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 t