Z9 0 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 EI 1872-7352 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD AUG PY 2015 VL 88 BP 119 EP 127 DI 10.1016/j.csda.2015.02.006 PG 9 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA CH0TC UT WOS:000353734300009 ER PT J AU Redd, AD Wendel, SKJ Longosz, AF Fogel, JM Dadabhai, S Kumwenda, N Sun, J Walker, MP Bruno, D Martens, C Eshleman, SH Porcella, SF Quinn, TC Taha, TE AF Redd, Andrew D. Wendel, Sarah K. J. Longosz, Andrew F. Fogel, Jessica M. Dadabhai, Sufia Kumwenda, Newton Sun, Jin Walker, Michael P. Bruno, Daniel Martens, Craig Eshleman, Susan H. Porcella, Stephen F. Quinn, Thomas C. Taha, Taha E. TI Evaluation of postpartum HIV superinfection and mother-to-child transmission SO AIDS LA English DT Article DE breastfeeding; HIV; mother-to-child transmission; superinfection ID VIRAL LOAD; UGANDA; RAKAI; PROPHYLAXIS; INFECTION; COUPLES; MALAWI; TRIAL; VIRUS; RATES AB Objective: This study examined HIV superinfection in HIV-infected women postpartum, and its association with mother-to-child transmission (MTCT). Design: Plasma samples were obtained from HIV-infected women who transmitted HIV to their infants after 6 weeks of age (transmitters, n=91) and HIV-infected women who did not transmit HIV to their infants (nontransmitters, n=91). These women were originally enrolled in a randomized trial for prevention of MTCT of HIV in Malawi (Post-Exposure Prophylaxis of Infants trial in Malawi). Methods: Two HIV genomic regions (p24 and gp41) were analyzed by next-generation sequencing for HIV superinfection. HIV superinfection was established if the follow-up sample contained a new, phylogenetically distinct viral population. HIV superinfection and transmission risk were examined by multiple logistic regression, adjusted for Post-Exposure Prophylaxis of Infants study arm, baseline viral load, baseline CD4(+) cell count, time to resumption of sex, and breastfeeding duration. Results: Transmitters had lower baseline CD4(+) cell counts (P=0.001) and higher viral loads (P<0.0001) compared with nontransmitters. There were five cases of superinfection among transmitters (rate of superinfection=4.7/100 person-years) compared with five cases among the nontransmitters (rate of superinfection=4.4/100 person-years; P=0.78). HIV superinfection was not associated with increased risk of postnatal MTCT of HIV after controlling for maternal age, baseline viral load, and CD4(+) cell count (adjusted odds ratio=2.32, P=0.30). Longer breastfeeding duration was independently associated with a lower risk of HIV superinfection after controlling for study arm and baseline viral load (P=0.05). Conclusion: There was a significant level of HIV superinfection in women postpartum, but this was not associated with an increased risk of MTCT via breastfeeding. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved. C1 [Redd, Andrew D.; Wendel, Sarah K. J.; Longosz, Andrew F.; Quinn, Thomas C.] NIAID, Immunoregulat Lab, NIH, Baltimore, MD USA. [Redd, Andrew D.; Fogel, Jessica M.; Eshleman, Susan H.; Quinn, Thomas C.] Johns Hopkins Univ, Johns Hopkins Sch Med, Baltimore, MD USA. [Dadabhai, Sufia; Kumwenda, Newton; Sun, Jin; Taha, Taha E.] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Walker, Michael P.; Bruno, Daniel; Martens, Craig; Porcella, Stephen F.] NIAID, Genom Unit, Div Intramural Res, Res Technol Branch,Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Redd, AD (reprint author), Rangos Bldg Room 527,855 N Wolfe St, Baltimore, MD 21205 USA. EM aredd2@jhmi.edu FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Centers for Disease Control and Prevention [5-U50-PS022061-05, U50-CC0222061]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; [UM1-AI068613]; [1R01-AI087139] FX This study was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by grants UM1-AI068613 and 1R01-AI087139 (S.H.E., principal investigator). The P.E.P.I. trial was supported by a cooperative agreement (5-U50-PS022061-05; award U50-CC0222061) from the Centers for Disease Control and Prevention and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. ClinicalTrials.gov number, NCT00115648. NR 19 TC 2 Z9 2 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUL 31 PY 2015 VL 29 IS 12 BP 1567 EP 1573 DI 10.1097/QAD.0000000000000740 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA CV6RN UT WOS:000364398100001 PM 26244396 ER PT J AU Lei, LL West, J Yan, ZJ Gao, XL Fang, P Dennis, JH Gnatovskiy, L Wang, WD Kingston, RE Wang, Z AF Lei, Lenglam West, Jason Yan, Zhijiang Gao, Xiaolin Fang, Peng Dennis, Jonathan H. Gnatovskiy, Leonid Wang, Weidong Kingston, Robert E. Wang, Zhong TI BAF250a Protein Regulates Nucleosome Occupancy and Histone Modifications in Priming Embryonic Stem Cell Differentiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHROMATIN-REMODELING COMPLEX; TRANSCRIPTIONAL NETWORK; SELF-RENEWAL; PLURIPOTENCY; GENOME; ESBAF; PROMOTERS; COMPONENT; CLUSTERS; REGIONS AB The unique chromatin signature of ES cells is fundamental to the pluripotency and differentiation of ES cells. One key feature is the poised chromatin state of master developmental genes that are transcriptionally repressed in ES cells but ready to be activated in response to differentiation signals. Poised chromatin in ES cells contains both H3 Lys-4 trimethylation (H3K4me3) and H3 Lys-27 trimethylation (H3K27me3) methylation, indicating activating and repressing potential. However, the contribution of non-covalent chromatin structure to the poised state is not well understood. To address whether remodeling of nucleosomes is important to the poised state, we characterized the function of BAF250a, a key regulatory subunit of the ES cell ATP-dependent Brahma-associated factor (BAF) chromatin remodeling complex (esBAF). Acute deletion of BAF250a disrupted the differentiation potential of ES cells by altering the expression timing of key developmental genes and pluripotent genes. Our genome-wide nucleosome and histone modification analyses indicated that the disruption of gene expression timing was largely due to changes of chromatin structures at poised genes, particularly those key developmental genes mediated by BAF250a. Specifically, BAF250a deletion caused a nucleosome occupancy increase at H3K4me3- and/or H3K27me3-associated promoters. Moreover, H3K27me3 levels and the number of bivalent promoter genes were reduced in BAF250aKOES cells. We revealed that BAF250a ablation led to elevated Brg1 but reduced Suz12 recruitment at nucleosome occupancy-increased regions, indicating an unexpected and complicated role of BAF250a in regulating esBAF and Polycomb repressive complex (PRC) activities. Together, our studies identified that BAF250a mediates esBAF and PRC functions to establish the poised chromatin configuration in ES cells, which is essential for the proper differentiation of ES cells. C1 [Lei, Lenglam; Gnatovskiy, Leonid; Wang, Zhong] Univ Michigan, Dept Cardiac Surg, Cardiovasc Res Ctr, Ann Arbor, MI 48109 USA. [West, Jason; Kingston, Robert E.] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. [Gao, Xiaolin; Fang, Peng] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Yan, Zhijiang; Wang, Weidong] NIA, Genome Instabil & Chromatin Remodeling Sect, NIH, Baltimore, MD 21224 USA. Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. RP Wang, Z (reprint author), Univ Michigan, Dept Cardiac Surg, Cardiovasc Res Ctr, 2800 Plymouth Rd, Ann Arbor, MI 48109 USA. EM zhongw@med.umich.edu RI Regan, Clinton/E-6250-2012; West, Jason/I-4445-2014 OI West, Jason/0000-0002-7252-8651 FU National Institutes of Health [HL109054]; Intramural Research Program of the NIA/National Institutes of Health [AG000650-10]; Samuel and Jean Frankel Cardiovascular Center, University of Michigan (Inaugural Fund) FX This work was supported, in whole or in part, by National Institutes of Health Grant HL109054 (to W. Z.) and Intramural Research Program of the NIA/National Institutes of Health Grant AG000650-10 (to W. W.). This work was also supported by the Samuel and Jean Frankel Cardiovascular Center, University of Michigan (Inaugural Fund) (to W. Z.). The authors declare that they have no conflicts of interest with the contents of this article. NR 35 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 31 PY 2015 VL 290 IS 31 BP 19343 EP 19352 DI 10.1074/jbc.M115.637389 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CN9PK UT WOS:000358781100045 ER PT J AU McFarland, HI Berkson, JD Lee, JP Elkahloun, AG Mason, KP Rosenberg, AS AF McFarland, Hugh I. Berkson, Julia D. Lee, Jay P. Elkahloun, Abdel G. Mason, Karen P. Rosenberg, Amy S. TI Rescue of CD8+T cell vaccine memory following sublethal gamma irradiation SO VACCINE LA English DT Article ID IONIZING-RADIATION; LISTERIA-MONOCYTOGENES; T-CELLS; LYMPHOCYTES; INDUCTION; RESPONSES; EXPOSURE; RADIOSENSITIVITY; TRANSPLANTATION; EXPRESSION AB Sublethal gamma irradiation eliminates CD8+ T cell mediated memory responses. In this work, we explored how these memory responses could be rescued in the aftermath of such exposure. We utilized two models of CD8+ T cell mediated immunity: a mouse model of Listeria monocytogenes (LM) infection in which CD8+ T cells specific for LM expressed antigens (Listeriolysin 0, LLO) can be tracked, and a murine skin graft model in which CD8+ T cells mediate rejection across a MHC class I (D-d) disparity. In the LM immunized mice, LLO specific CD8+ T memory cells were lost on irradiation, preserved with rapid revaccination with an attenuated strain 1-3 days post-irradiation (PI), and these mice survived a subsequent wild type LM challenge. A genetic "signature of rescue" identified a group of immune-associated mRNA maintained or upregulated following irradiation and rescue. A number of these factors, including IL-36 gamma, dectin-2 (Clec4n), and mir101c are upregulated rapidly after exposure of mice to sublethal gamma radiation alone and are sustained by early, but not later rescue. Such factors will be evaluated as potential therapeutics to replace individual vaccines for global rescue of CD8+ T memory cell responses following sublethal gamma irradiation. The skin allograft model mirrored that of the LM model in that the accelerated D-d skin allograft rejection response was lost in mice exposed to sublethal gamma radiation, but infusion of allogeneic D-d expressing bone marrow cells 1-4 days PI preserved the CD8+ T memory mediated accelerated rejection response, further suggesting that innate immune responses may not always be essential to rescue of CD8+ memory T cells following gamma irradiation. Published by Elsevier Ltd. C1 [McFarland, Hugh I.; Berkson, Julia D.; Lee, Jay P.; Mason, Karen P.; Rosenberg, Amy S.] US FDA, Div Res & Review 3, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Elkahloun, Abdel G.] NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. [Lee, Jay P.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20037 USA. [Mason, Karen P.] NIAID, Intramural Adm Branch, NIH, Bethesda, MD 20892 USA. RP McFarland, HI (reprint author), US FDA, Div Res & Review 3, Off Biotechnol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM hugh.mcfarland@fda.hhs.gov; julia.berkson@fda.hhs.gov; jlee17@gwmail.gwu.edu; abdel@nhgri.nih.gov; karen.mason2@nih.gov; amy.rosenberg@fda.hhs.gov RI McFarland, Hugh/K-1503-2016 OI McFarland, Hugh/0000-0002-3322-038X FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; U.S. Food and Drug Administration Medical Countermeasures Initiative FX We wish to thank Dr. Sing Sing Way and Dr. Karen Elkins for kindly providing the Listeria monocytogenes strains, Weiwei Wu for microarray technical assistance, and Drs. Michael Norcross and Daniela Verthelyi for advice and careful reading of the manuscript. This research was supported [in part] by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, and the U.S. Food and Drug Administration Medical Countermeasures Initiative. NR 26 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUL 31 PY 2015 VL 33 IS 32 BP 3865 EP 3872 DI 10.1016/j.vaccine.2015.06.070 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CN5HN UT WOS:000358460500013 PM 26122582 ER PT J AU Burgess, TH Murray, CK Bavaro, MF Landrum, ML O'Bryan, TA Rosas, JG Cammarata, SM Martin, NJ Ewing, D Raviprakash, K Mor, D Zell, ER Wilkins, KJ Millar, EV AF Burgess, Timothy H. Murray, Clinton K. Bavaro, Mary F. Landrum, Michael L. O'Bryan, Thomas A. Rosas, Jessica G. Cammarata, Stephanie M. Martin, Nicholas J. Ewing, Daniel Raviprakash, Kanakatte Mor, Deepika Zell, Elizabeth R. Wilkins, Kenneth J. Millar, Eugene V. TI Self-administration of intranasal influenza vaccine: Immunogenicity and volunteer acceptance SO VACCINE LA English DT Article DE Influenza; Vaccine; Self-administration; Military ID MILITARY SERVICE MEMBERS; US MILITARY; REPORTED INCIDENCE; LIVE; IMMUNIZATION; ILLNESS; SAFETY AB Background: In outbreak settings, mass vaccination strategies could maximize health protection of military personnel. Self-administration of live attenuated influenza vaccine (LAIV) may be a means to vaccinate large numbers of people and achieve deployment readiness while sparing the use of human resources. Methods: A phase IV, open-label, randomized controlled trial evaluating the immunogenicity and acceptance of self-administered (SA) LAIV was conducted from 2012 to 2014. SA subjects were randomized to either individual self-administration or self-administration in a group setting. Control randomized subjects received healthcare worker-administered (HCWA) LAIV. Anti-hemagglutinin (HAI) antibody concentrations were measured pre- and post-vaccination. The primary endpoint was immunogenicity non-inferiority between SA and HCWA groups. Subjects were surveyed on preferred administration method. Results: A total of 1077 subjects consented and were randomized (529 SA, 548 HCWA). Subject characteristics were very similar between groups, though SA subjects were younger, more likely to be white and on active duty. The per-protocol analysis included 1024 subjects (501 SA, 523 HCWA). Post-vaccination geometric mean titers by vaccine strain and by study group (HCWA vs. SA) were: A/H1N1 (45.8 vs. 48.7, respectively; p = 0.43), A/H3N2 (45.5 vs. 46.4; p=0.80), B/Yamagata (17.2 vs. 17.8; p=0.55). Seroresponses to A components were high (similar to 67%), while seroresponses to B components were lower (similar to 25%). Seroresponse did not differ by administration method. Baseline preference for administration method was similar between groups, with the majority in each group expressing no preference. At follow-up, the majority (64%) of SA subjects preferred SA vaccine. Conclusions: LAIV immunogenicity was similar for HCWA and SA vaccines. SA was well-tolerated and preferred to HCWA among those who performed SA. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Burgess, Timothy H.] Walter Reed Natl Mil Med Ctr, Bethesda, MD 20889 USA. [Murray, Clinton K.; Landrum, Michael L.; O'Bryan, Thomas A.; Rosas, Jessica G.] San Antonio Mil Med Ctr, San Antonio, TX 78234 USA. [Bavaro, Mary F.; Cammarata, Stephanie M.] Naval Med Ctr, San Diego, CA 92134 USA. [Landrum, Michael L.; O'Bryan, Thomas A.; Rosas, Jessica G.; Cammarata, Stephanie M.; Mor, Deepika] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Dept Prevent Med & Biostat, Rockville, MD 20852 USA. [Martin, Nicholas J.; Ewing, Daniel; Raviprakash, Kanakatte] Naval Med Res Ctr, Silver Spring, MD 20910 USA. [Zell, Elizabeth R.] Stat Epi Associates Inc, Ponte Vedra Beach, FL 32082 USA. [Wilkins, Kenneth J.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. RP Millar, EV (reprint author), Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Dept Prevent Med & Biometr, 11300 Rockville Pike,Suite 1211, Rockville, MD 20852 USA. EM timothy.h.burgess.mil@mail.mil; clinton.k.murray.mil@mail.mil; mary.bavaro@med.navy.mil; michael.l.landrum@att.net; thomas.a.obryan2.ctr@mail.mil; jessica.geistman@gmail.com; stephanie.cammarata.ctr@med.navy.mil; nicholas.martin@fe.navy.mil; daniel.ewing@med.navy.mil; kanakatte.raviprakash@med.navy.mil; dmor@idcrp.org; erzell@stat-epi.com; kenneth.wilkins@nih.gov; emillar@idcrp.org FU Military Vaccine Agency (MIL-VAX) [HU0001-11-1-0020]; Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program through the Uniformed Services University of the Health Sciences; National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) [Y1-AI-5072] FX The work was supported by the Military Vaccine Agency (MIL-VAX), under the award HU0001-11-1-0020. Additional funding was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences, supported with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), under Inter-Agency Agreement Y1-AI-5072. NR 10 TC 1 Z9 1 U1 1 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 31 PY 2015 VL 33 IS 32 BP 3894 EP 3899 DI 10.1016/j.vaccine.2015.06.061 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CN5HN UT WOS:000358460500017 PM 26117150 ER PT J AU Ma, XF Ito, Y AF Ma, Xiaofeng Ito, Yoichiro TI New analytical spiral tube assembly for separation of proteins by counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Counter-current chromatography; Spiral tube; Polymer phase system; Proteins ID STATIONARY-PHASE RETENTION; COIL PLANET CENTRIFUGE; PARTITION CHROMATOGRAPHY; DESIGN; COLUMN AB A new spiral column assembly for analytical separation by counter-current chromatography is described. The column is made from a plastic spiral tube support which has 12 interwoven spiral grooves. The PTFE tubing of 1.6 mm ID was first flattened by extruding through a narrow slit and inserted into the grooves to make 5 spiral layers with about 60 ml capacity. The performance of the spiral column assembly was tested with separation of three stable protein samples including cytochrome C, myoglobin and lysozyme in a polymer phase system composed of polyethylene glycol 1000 and dibasic potassium phosphate each at 12.5% (w/w) in water. At 2 ml/min, three protein samples were well resolved in 1 h. The separation time may be further shortened by application of higher revolution speed and flow rate by improving the strength of the spiral tube support in the future. Published by Elsevier B.V. C1 [Ma, Xiaofeng; Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Ma, Xiaofeng] Univ Chinese Acad Sci, Coll Life Sci, Beijing 100049, Peoples R China. RP Ito, Y (reprint author), NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, 10 Ctr Dr,Bldg 10,Rm 8N230, Bethesda, MD 20892 USA. EM itoy@nhlbi.nih.gov FU Special Science and Technology Projects for Outstanding Young in Life Sciences, Youth Innovation Promotion Association, CAS [KSCX2-EW-Q-19] FX This work was partially supported by the Special Science and Technology Projects for Outstanding Young in Life Sciences (KSCX2-EW-Q-19), Youth Innovation Promotion Association, CAS. NR 20 TC 4 Z9 4 U1 3 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUL 31 PY 2015 VL 1405 BP 193 EP 196 DI 10.1016/j.chroma.2015.05.051 PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CM5UD UT WOS:000357753500020 PM 26074099 ER PT J AU Butali, A Mossey, P Tiffin, N Adeyemo, W Eshete, M Mumena, C Audu, R Onwuamah, C Agbenorku, P Ogunlewe, M Adebola, A Olasoji, H Aregbesola, B Braimah, R Oladugba, A Onah, I Adebiyi, E Olaitan, P Abdur-Rahman, L Adeyemo, A AF Butali, Azeez Mossey, Peter Tiffin, Nikki Adeyemo, Wasiu Eshete, Mekonen Mumena, Chrispinanus Audu, Rosemary Onwuamah, Chika Agbenorku, Pius Ogunlewe, Mobolanle Adebola, Adetokunbo Olasoji, Hecto Aregbesola, Babatunde Braimah, Ramat Oladugba, Abimibola Onah, Ifeanyichukwu Adebiyi, Ezekiel Olaitan, Peter Abdur-Rahman, Lukman Adeyemo, Adebowale TI Multidisciplinary approach to genomics research in Africa: the AfriCRAN model SO PAN AFRICAN MEDICAL JOURNAL LA English DT Article DE Genomics; Africa; Multidisciplinary team ID NONSYNDROMIC CLEFT-LIP; OROFACIAL CLEFTS; WIDE ASSOCIATION; ETHICAL-ISSUES; PALATE; MUTATIONS; EVOLUTION; VARIANTS; DISEASE; CONSENT AB This article is an outcome of the African Craniofacial Anomalies Research Network (AfriCRAN) Human Hereditary and Health (H3A) grant planning meeting in 2012 in Lagos, Nigeria. It describes the strengths of a multidisciplinary team approach to solving complex genetic traits in the craniofacial region. It also highlights the different components and argues for the composition of similar teams to fast track the discovery of disease genes, diagnostic tools, improved clinical treatment and ultimately prevention of diseases. C1 [Butali, Azeez] Univ Iowa, Coll Dent, Dept Oral Pathol Radiol & Med, Iowa City, IA 52242 USA. [Mossey, Peter] Univ Dundee, Dept Orthodont, Dundee DD1 4HN, Scotland. [Tiffin, Nikki] Univ Western Cape, South African Natl Bioinformat Inst, ZA-7535 Bellville, South Africa. [Adeyemo, Wasiu; Ogunlewe, Mobolanle] Univ Lagos, Coll Med, Dept Oral & Maxillofacial Surg, Lagos, Nigeria. [Eshete, Mekonen] Univ Addis Ababa, Fac Hlth Sci, Sch Med, Dept Surg, Addis Ababa, Ethiopia. [Mumena, Chrispinanus] Kigali Hlth Inst, Dept Oral & Maxillofacial Surg, Kigali, Rwanda. [Audu, Rosemary; Onwuamah, Chika] Nigerian Inst Med Res, Human Virol Lab, Lagos, Nigeria. [Agbenorku, Pius] Kwame Nkrumah Univ Sci & Technol, Dept Plast Surg, Kumasi, Ghana. [Adebola, Adetokunbo] Aminu Kano Univ, Dept Oral & Maxillofacial Surg, Teaching Hosp, Kano, Nigeria. [Olasoji, Hecto] Univ Maiduguri, Dept Oral & Maxillofacial Surg, Teaching Hosp, Maiduguri, Nigeria. [Aregbesola, Babatunde; Braimah, Ramat] Obafemi Awolowo Univ, Dept Oral & Maxillofacial Surg, Ife, Nigeria. [Oladugba, Abimibola] Univ Nigeria, Dept Biostat, Nssukka, Nigeria. [Onah, Ifeanyichukwu] Natl Orthoped Hosp, Dept Plast Surg, Enugu, Nigeria. [Adebiyi, Ezekiel] Covenant Univ, Dept Comp & Informat Sci, Ota, Nigeria. [Adebiyi, Ezekiel] Covenant Univ, Covenant Univ Bioinformat Res CUBRe, Ota, Nigeria. [Olaitan, Peter] Ladoke Akintola Univ Ogbomosho, Dept Plast & Reconstruct Surg, Ogbomosho, Nigeria. [Abdur-Rahman, Lukman] Univ Ilorin, Dept Pediat, Ilorin, Nigeria. [Adeyemo, Adebowale] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Butali, A (reprint author), Univ Iowa, Coll Dent, Dept Oral Pathol Radiol & Med, Iowa City, IA 52242 USA. OI Adeyemo, Adebowale/0000-0002-3105-3231 FU NIDCR NIH HHS [K99 DE022378, K99/R00 DE022378, R00 DE022378]; Wellcome Trust NR 32 TC 0 Z9 0 U1 0 U2 1 PU AFRICAN FIELD EPIDEMIOLOGY NETWORK-AFENET PI KAMPALA PA PO BOX 12874, KAMPALA, 00000, UGANDA SN 1937-8688 J9 PAN AFR MED J JI Pan Afr. Med. J. PD JUL 30 PY 2015 VL 21 AR 229 DI 10.11604/pamj.2015.21.229.7380 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DN0GB UT WOS:000376741300009 PM 26523171 ER EF